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Physiology DKA NOTES
Physiology DKA NOTES
PHYSIOLOGY
PHYSIOLOGY)[DKA)(201632017)]) 1)
)
DISCLAIMER
This reviewer, including examples or pictures, aims to provide general
information and guidance towards the subject matter and should not be
relied upon technical answers. The author claims no warranties (expressed
or implied) with respect to the accuracy and completeness of the contents of
this reviewer.
All information in this reviewer were gathered from the summary of the
First-Year Physiology handouts given by the University of Santo Tomas
Faculty of Medicine and Surgery Department of Physiology, PowerPoint
presentation of the lecturers, and some side notes. Pictures were taken
from the reference book/internet.
For your better understanding, the author suggests that you read the
reference book or handouts given by the department. This reviewer only serves as a guide for better
comparison of must-know concepts, which are in BOLD or Italicized. Any human, typographical, and/or
grammatical errors might also be expected.
In line with this, the author would like to request for your understanding to respect the integrity of this
reviewer and to not photocopy or reproduce in any form the contents of this reviewer.
PHYSIOLOGY)[DKA)(201632017)]) 2)
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TABLE OF CONTENTS
1.! Cell Generalities 16.! Renal 1,2
15.! GI 1,2,3
PHYSIOLOGY)[DKA)(201632017)]) 3)
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GENERALITIES IN PHYSIOLOGY
Process Related to Homeostasis
Adaptation Inherited Evolved to favor survival
Acclimatization Enhancement Due to prolonged exposure
to stress
Biological Rhythmic Adds anticipatory
Rhythms pattern component
Levels of Involvement
Control System Chemical Messenger
Organization of Human Body: Local Occurs only in Paracrine Cell to nearby cells
the area of Autocrine Cell to own
Membrane Junctions stimulus plasmalemma
1.! Desmosomes Adjacent cells firmly together (stretching)
Systemic Involves regions Hormone Cells to cell using
2.! Tight Adjacent plasma membrane joins together distant from the bloodstream
Junction (NO extracellular space) area of Neuro- Nerve to nerve or
3.! Gap Junction Links cytosol to adjacent cell stimulus transmitter Muscle
)
port/Antiport gradient Primary Ion
)
)
PHYSIOLOGY)[DKA)(201632017)]) 5)
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MEMBRANE EXCITABILITY AND SYNAPSE)
Nernst Potential = Potential WITHIN the cell Channel Feedback Loop )
Gibbs Donnan Equilibrium = steady state properties of Na Positive Depolarization )
mixture of permeant and impermeant ions K Negative Repolarization )
K+ = most permeable ion
)
Goldman Equation = Vm Membrane potential
ALL OR NONE RELATIONSHIP for AP
Factors affecting ion movements Stimulus Intensity Note
Con’c Gradient Greater to lesser con’c Threshold Lowest to trigger 15mV less – than
RMP (-55mV)
Electrical Gradient Towards opposite its charge Subthreshold Will not trigger
)
>Concentration Gradient = >Equilibrium Potential )
Electrically negativity
Cytoplasm Extracellular fluid
>
Concentration Gradient: K > Cl > Na
Resting Membrane Potential (neurons): -70mV
RMP in other cells: -90mV (-86mV)
Na-K ATPase Pump: -4mV
)
PHYSIOLOGY)[DKA)(201632017)]) 6)
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Changes: Na Na K K MP Period Action Potential Response to
Channels Flow Channels Flow Stimulus
RMP Close / Close / / Non- RMP till Threshold
Depolarization Open Influx Close / - to + Refractory depolarization below Stimulus
Repolarization Close / Open Efflux Less + more threshold
- Absolute Depolarization & None
Hyperpolarization Close / Open Efflux More – than Refractory Repolarization above
RMP threshold
Relative Repolarization below Above
)
Refractory threshold & Threshold
Na channels Activation Inactivation AP Excitability Hyperpolarization Stimulus
states Gate (M) Gate (H) Threshold
Resting Close Open potential
Activated Open Open Resting
Inactivated Open Close Membrane
Potential
)
Refractory periods = respond to stimulus depending on AP
Absolute = unable to fire a 2nd AP no matter how strong
Relative = able to fire a 2nd AP but a stronger is required
= Unidirectional conduction of AP)
Differences Graded Potential Action Potential
Amplitude Varies Independent
Summed Can Cannot
Threshold None Has
Refractory None Has
Conduction Decremental Non-decremental
)
Duration Varies Constant
FACTORS AFFECTING AP PROPAGATION
Depolarization Can Can Time Constant Time response
Hyperpolarize Can Cannot
Initiation Stimulus Graded Potential Space (Length) Length Propagation
Mechanism Ligand-gated Voltage-gated
) Diameter Fiber Velocity
Presence of Myelination Conduction
Myelin Sheath Resistance
Graded Potential Intensity Change in MP )
PHYSIOLOGY)[DKA)(201632017)]) 7)
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Types of Synaptic Connections ) Pathways of Synaptic Vesicles:
Synapse Pre-synaptic Post-synaptic a.! Endocytic – coated pits in plasma membrane
Convergence 2 or more Single b.! Kiss and Run – transient fusion of vesicle
Divergence Single 2 or more
Types of Ligand-gated receptor that NT binds
Types of Synapse
a.! Ionotropic – ion channel itself
Synapse Pre and Post Communication
b.! Metabotropic – generation of second messenger
Electrical Joined by Gap Junction Rapid
Chemical Separated by Synaptic Cleft Slow
Synaptic Integration
Summation Presynaptic cell Interval
Type of Chemical Synapse Temporal Same Short
Excitatory Inhibitory Spatial Different Simultaneous
NT-receptors Na influx Cl influx
K efflux Modulation of Synaptic Activity
MP Depolarizing Hyperpolarizing Repeated Time before
(less -) (more +) stimulation Cessation
Synaptic Potential EPSP IPSP Facilitation Shorter
Distance to Threshold Closer Farther
Potential Posttetanic potentiation Longer
Probability of Firing AP Increase Decrease
Example Glutamate GABA/ Glycine
SIGNAL TRANSDUCTION
Modes of intracellular communication: Classification of Receptors
1.! Autocrine – one cell to same cell Receptors Intracellular Extracellular
2.! Paracrine – one cell to another nearby cell Messengers Lipid-soluble Water-soluble
3.! Endocrine – release of hormone to act Solubility
upon another cell type Function Nucleus Ligand-gated; Enzymes
4.! Synaptic – neurotransmitter at a synapse Transcription factors G-coupled protein
5.! Cell to cell – gap junction or chemical JAK Kinase
messengers
PHYSIOLOGY)[DKA)(201632017)]) 8)
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Signal Transduction by Intracellular pathway Signal Transduction by Enzymes
a.! Ligand binds to receptor Receptor Tyrosine Receptor Guanylyl
(Cytoplasm/Nucleus) Kinase Cyclase
b.! Activates Receptor Ligand-binding Activation Activation
c.! Binds specific sequence near gene DNA Receptor Phosphorylates protein Dephosphorylates
d.! Transcription factor containing Tyrosine GTP
e.! mRNA moves out the nucleus into Second Phosphotyrosine (docking cGMP
ribosome Messenger site)
f.! Synthesis of protein Protein Kinase Tyrosine Kinase PKG
g.! Increase cellular con’c Downstream Cascade of protein Cellular response
h.! Increase cellular response effector Protein activation -> cellular
response
Signal Transduction by cytoplasmic JAK Kinase Signal Transduction by G-protein coupled receptor
Receptor JAK Kinase G-protein attached to receptor
Ligand-binding Conformational change ! = binds and hydrolyzes GTP
Receptor Activates JAK kinase "-# = forms stable, tight, non-covalent bond
Protein Kinase JAK (Just Another Kinase) phosphorylate Steps:
Downstream Cascade of protein activation -> cellular 1.! Ligand-binding receptor activation
effector Protein response 2.! G-protein detaches receptor
Signal Transduction by Plasma membrane 3.! GDP-GTP to receptors
a.! Ligand-gated channel 4.! G-protein subunit dissociates (! from "-#)
b.! Binds to channel receptor 5.! Attachment to effector protein
c.! Pore of channel receptors opens 6.! GTP is hydrolyzed and replaced by GDP
d.! Ions go through 7.! Subunits are reassembled
e.! Ligand dissociates Ca as Second Messenger
f.! Pore closes ECF Ca entry Endoplasmic Ca release
ACH receptor Ligand-gated Ca channels Voltage-gated IP3
Ligand ACH Opening of Ca channels Ligand-gated Ca induced
Entry of Na Entry of Ca Second Messenger
Change in MP Binds to Calmodulin; Cellular response >Input Ca
>Output Ca
PHYSIOLOGY)[DKA)(201632017)]) 9)
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Components cAMP cGMP IP3 & DAG Arachidonic Acid
Ligand Ligand-binding
Receptor Receptor Activation
G protein Gs/Gi GT GQ G protein
Effector Adenylyl Phosphodiesterase Phospoholipase C Phospholipase A2
Protein Cyclase
Second cAMP cGMP IP3 (stimulates Ca then Arachidonic Acid (eicosanoids)
Messenger Calmodulin)
& DAG (stimulates PKC)
Protein PKA PKG Ca-Calmodulin Cyclooxygenase = thromboxane;
Kinase PKC prostacyclin; prostaglandins
Lipooxygenase = 5HETE & leukotrienes
Epoxygenase = HETEs & EETS
Downstream Cascade of Proteins ! Cellular Response
Acetylcholine Receptor Adrenergic Receptor (Epinephrine and Norepinephrine)
Receptor Location Post-receptor Linked G-protein
Muscarinic Location Postreceptor
!1 Vessels; IP3 DAG GQ
M1 Nerves IP3 DAG Formation Dome-shaped Formation
M2 Heart cAMP Inhibition !2 Smooth cAMP Gi
Activation of K muscle Inhibition
M3 Glands and IP3 DAG Formation "1 Heart cAMP
Smooth Muscles "2 Lungs Formation Gs
M4 CNS cAMP Inhibition Adipose
"3
M5 IP3 DAG Formation
Nicotinic Location Postreceptor Receptor Saturation
NM Skeletal Muscle Activation of K/Na Con’c of Ligand Saturation
NN Postganglionic Activation of K/Na
Adaptation of Cell Affinity to Bind in Receptor
Downregulation # of Ligand Epinephrine Norepinephrine
receptors
>
Upregulation # of receptors Ligand
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SKELETAL MUSCLE
Characteristic of Muscles
Type Skeletal Cardiac Smooth
Location Skeleton Heart Visceral Organs
Striation Striated Striated Non-striated
Output High High Low
Neural control Voluntary Involuntary Involuntary
Typical Activity Relaxed Pump Contracting
Structural Organization
Layer Encases Components
Endomysium Muscle Fibers Muscle Cells
Perimysium Muscle Fascicles Muscle Fibers
Epimysium Muscle Organ Muscle Fascicles
PHYSIOLOGY)[DKA)(201632017)]) 11)
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Actin (A)
-! Globular actin/ G-actin Myosin (M)
-! Filamentous actin (twisted double helical structure) -! 6 different polypeptides
-! Active Site •! 2 pairs of light chain
#!Essential - critical for ATPase activity
Tropomyosin – 2 helical polypeptides; covers myosin binding #!Regulatory – kinetics of actin and myosin
site binding
•! 1 pair Heavy chain
Troponin complex – only seen in striated muscles #!1 tail
$! Trop T – troponin attached to tropomyosin #!2 arms
$! Trop C – binds w/ calcium #!2 heads
$! Trop I – facilitates inhibition of myosin binding to actin •! Myosin Head
by Tropomyosin
Titin – organization and alignment of thick filament in
Nebulin – elongated cytoskeletal protein extending along the sarcomere
actin filament and helps regulate length of thin filament
During Contraction
H band narrows
A band constant
I band narrows
Sarcomere narrows
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Steps involved in neuromuscular transmission: (AIR-NID-DRoC) Critical Level Myoplasmic Calcium Con’c =
A.! Signal sent to Anterior Horn Cell via Corticospinal tract Cross bridge cycling stops
B.! Anterior Horn Cell depolarizes and AP is transmitted Calcium Path Stimulation
C.! Voltage Gated Calcium Channel open up and allow Ca
influx
Efflux SR to cytoplasm AP
D.! Rise of intra Ca triggering Ach Exocytosis containing Influx Cytoplasm to Ca-Mg
vesicles SR ATPase/
E.! ACh traverses synaptic cleft and stimulate nicotinic SERCA
receptors
F.! Influx of Sodium Decrease Myoneural Junction = Generation of AP
G.! Depolarization of Membrane potential stops = Stimulation of Nm receptor stops
1.! Excitatory Post Synaptic Potential (EPSP) – does not -! Pumping back of Ach into axon
reach threshold potential -! Diffusion of Ach out of MNJ
2.! Action Potential (AP) – reaches threshold potential -! Degradation of Ach via AChE
H.! Dihydropyridine Voltage stimulation and conformational
change SERCA – sarcoplasmic endoplasmic reticulum
I.! Ryanodine Receptors Open calcium ATPase; stimulated by increase in
J.! Calcium release of the Sarcoplasmic Reticulum myoplasmic Calcium
K.! Calcium binds with Troponin C
L.! Uncovering of Actin Active Site
M.!Triggering of Cross bridge cycling
Energetics
1.! ATP usage Energy Source = ATP major source
a.! Maintenance of RMP
b.! Cross Bridge Cycling (Power Stroke) Type Direct Glycolysis Oxidative
Phosphorylation Phosphorylation
c.! Pumping Ca back into the SR
2.! Efficiency – quotient of mechanical work ATP Rapid Rapid Slow
over ATP consumed generation
Skeletal Muscle (40-45% Efficiency) Oxygen No No Yes
Cycling Rate dependent on Myosin Isoform Time Few Seconds Minutes Indefinitely
and Load on Muscle Efficiency Low Low High
Cycling ATP Load
Rate consumption
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Obliqueness Force # of Shortening Contraction Sarcomere # Muscle Relationship
parallel Velocity Velocity of series length according to
Orientation
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Cross Bridge Cycling
A-M Actin-Myosin attached to each other State M-ATP M-ADP-Pi
A+M Actin-Myosin detached to each other Energy/Affinity
Orientation 45 degrees 90 degrees
Myosin head –
Steps Description
intrinsic ATPase
Attachment of M-ADP-Pi binds to actin
activity; cleaves
head to active
ATP
site
Power stroke – Powerstroke ADP-Pi released producing
orientation of (90 to 45) A-M; 90 to 45 degrees; A-M
cycle changed bind with ATP
from 90 to 45 Release of A release (A+M-ATP)
degrees binding of forming M-ATP
Cocked - head to active
orientation of site
cycle changed Return of head M cleaves ATP from M-ADP-
from 45 to 90 (45 to 90) Pi; Free cross bridging goes
degrees back from 45 to 90
Types of Muscle Contraction Intensity Response
Subthreshold Not visible Resting Length (Lo) = length
Type Isotonic Isometric Threshold Visible of muscle generating max
Constant Force Length force or stress
Submaximal Bet. threshold
Variable Length Force & maximal Equilibrium Length (Le) =
Work Done Done Not done Maximal Highest visible length of muscle unattached
Power and Measured Not Supramaximal Above maximal
Velocity measured Intensity of stimulus Number of motor unit Stress Muscle
Frequency Summation Passive Not stimulated
Frequency Response Active During
Low Small unit contraction
Subtetanizing Single twitch High Large unit Total Sum of both
Incomplete Relaxed Incompletely Maximal No change
Complete Contracted
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AUTONOMIC NERVOUS SYSTEM
Autonomic Nervous System – portion that controls Preganglionic neurons
visceral function •! B fiber – myelinated nerve
•! Sympathetic nervous system •! C fiber – unmyelinated nerve
•! Parasympathetic nervous system
•! Enteric nervous system Splanchnic nerve – innervates the viscera; contains both
Role of ANS: visceral afferents and autonomic fibers
$! Maintain homeostasis
$! Commands that lead to compensatory actions Sympathetic Preganglionic neurons = ipsilateral
$! Rapidity and intensity that changes visceral Exception:
function Intestine and pelvic viscera = bilateral
$! Purely motor, accompanied by visceral afferent
fibers originating from sensory receptors 75% parasympathetic nerve = Vagus nerve
PHYSIOLOGY)[DKA)(201632017)]) 16)
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Autonomic receptors
Type Sympathetic Parasympathetic Metabolic Effect
Receptor Alpha (1,2) and Muscarinic (M1-M5) and Epinephrine > Norepinephrine
Beta (1,2,3) Nicotinic (Nm,Nn)
Special Can be both Muscarinic – on all Enteric Nervous Location Function
characteristics excitatory and effector cells System
inhibitory; Nicotinic – Autonomic Myenteric Bet. Control GI
affinity of ganglia and skeletal Plexus Longitudinal & motility
hormones for the Fast EPSP – activation of circular muscle
receptors Nicotinic layers of the gut
Slow EPSP – mediated by Submucosal Submucosa of Regulate
Muscarinic Plexus the gut body fluid
Pathways IP3-DAG IP3-DAG homeostasis
involved cAMP cAMP
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CARDIAC MUSCLE
Cardiac Muscle Types of Cardiac Cells and AP
Myocardial Cells – tightly bound layers and encircle the Cells AP
blood-filled chambers; striated Pacemaker Slow
Oxidative Capacity Conducting Fast
Cardiac > Skeletal Contractile/Working Fast
Connective Tissue Content
Cardiac Skeletal Syncytium – functioning of heart as a unit
> Intercalated disk – combination of mechanical junctions
Extracellular Ca requiring and electrical connections
Cardiac > Skeletal Desmosomes and Fascia adherens – keep the cell from
Conducting System – in contact with cardiac cells via gap being pulled apart
junctions Gap junctions – electrical connections of AP from cell to
Atrial Natriuretic Peptide (ANP) – hormone secrete by atria cell
Electrochemical coupling
•! Ca-induced release of Ca
•! Coupling between skeletal muscle between dihydropyridine
receptor (DHPR) in T tubule & ryanodine receptor (RYR) in
SR
•! Heart requires Cardiac Cycle
extracellular Ca Systole Diastole
Ventricular Ventricular
Contraction Filling
Atrial Filling Atrial Contraction
muscle muscle
length length
ventricular ventricular
blood volume blood volume
tension tension
Biphasic Direct
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Overview of Heart Contraction: Difference between Skeletal and Cardiac
a.! Sinoatrial Node (SA) generates spontaneous AP Skeletal Cardiac
b.! Undergo spontaneous depolarization and generate Dihydropyridine receptor Closed Opens
AP ECF Ca++ No role Triggered
c.! AP between atrial cells via gap junctions SR Ca++ release Constant Variable
d.! AP pass thru atrioventricular node
e.! AP pass throughout ventricle via specialized Factors Increasing Cardiac Contractility
conduction pathway and gap junctions %! Higher ECF Calcium
f.! AP reaches working cells %! Stimulation of DHP and RYR Receptors
g.! Contraction triggered %! Inhibition of Active Ca pump, Na-Ca and Na-K Pump
No. of Active %! Stretch of heart Action Potential
Cross bridges ! Presence of Fast-Na Channel Cardiac
Strength of ! Presence of Slow-Ca Channel > Skeletal
cardiac ! 5x decrease in K permeability
Ca release Relationship:
1.! Excitability State
Contraction Coupling Period Stimulation Stimulus
Skeletal Cardiac Resting Membrane Can Threshold
2 High affinity Single Low affinity Absolute Refractory Cannot None
2 Low affinity Relative Refractory Can Suprathreshold
Steps in excitation contraction coupling: 2.! Tetanization
-! DHPR opens up response to AP Tetanization Phase Re-stimulation
-! Influx of Ca to ECF Incomplete Relaxation To contract
-! SR Ca binds to Trop I (requiring movement of Complete Contraction To contract further
Trop-Tropomyosin complex on actin before 3.! Temporal Summation
myosin binds) Muscle ARP End phase Generation phase
-! High Ca triggers cross bridge cycling Skeletal Shorter Contraction Contraction
-! Relaxation intracytoplasmic Ca Cardiac Longer Relaxation Relaxation
a.! Primary Active Ca – responsible for 70% Ca Cardiac Cycle
removal; inhibited by phospholamban Systole Diastole
b.! Plasma membrane: Ca-ATPase pump and 3Na-1Ca Ventricular Filling Ventricular Contraction
antiporter Amount of Blood Flow Pressure as Surrogate Marker
PHYSIOLOGY)[DKA)(201632017)]) 19)
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SMOOTH MUSCLE
Smooth Muscle Types
Gap Junction – facilitate cellular Based on Duration of Contraction
communication Contracts Response to
Caveolae – invagination of sarcolemma Phasic Intermittently/rhythmically AP
analogous to T tubules Tonic Continuously Membrane Potential
Extracellular Ca – pivotal role in Based on Coordination of Contraction
regulation of contraction Unit Contraction Electrically Control
Sarcoplasmic Reticulum Single Coordinated Yes Intrinsic/Pacemaker/Phasic
Myofilaments – not striated Multi Independently No Extrinsic/Hormonal/Tonic
More Actin Less Myosin
No Troponin; Addt’l protein like cAMP Ca2+
Caldesmon & Calponin cGMP Ca2+
PHYSIOLOGY)[DKA)(201632017)]) 20)
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Relaxation Relationship between Membrane Potential and Force
$! Dephosphorylation of Myosin Light Chain Generation
$! Activation of Myosin Phosphatase Type Potential Force Generation
$! Inactivation of MLCK due to low myoplasmic Ca A Twitch Frequency Summation
B Fluctuates Rhythmic Contraction
Regulation of Myoplasmic Calcium: C Fluctuates Rhythmic Contraction
Effluxers Influxers Indirectly D No change None
activated
Na-Ca Exchange Ca channels: Na-K ATPase Relationship
Pump (3Na-1Ca Ligand-gated Pump Linear relationship Cross bridges & contraction velocity
antiporter) Voltage-gated K+ Conduction Sigmoidal relationship Cross bridges & force generated
Active Ca Pump Leak
Hyperbolic rel. Stress-velocity (Opt. output = 30%
Fo)
COMPARATIVE PHYSIOLOGY OF MUSCLE TYPES
Muscle Type SKELETAL CARDIAC SMOOTH
Excitation Myoneural Transmission Pacemaker cells via gap Synaptic; Pacemaker;
junction Receptor Activation
Electrical Activity AP Spikes AP Plateaus AP spikes and Plateaus
Site of Ca sensor Troponin C Troponin I Calmodulin
Source of Calcium ECF/SR ECF Ca/ Ca released from SR ECF
Site of Ca regulation Sarcoplasmic reticulum Sarcoplasmic reticulum/ Sarcolemma
Sarcolemma
Excitation-contraction Dihydropyridine receptor Ca entry via DHP triggers Ca Ca entry via Voltage,
coupling stimulates Ca release from SR release from SR Ligand-gated, IP3 mediated
SR Ca release
Regulation of Force Frequency & Intensity Regulation of Ca entry Latch State (Balance bet.
MLCK phosphorylation)
Metabolism Oxidative; Glycolytic Oxidative Oxidative
Termination Dec. ACh in MNJ; Low ICF Ca Repolarization of AP Twitch Duration
Actin Less More More
Myosin More Less Less
Speed of contraction Type I (slow)/II (fast) Slow Depends on MLC
phosphorylation
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REFLEX PHYSIOLOGY
Motor Units – building blocks of all coordinated body movements; Bell-Magendie Law
activated in a precise temporal order Dorsal Ganglion – Sensory
Anterior Horn – Motor
Voluntary Involuntary
Conscious awareness Unconscious Local Control System – points for
Toward the action and its purpose Automatic and reflex actions instructions to motor neurons from higher
Contains High center, Middle level and Low level movements centers; major role in adjusting motor unit
activity;
Conceptual Motor Control Hierarchy for Movements
Motor control High levels Middle levels Low levels Interneurons Local Afferent
Function Complex Converts plans; Specifies Input
plans; From highest level tension of 90% spinal cord Afferent fibers
according to to small motor particular neurons
individual’s programs; pattern muscles and Synapse with Negative feedback
intention of neural activation angle of specific nearby motor control over muscles
joints neurons/ and proprioception
Transmission/ Command Descending Middle control neurons in spinal
Communication neurons pathways to local levels cord segments
level Integrate input Carry information
Structure Cerebral Sensorimotor Levels of from higher from sensory
cortex; cortex; basal brainstem; centers/ receptors in muscles
memories & nuclei; spinal cord peripheral controlled by motor
emotions cerebellum; receptors/ other neurons; nearby
brainstem nuclei interneurons muscles, tendons,
joints and skin;
Propriospinal system receptors monitor
'! Run up and down the spinal cord length and tension
'! Coordination of motor neurons for locomotion of muscles
Somatic Motor Function
(! Performance of basic involuntary reflex movements in response to
environmental stimuli; maintenance of posture and position
)
)
)
PHYSIOLOGY)[DKA)(201632017)]) 22)
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Response in each part of the reflex arc
Reflex – involuntary change in response of an effector Part Response
organ to stimulus; non-volitional, relatively fixed, graded Sense organ Generator Potential
biological response by specific stimulus Afferent neuron Action Potential
Synapse EPSP/IPSP
Reflex arc – basic unit of integrated neural activity Efferent neuron Action Potential
$! Afferent sensory input Mononeural junction End-plate Potential
$! Central integration Muscle Action Potential
$! Processing
$! Efferent output Elements of a reflex
Receptor and junctions of Portions of the arc Element Example
the arc specialized for transmission Reflex Muscle spindle
NON-PROPAGATED ALL OR NONE RESPONSE Afferent fibers Type IA and II
RESPONSE = Magnitude Interneurons Spinal Cord
of response Efferent fibers Motor neurons
Effector organ Extrafusal muscle
Types of reflex
Monosynaptic Polysynaptic
Synapse Single Several
Response Discrete/local Generalized
Other notes Simplest form Start & terminate slowly;
diminish w/ time
PHYSIOLOGY)[DKA)(201632017)]) 23)
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Types of MSO Muscle Spindle Organ (MSO) – muscle length
Type Nuclear Bag fibers Nuclear Chain fibers receptor
Nuclei Many Few Anatomy:
Discharge Rapidly being stretched Increased throughout #!2-10 muscle fibers (Intrafusal fibers) in
period of stretch connective tissue capsule
Function/Other determines the rate of Lacks definite bag; #!Parallel rest within muscle fibers and
notes change of length shorter; thinner have less distinct striations
Response Dynamic Stretch
Afferent Primary Primary & Secondary Principal Stimulus for Afferent Fibers
Efferent Gamma efferent Gamma efferent a.! Lengthening of central/equatorial portion
of intrafusal muscle fibers
Types of Afferent Fibers b.! Activated by stretch of whole muscle
Types Primary(Annulospiral) Secondary (Flower-spray)
Nerve endings Type Ia Type II Intrafusal muscle = parallel to = Extrafusal
Diameter 17um 8um muscle
Supply Nuclear bag & chain Nuclear chain
Alpha-Gamma linkage – increased gamma
discharge with increased alpha motor neuron
Afferent fibers Concomitant ! & # Coactivation
discharge
stimulation
Synapse ! neurons # neurons ! & # neurons
Connection of Primary Spindle Efferent Fibers
Response Contraction of Excitation of Monosynaptic Excitatory Synapse - ! motor
same muscle intrafusal muscle
neurons to same muscle (homonymous muscle)
Effect Shortening of Contraction of Shortening of
muscle contractile ends whole muscle Weaker Polysynaptic connections – innervating
Intrafusal Shortens Stretched out synergistic and partially synergistic muscle
muscle
Equatorial Outwards No change Excite neurons give rise to spinocerebellar and
length cuneocerebellar tracts
change
AP Increased No change
frequency
PHYSIOLOGY)[DKA)(201632017)]) 24)
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Physiologic role of Spindle Reflex Types of Fibers
Resting Muscle = moderate level of excitation of ! Types Primary Secondary
neurons (Annulospiral) (Flower-
spray)
Movement With No Load With Load Nerve Type Ia Type II Type Ib
Weight lifted None Present endings
Coactivation Muscle Less shortening of Diameter 17um 8um 16um
of ! & # shortening & muscle & muscle Supply Nuclear bag & Nuclear Golgi Tendon;
shortening of spindle chain chain Higher level of
overall length motor control
Activation of Lengthens Lengthens equatorial Organ MSO MSO GTO
# neurons equatorial region
region Motor control
Overall Shortening Less shortening GTO > MSO
spindle
length
Efferent Fiber Types
Result No change Net lengthening of
! fibers # fibers
equatorial region;
Increase spindle Neuron size Large Small
Innervated fibers Extrafusal Intrafusal
efferent, ! motor
neuron, contraction, Diameter >70um <35um
reflex excitation GTO MSO
Golgi Tendon Organs (GTO) Polysynaptic Reflex – fragments of postural states and of
-! Feedback is necessary integrated behavior
-! Muscle tendon receptors
-! Sensitive when muscle is contracted Stepping and Walking Movements
-! Contribute to feedback system causing inhibition of -! Rhythmic stepping seen in limbs
contracting muscle and their synergist and -! Forward flexion then backward extension
stimulation of antagonistic muscle -! Mutually reciprocal inhibition oscillates between agonist
and antagonist muscles
Functional Anatomy Reciprocal Stepping – forward direction of one limb =
(! Type Ib muscle fibers automatic opposition of other limb; results in reciprocal
(! Large (16um) innervation of limbs
PHYSIOLOGY)[DKA)(201632017)]) 25)
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Model of polysynaptic reflex 4.! Characteristics of withdrawal reflex
Withdrawal (flexor,pain) reflex – effect the removal of body part from a Long Small & slow conducting
painful stimulus latency fibers & Many synapse
Receptors: Nociceptors of A% and C fibers Response Results from parallel
Effector organs: Skeletal Muscles; Flexors in physiologic not anatomic outlasts pathways and reverberating
Polysynaptic pathway: Limb withdrawal; stimulation of cutaneous pain; stimulus circuits; causes response to
firing of alpha motor neuron outlast stimulus
1.! Excitation – pain fibers synapse on many interneurons; convey Patterned Crossed extensor reflex
information in CNS Stimulus producing patterned response
Description while contralateral limb
After- Continuation of reflex withdrawal Produced by extends
discharge after sensory receptor stopped Reverberating
firing circuits Control Posture and Balance
Local Sign Ability of reflex to confine Affected by Maintenance of posture – sensory inputs
withdrawal noxious stimulus influences motor output permitting set
Irradiation Activation of large number of When noxious position in face of changing external influences
muscles stimulus is strong = Multiple Reflex Response
Crossed Interneurons cross the spinal Levels of Motor activity
Extensor cord to innervate the extensor Neuraxis
Reflex motor neurons on Afferent Eyes, Vestibular apparatus,
CONTRALATERAL side & Proprioceptors in joints,
muscles & touch receptors
2.! Inhibition of antagonist Integrating Neurons in brainstem, and
Begins Ends Reciprocal innervation System spinal cord
stimulation inhibition of type of neuronal organization Effector ! motor neurons to skeletal
of Alpha motor where reflex pathway activating one muscles
cutaneous neuron group of Alpha motor neurons
pain innervating inhibits antagonistic motor neuron
antagonist muscle
3.! Integration – occurs when final pathway through which afferent
fibers act
Domination Alpha neuron
Excitatory pathway Train of Action Potentials
Inhibitory pathway No firing
PHYSIOLOGY)[DKA)(201632017)]) 26)
)
MAJOR POSTURAL REFLEX
Reflex Stimuli Response Function Level on Remarks
integration
Stretch (Myotatic) Stretching of Contraction Maintains status Spinal cord & Contains (+) &
muscle quo medulla (-) component
(+) supporting rxn Pressure on Extension of foot Keep from falling Local pressure
(magnet reaction) footsole & to same side Spinal cord of footpad
footpad
(-) supporting rxn Stretch to Release of (+) Prevents from
extensor muscle supporting rxn falling
Tonic Effect of gravity Contraction of Supports the Medulla
Labyrinthine limb body
Tonic Neck rxn Stimulation of Turns head to
neck side, up & down
Placing rxn Visual, Foot placed on Supports the
proprioceptive & supporting surface body
exteroreceptive Cerebral cortex
Hopping rxn Lateral Hops/maintain Support body
displacement limbs
Flexor reflex Contraction of Afterdischarge Reciprocal
(withdrawal) Nociceptive muscle innervation/
stimuli Sensory nerves local sign
Crossed extensor Extension of Away from Longer
reflex opposite limbs source of pain afterdischarge
R Labyrinth Effect of gravity Head is kept
I Neck Stretch neck Righting of thorax
G & shoulders Keep head and
H Body on body Pressure on side Righting of body body in right Midbrain
T Body on neck plane
I Optic Visual cues Righting of head Needs intact
N cerebral cortex
G
PHYSIOLOGY)[DKA)(201632017)]) 27)
)
HEMATOPOIESIS
Blood – opaque; red; 6-8%; 70-80ml/kg body weight B.! Function
A.! Composition 1.! Transport
1.! Cellular components – A.! Exchange of gases
)! Erythrocytes (RBC) B.! Conduction of heat
)! Leukocytes (WBC) C.! Cleansing and removal of wastes
$! Granulocytes (Neutrophils; Eosinophils; Basophils) D.! Provision of nutrients
$! Agranulocytes (Monocytes; Lymphocytes) 2.! Immunity = responsible for host
)! Thrombocytes (Platelets) defense
2.! Serum = plasma without fibrinogen 3.! Hemostasis = prevents unnecessary
3.! Plasma: (organic = 6%); (inorganic = 1%); water = 93%); (maintenance clot formation
of normal pH and osmolality 4.! Homeostasis = provides optimal
#!Inorganic Solutes – Minerals and Electrolytes environment for cellular metabolism
#!Organic Solutes
! Plasma carbohydrates Adult Development
Glucose = primary source of energy
! Plasma lipids Bone Marrow – main sit of hematopoiesis
Cholesterol = important component of cell membrane; building Other areas of the body where
block for hormones hematopoiesis may occur:
Triglycerides = important for food-derived energy a.! Ribs
! Plasma proteins b.! Sternum
Plasma content Function c.! Vertebral Column
Albumin 60% Maintain oncotic pressure; d.! Iliac crest
produced by the liver e.! Femur/Tibia
Globulin 36%
! & " globulin Transports lipids and fat- Pluripotent Stem Cell = single type of cell
soluble vitamins where all cells originated
# globulin Immunoglobulins Types of Pluripotent SC:
Fibrinogen 4% For clotting 1.! Long-Term HSC – capable of
renewal
Hematopietic Growth Factors and Cytokines 2.! Short-Term HSC (committed SC) –
-! Sustains and control growth, proliferation, differentiation, and survival capable of differentiation and
of immature hematopoietic stem cells maturation
PHYSIOLOGY)[DKA)(201632017)]) 28)
)
Hematopoiesis – is the continuous regulated process of producing blood Erythropoiesis = process of rbc production;
cells including the renewal, proliferation, differentiation and maturation. multiple discrete anatomic sites
Minimum = 2nd week of life
Fetal Development: Maximum = 3rd month of age
Phase Development Site Note
Yolk sac 2-4 weeks of Mesoblastic Primitive blood Rate of HgB Synthesis
(Mesoblastic) gestation tissue formation Decrease Span Cause
Hepatic 5-6 weeks of Liver/ Spleen/ Primitive HgB 2-3x First few days Sudden
gestation Thymus to Fetal HgB 10x First few weeks increase in
Medullary 5th month of Bone Marrow Fat cells turns tissue oxygen
(Myeloid) gestation into yellow
marrow 55%-65% = Total HbF synthesis
PHYSIOLOGY)[DKA)(201632017)]) 29)
)
Androgen = capacity to stimulate EPO
production; induce differentiation of marrow
stem cells; parts for Higher HCT in male
PHYSIOLOGY)[DKA)(201632017)]) 30)
)
Synthesis of HgB Role of Iron and its Metabolism
a.! Pyrrole Molecule = Succinyl CoA (formed by "! Element which oxygen binds on HgB molecule
Kreb’s) + Glycine "! Needed for the formation of essential elements
b.! Protoporphyrin IX = Four pyrroles combined (myoglobin, cytochromes, cytochrome oxidase,
c.! Heme = Protoporphyrin IX + Iron peroxidase, catalase)
d.! Hemoglobin = Heme + Synthesized Globin "! 4-5grams
(ribosomes) 65% Hemoglobin
e.! Whole HgB molecule = 4 HgB chains 15-30% Ferritin (stored Fe; in the liver)
4% Myoglobin
Forms of HgB 1% heme compounds
Stage Globin Chain synthesized 0.1% transferrin
&&'' Gower 1 "! Absorbed in small intestine
Embryo &&## Portland "! Apotransferrin – combines in blood plasma w/ beta
!!'' Gower 2 globulin
Fetus !!## Fetal HgB "! Transferrin – transfers Fe
Adult !!(( HbA2 "! Ferritin – stored form of Fe
!!"" HbA "! Recycling = through senescent RBC
"! Loss of iron via urine, feces, sweat
Most dominant and common in adult human = HbA "! Homoeostatic balance of iron resides in intestinal
Highest Affinity to Oxygen = HbF epithelium
"! Hemochromatosis = excess iron in the body
Each HgB molecule = 4 Fe = 1 oxygen molecule
Red Cell Metabolic Pathways
RBC Structure Cytoplasmic enzymes of mature rbc:
+! Proteins (55%) – integral proteins (band 3; a.! Metabolize glucose – forming small amounts of ATP
glycophorins); peripheral (actin; spectrin) b.! Maintains pliability of cell membrane
+! Lipids (45%) – phospholipids and unesterified c.! Maintain Fe transport
(free) cholesterol d.! Keep Fe of cell’s HgB in Ferrous form
e.! Prevent oxidation of proteins
Characteristics: EMB Pathway
%! Deformability Cell Rigidity Survival
%! Red Cell Membrane Permeability
*Ability to maintain constant volume Rapoport-Luebering
Potassium Sodium Calcium Affinity for Oxygen HgB release
PHYSIOLOGY)[DKA)(201632017)]) 31)
)
4 glucose-supported metabolic pathways Changes occurring during aging of RBCs
Pathway Description Increases Decreases
Embden-Meyerhoff Non-oxidative (anaerobic); generates 90% MCHC MCV
(Glycolytic) of ATP; generates NADH from NAD Sodium Potassium
Phosphogluconate 5-10% glucose metabolized; prevents globin Oxygen affinity Protoporphyrrin
(Hexose Monophosphate denaturation; dependent of G6PD; Methemoglobin Phospholipid
Shunt) Agglutinability Cholesterol
Rapoport-Luebering Production of 2,3-DPG; HgB affinity to Spheroidal shape Sialic Acid
Oxygen Density Deformability
Methemoglobin Pathway Maintains Heme iron in reduced state Internal Viscosity Enzyme activity
(Ferrous State) Membrane-bound IgG
PHYSIOLOGY)[DKA)(201632017)]) 32)
)
Characteristics of Blood Cells
Red Blood Cells White Blood Cells Platelets
Other name Erythrocytes Leukocytes Thrombocytes
Diameter 7.8um (6-8um) 10-15um 2-3um
Average vol. in 4.0-6.0 x106 4,000-10,000 200,000-500,000
blood
Lifespan 120 days 4-5 days; weeks/ months 10 days
for
Nuclei Absent Granulocytes (2-3 lobes) Absent
Agranulocyetes (1)
Organelles Absent Granules for some Alpha granules storing fibrinogen; Von
granulocytes Willebrand factor & factor V
Dense core granules storing Ca; serotonin; ATP
Function Delivers Oxygen Main defense system of the Coagulation cascade
to the body body
RBC Parameters
MCV HCT/RBC x10 Microcytic, macrocytic
MCH HgB/RBC x10 Average HgB content
MCHC HgB/HCT x100 Hypochromic, normochromic
RDW RBC width Degree of anisocytosis
PHYSIOLOGY)[DKA)(201632017)]) 33)
)
Blood Group System – antigens inherited in ABO Blood Group System
simple Mendelian fashion Antigens H A B
Phenotype – observed serological red cell Terminal sugar L-fucose N-acetylgalactosamine D-galactose
antigen type
Genotype – family studies ABO Hemolytic Disease of the Newborn – most commonly seen in
non-Type O infants
Antigens – branched or linear carbohydrate
structures Blood typing – performed by mixing RBC with antisera
1.! Glycosphingolipids – ABH
2.! Glycoproteins – A (MN) Rh System – second most significant RBC antigens; also known as D
3.! Proteolipids – D (Rh) antigen; antigens (D, C, c, E, e)
PHYSIOLOGY)[DKA)(201632017)]) 34)
)
RESPIRATORY PHYSIOLOGY
Partial Pressure – fractional con’c X total pressure of all
gas Pgas = % Tgas X Ptot O2 tension CO2 tension
Dalton’s Law of Partial Pressure Alveolar 104 40
Total Pressure = Sum of all individual partial pressures >
End 104 > 40
Composition of Room Air at atmospheric pressure of Capillary
760mmHg or 1 torr Mixed 40 < 45
Gas Fractional Con’c Partial Pressure Venous
Nitrogen 78.62 596.5
Oxygen 20.84 158.4 Factors affecting the diffusive transfer of gases:
H2O vapor 0.50 3.8 Law Definition
CO2 0.04 0.3 Graham’s Gas through a liquid
Henry’s Amount of gas w/ch dissolves in unit vol
N >O2 >H2O vapor >CO2 of liquid at given temp.
Fick’s Diffusion of gas across sheet of tissue
Altitude
Altitude Barometric Pressure Graham’s
Cause of Hypoxia in Barometric Pressure Diffusion Solubility Square root
Altitude PO2 Rate coefficient of gas of MW
PHYSIOLOGY)[DKA)(201632017)]) 35)
)
Fick’s Law O2 Diffusion during exercise due to:
Diffusion Surface area of Surface Area Recruitment & Distension
Tissue
Diffusion constant tissue thickness ventilation- alveolar ventilation
& Partial Pressure perfusion area
of specific gas pulmonary blood flow
PHYSIOLOGY)[DKA)(201632017)]) 36)
)
95mmHg PaO2 drop mixture of Oxygenated & Dead space ventilation
Deoxygenated blood Dead Space Types
95mmHg = PO2 Arterial blood reaches peripheral ventilation
tissues Physiologic Anatomic Upper airways/ conducting
40mmHg = PO2 Interstitial fluid surrounding airways does not
peripheral tissue participate
40mmHg = PO2 Blood leaves peripheral tissue Alveolar Volume of gas entering
via veins (High VQ ventilated but unperfused
ratio) alveoli
Solubility of O2 in water is temperature-dependent Pathologic Airways & (VQ mismatch)
0.03mL/L/mmHg or 0.003/mL/100mL/mmHg Lung (VD/TV > 0.3)
= solubility coefficient of O2 dissolved in 1L of H2O parenchyma Converts alveolar space
Temperature Solubility into alveolar dead space
))
Examples:
a.! Pulmonary vasculature
SvO2 and PvO2 = best Normal Values
b.! Low venous return & Low right ventricular output
measured in pooled/ mixed SvO2 73%
c.! High Alveolar pressure
venous blood PvO2 40mmHg
CvO2 15mL/dL Dead space Alveolar Alveolar Space
Disease Effect on CaO2 ventilation ventilation
Anemia 50% HgB 50% CaO2
Oxyhemoglobin dissociation curve
Hypoxemia 50% PaO2 18% CaO2 PaO2 HgB O2 Saturation
PHYSIOLOGY)[DKA)(201632017)]) 37)
)
PO2 Capillary O2 <> HgB PO2 value O2-HgB sat.
Pulmonary Bind 95mmHg 97% Bohr CO2 & H+ con’c O2 loading
Mnemonics: (CaDET face Right) Upper Airway = nose, nasopharynx & larynx
Lower Airway = trachea to alveoli
Shift to the LEFT Factors Shift to the RIGHT
•! Conducting Zone 1st-16th
Loves O2 Rejects
$! 1st-9th = large and medium airways
p50
$! 10th-16th = small and peripheral airways
H+
CO2 •! Respiratory Zone 17th-23rd
Temperature $! 17th-19th = respiratory bronchioles
2,3-DPG $! 20th-23rd = alveolar ducts and sacs
HgB-O2 sat Total X-sectional area
Alveoli Trachea
pH
O2 affinity
>
Pulmonary circulation Bronchial circulation
CO2 = major end-product of oxidative metabolism
$! Deoxygenated blood from $! Aorta to lung
right ventricle to gas- parenchyma incl. walls of
PaCO2 of 2-fold increase in Arterial PO2 drop
exchanging units bronchi, bronchioles,
5mmHg VE dot to 55mmHg
$! Capillary volume = 70mL blood vessels, and nerves
$! During Exercise = $! 1/3 returns to right
CO2 + H2O ! H2CO3 (carbonic anhydrase)
inceases to 200mL atrium through bronchial
veins
HCO3 in red cell is pumped back to plasma in exchange for Cl-
Innervation
CO2 + free AA on HgB = carbamic acid = HbNHCOO + H+
Parasympathetic Constriction
Total CO2 = dissolved CO2 + HCO3 con’c + carbamino CO2 Sympathetic Relaxation
Nonadrenergic noncholinergic inhibitory Relaxation
Total CO2 (23mEq/L) = plasma (17mEq/L) + red cell (6mEq/L) Nonadrenergic noncholinergic stimulatory Constriction
PHYSIOLOGY)[DKA)(201632017)]) 38)
)
VENTILATION COMPUTATIONS
Symbol Description Formula Unit
V dot Ventilation Volume x respiratory frequency V dot = V x f mL/min
VE dot Minute Total air volume moving in and VE dot = TV x f mL/min
ventilation/Total out of lungs per minute VE dot = VA dot + VD dot
Ventilation
VD dot Dead space ventilation Normally 1/3 of tidal volume VD dot = TV/3 mL/min
or wasted ventilation VD dot = VD x f
VD dot = VE dot – VA dot
VA dot Alveolar ventilation Volume of air per minute that VA dot = VA x f mL/min
reaches alveoli; participates in gas VA dot = VE dot – VD dot
exchange
VD Dead Space Volume Portion of inhaled gas doesn’t VD = TV - VA
participate in gas exchange
PAO2 Alveolar Gas Equation Relationship between PO2 and PAO2 = FiO2 x PB – PACO2/R
PCO2
CaO2 Arterial Oxygen Summed contribution of O2 bound CaO2 = HbO2 + Dissolved O2
Content to HgB and O2 dissolved in CaO2 = (1.34 x HgB x SaO2) +
plasma (0.003 x PaO2)
HbO2 Hemoglobin Bound O2 Hb = HgB con’c in blood; HbO2 = 1.34 x HgB x SO2 g/dL
1.34 = O2 binding capacity of HgB
SO2 = ratio of oxygenated HgB to
total HgB in blood
Dissolved Con’c of Dissolved in Solubility of O2 in temp- Dissolved O2 = 0.003 x PO2 mL/dL
O2 O2 dependent
PO2 = partial pressure of O2
CvO2 Venous Oxygen Con’c of Oxygen in venous blood CvO2 = (1.34 x HgB x SvO2) +
Content (0.003 x PvO2)
DO2 Oxygen Delivery Rate of O2 delivery via cardiac DO2 = CO x O2 content (x 10 =
output if CO is in L)
VO2 Oxygen uptake Rate of O2 dissociation from HgB; VO2 = CO x (CaO2 – CvO2) mL/min
O2 consumption of tissues Normal: 200-300mL/min;
110-160mL/min/m2
PHYSIOLOGY)[DKA)(201632017)]) 39)
)
Normal spirometry = unable to measure residual volume During respiration
IC IRV -! synchronous expansion of chest and abdominal wall
TLC VC TV -! tidal breathing: negative pressue = 2.5cm
FRC ERV -! Apnea phase: bet. Expiration and inspiration
RV RV -! Normal rato of I:E = 1:2/ 1:3
Pressures Value Remarks Elastance = property of substance to go back to its original shape
Compliance = property to be deformed
Atmospheric 760mmHg
Mouth Opening 760mmHg
Hysteresis = difference in compliance during inspiration and expiration
Alveolar 760mmHg Curve = 2 flat portion and 1 steep portion
Airway 0mmHg Mouth – Alveolar
Intrapleural 756mmHg Surfactant = released by type II pneumocytes; mixture of CHONS and
Transpulmonary 5mmHg Alveolar – phospholipid structures
Intrapleural
Transmural Pleural – chestwall Diaphragm; Thoracic Intrapleural Alveolar Air-
intercostal cage pressure pressure alveoli
Forces promoting muscles
Open Surfactant Inspiration Contracts Expand More - - In
collapse Tension Expiration Relaxes Contracts - + Out
PHYSIOLOGY)[DKA)(201632017)]) 40)
)
Transpulmonary pressure Airway resistance
= alveolar pressure – intrapleural pressure Bronchioles Trachea
<
Alveolar pressure = not affected by gravity
Effect of gravity Velocity
Alveolar pressure Intrapleural pressure Laminar Flow Airways
< Resistance
Change in volume
Base Apex
> Factors airway caliber
Negative intrapleural pressure •! Smooth muscle contraction
Base Apex
< •! Mucosal edema
Ventilation during Tidal breathing •! Mucus hypersecretion
Base Apex •! Bronchial gland hyperplasia
> •! Decrease lung elastance
PHYSIOLOGY)[DKA)(201632017)]) 41)
)
Airflow Pulmonary capillaries – where exchange of solutes and liquid occur
Taller Shorter between blood, lung interstitium and alveolar cells
>
Male Female
> (+) flux
(-) flux
Fluid accumulation (drained by the lymphatics)
Reabsorption
0-25 y/o 25 y/o up
> Edema Formation – abnormal accumulation of fluid in interstitium
or alveoli
Lung elasticity Pc Pi
(+) flux )c
TLC RV
> %
Mnemonics: OR/CR
Pathology Restrictive Obstructive Circulation Systemic Pulmonary
Mechanical Compliance Resistance Function Supply regulation Gas exchange
Property affected Resistance
TLC Low Normal Pressure >
FVC Low Normal to low Response to Hypoxia
FEV1 Normal to low Low
FEV1/FVC >70 <70 Factors controlling Pulmonary blood vessel radius
Radius Radius
Pulmonary circulation = optimal gas exchange along
alveolo-capillary membrane PVR PVR
Deoxygenated blood/ carbon-rich – systemic capillary to Relaxants Contractors
right ventricle
PaO2; pH PaO2; pH
Oxygenated blood/ carbon-less – drains into pulmonary
vein to left ventricle PACO2 PACO2
PHYSIOLOGY)[DKA)(201632017)]) 42)
)
Perfusion Pressure
Perfusion pressure No change Zone Relative Pressure Remarks
Distention intraluminal pressure 1 Pa > Ppa > Ppv Does not exist in normal lung
Blood flow 2 Ppa > Pa > Ppv Upper 1/3 of lung; waterfall
effect
Alveolar blood vessels 3 Ppa > Ppv > Pa
Alveolar pressure 4 Ppa > Ppv > Pa Collapsed due to Tethering
Lung volume Alveolar radius effect
Alveolar vessel Resistance Always Ppa>Ppv
V/Q mismatching = relationship of respiratory unit’s ventilation (V)
Extra-alveolar vessel with perfusion or blood flow (Q)
Extra-alveolar radius V/Q
Lung volume Extra-alveolar
Lung elastance resistance 0 <1 Ideal 1 >1 Infinity
Radius >Perfusion <Perfusion
Hypoventilation Hyperventilation
PVR = alveolar resistance + extra-alveolar resistance Hyperperfusion = Hypoperfusion
Lung volume True Shunt Shunt Dead Space
Alveolar vessel Extra-alveolar Effect
Resistance resistance Low Lung Mid Lung High Lung
Lung Dx Heart Dx
PVR and Lung volume = biphasic relationship
-----------------------------------------------! O2 Tension
Lung volume PVR
CO2 tension -----------------------------------------------
RV to FRC
Pneumonia; Asthma; Partial Complete
ARDS COPD; vessel obstruction
Lowest at FRC pulmonary obstruction
FRC to TLC fibrosis
PHYSIOLOGY)[DKA)(201632017)]) 43)
)
Shunt = condition wherein blood was not allowed to have gas Compensatory Mechanism
exchange with alveolar gas VQ Ventilation Perfusion Airway Compliance
$! Anatomic ratio resistance
'! Bronchial vein = pulmonary vein anastomoses
High Hyper
'! Thebesian vein = left ventricle drainage
$! Alveolar
'! True shunt = VQ=0; no volume; blood flow not allowed to
undergo gas exchange Low Hypo
'! Shunt effect = VQ<1; inadequate volume
$! Total Shunt = sum of shunts due to anatomic and alveolar Ventilatory Control Mechanism
shunt; 4% of total CO &! Automatic rhythm for contraction
4% Total CO = Physiologic Shunt &! Adjust for metabolic demands; non-ventilatory effect
effect on adding deoxygenated blood well-oxygenated blood
Arterial O2 Tension < Ideal VQ end O2 tension Respiratory Related Neurons RRN
Alveolar Shunt Interneurons Interconnection to other RRn
Lower lung > Upper Lung Premotor Innervates motor neurons
Motor Innervates ventilatory muscles
$! Pathologic Shunt
Lung Dx alveolar shunt Central Pattern Generator (CPG) = groups of neurons located in
medulla responsible for rhythmic output
Heart Dx anatomic shunt
Chemoreceptors = ventilator system adjust to metabolic
demands
Dead Space Ratio Mechanoreceptors and Irritant receptors = mechanical
Normal Lung Lung Dx condition in lungs or presence of foreign bodies
TV 500 = 500 High centers = basis of why ventilator system can control
VD 150 > >150 speaking, playing musical instruments, swallowing and vomiting
PHYSIOLOGY)[DKA)(201632017)]) 44)
)
ELECTRICAL PROPERTIES OF THE HEART
Functional Anatomy of the heart:
,! Deliver raw materials for tissue metabolism Sequence of Depolarization:
,! Transport metabolic waste products to excrete organs Event Direction
,! Structures S/I R/L A/P
Right and left hearts are in series Atrial Depolarization I L P
Ventricles Inferiorly to the atrium Septal Depolarization H R A
Left chambers Posteriorly to right chambers Apical Depolarization I L A
Left chambers >muscle mass V. Free Wall Depolarization I L P
Posterobasal Depolarization S R A
Systemic !R heart ! Pulmonary !L heart !Systemic Ventricular Repolarization S R A
PHYSIOLOGY)[DKA)(201632017)]) 45)
)
Examination of waves:
Examination Remarks
P wave Duration, Longest duration: 0.10 sec
amplitude, Highest amplitude: 2.5mm
direction of Vector: 15-75 degrees
depolarization
QRS normal Visual Appearance of QRS complex
Q waves Leads I, aVL, & Small Q waves
V6 Duration: 0.04s
(left-sided Amplitude: <2mV
chest leads)
ST segment Usually Deviates -0.5 & 1mm from
isoelectric baseline
T wave Inverted only T in V1 taller than T in V6
in V1-V3 Usually not above 10mmin
precordial leads
P/QRS/T Meaning Event Direction Relation to Wave AMP Duration
electrodes
P wave Deflection Atrial Dep. ILP Towards + Modest O.1
Q wave First negative wave Septal Dep. HRA Away - Minimal
R wave First Positive wave Apical Dep. ILA/ Towards + Minimal
Free wall Dep. ILP /High O.10
S wave First negative wave after R wave Posterobasal Dep. SRA Away - Minimal
T wave Deflection Ventricular Rep. SRA Going/ + Modest
Away
QRS Deflection Ventricular ILP
complex depolarization
PQ Start of P - Start of Q Flat 0.12s-
interval (Time required for SA node impulse to travel through conduction system) 0.20s
QRS dur. Start of Q – End of S
QT Start of Q – End of T NV: 0.44s
interval (Time required for ventricular depolarization & repolarization)
ST Transition between depolarization & repolarization Flat
segment
PHYSIOLOGY)[DKA)(201632017)]) 46)
)
Physiologic information from ECG:
Parameters Axis measured Dependent on
P wave Y Quantity of atrial muscle mass
amplitude depolarizing; Direction of atrial
depolarization
QRS complex Y Quantity of ventricular muscle
mass depolarizing; Direction of
ventricular depolarization
T wave Y Direction of ventricular
amplitude repolarization
PR interval X Conduction velocity of conducting
system
QRS X Conduction velocity of ventricular
Duration mass
QT interval X Speed of ventricular
depolarization & repolarization
PHYSIOLOGY)[DKA)(201632017)]) 47)
)
Appearance of ECG waves Types of cardiac cells:
Depolarization Positive elec. Wave Predominance Type Function Location Type of AP
Atrial Towards P wave Upright/ + Contractile/ Contracts & Free wall of Fast
Away Downward/ - Working cell pumps blood atrium &
Ventricular Towards QRS Upright/ + ventricle
Away Complex Downward/ - Conducting Transmit AP Purkinje system Fast
Pacemaker Generates AP SA & AV node Slow
QRS Leads Predominance Ventricular dep.
Limb leads I, II, III & + Inferiorly & Ionic basis for Fast Type of AP
aVF leftwards Ions – across membrane & along con’c & electrical gradient
Chest leads V1 & V2 - Leftwards & Na & Ca > Extracellular
V5 & V6 + Posteriorly K > Intracellular
Abnormal T waves = frequently in healthy persons as variant Phase Other Names Main Ion Flow Negativity MP
pattern 0 Depolarization Na Influx
Conduction Measured Normal Value Time required
1 Rapid K Efflux
PR interval Limb leads 0.12-0.20s SA node impulse Repolarization
to travel 2 Plateau K Efflux/ No Significant
QRS interval Limb leads Longest= Ventricular Ca Influx change
<0.10s depolarization 3 Gradual K Efflux
QT(A) Lead w/ Ventricular Repolarization
interval most <0.425s depolarization & 4 RMP
QT(C) defined T repolarization
interval wave Voltage Gated Na Channels
QT(A) interval = actual State 1 2 3
QT(C) interval = computed M Gates Close Open Open
! Dividing measured QT interval by square root of RR interval
H Gates Open Open Close
Excitability Yes No No
ECG criteria for normal sinus rhythm:
Parameter Value
Beyond Threshold
Rate 60-100/min
! Not possible to generate a new AP
Regular rhythm >10%
! No available closed Na channels
(RR interval)
P wave Normal contour During Repolarization
P wave vector Uprights (Leads II, aVF, V5, V6) ! Na channels are closed
Inverted (Lead aVR) ! AP is only possible if intensity of stimulus is > threshold
PR interval Normal (0.12-0.20s) ! Only Intensity able to open Na channels
PHYSIOLOGY)[DKA)(201632017)]) 48)
)
Ionic basis for Slow response
PHYSIOLOGY)[DKA)(201632017)]) 49)
)
Automaticity:
-! Ability of the cardiac cell to generate spontaneous Conducting cells >Diameter >Conducting vel.
action potential
Conducting cells Fast type of AP
Ionic events responsible for pacemaker potential:
$! Leaky Na Channel Hyperkalemia effect:
$! Leaky Ca Channel Normal K serum levels: 3.5-4.5mEq
$! Tight K Channels Conduction Velocity
RMP Automaticity
Factors:
!@; !:+); 9; B; C
=%'"7:'(&'- = )/>:1+)?)9,"2+ = )
D; 6&>
Automaticity
PHYSIOLOGY)[DKA)(201632017)]) 50)
)
HEART AS A PUMP
Cardiac Cycle – sequence of mechanical and electrical
events that repeats every heart beat; 7 phases AV Valves Swings open to ventricles
Atrial Pressure > Ventricular
Atrial Pressure pressure
Volume; Pressure Surface area; AV Valves OPEN
Contraction Compliance
NIOOP)QOIMRK; SMLTIK)UOVEFHTEGOV SL Valves Swings open to great vessels
=EFGHI)JFKLLMFK = )
WMFXHTK)=FKH; UORYIGHVTK Ventricular > Great Vessel
Pressure Pressure
Atrial pressure during Reduced Filling State: SL Valves OPEN
Inflow of blood (vena > Outflow of blood
cava-pulmonary veins) During Inspiration
venous return to right pulmonary venous
heart return
Ventricular Pressure PROLONGS SHORTENS
Volume; Pressure Contraction R ventricular contraction L ventricular contraction
Relaxation LATER EARLIER
NIOOP)QOIMRK; SMLTIK)UOVEFHTEGOV closure of pulmonary valve closure of aortic valve
QKVEFGTMIHF)JFKLLMFK = )
WMFXHTK)=FKH; UORYIGHVTK
Duration of Systole and Diastole
Great Vessel Pressure during Isovolumetric Relaxation: Phase Systole Diastole
-! Elastic recoil of blood vessels propels blood to flow bi- Duration 0.28s < 0.52s
directionally Cardiac Cycle 35% (1/3) 65% (2/3)
-! Increase in blood volume ! dicrotic notch or incisura
ij(l/nop)
Duration)of)Cardiac)Cycle) = )
Pressure change rstuv)wtvs)(xstvl/nop)
Right heart < Left heart
Heart rate duration of diastole;
diastolic filling time
Ventricular wall compliance
Adult > Children
S1 = closure of mitral and tricuspid valves
S2 = closure of aortic and pulmonary valves
PHYSIOLOGY)[DKA)(201632017)]) 51)
)
Phases Isovolumetric Rapid Reduced Isovolumetric Rapid Filling Reduced Atrial
contraction ejection ejection relaxation 1st half 2nd half Filling Systole
Abbrev. IC RE SE IR RF SF AS
Initial Volume 120 120 70 50 50 100 120
Ejected Volume 0 50 20 0 50 20 +/- 0
Volume Left 120 70 50 50 100 120 120
Phase SYSTOLE DIASTOLE
Blood flow OUTFLOW INFLOW
Atrial Pressure
Area/ Volume area area volume volume volume volume area
Pressure
Pressure
Heart Sound S1 S2 S3 S4
Cause of sound Closure of AV Closure of SL RF vibration
Waves C WAVE V WAVE A WAVE
ECG Wave QRS COMPLEX T WAVE P WAVE
Ventricular phase Ventricular Ventricular Atrial
Depolarization Repolarization Depolarization
PHYSIOLOGY)[DKA)(201632017)]) 52)
)
Phase IC RE SE IR RF SF AS Phase
Great Vessel Pressure
> Starts to be < Starts to be > > > > > Ventricular Pressure
Inspiration
RIGHT Heart RA RV
T closes P close
LEFT Heart
LA LV
M closes A closes
{|
SV = EDV - ESV yz = )
}~|
PHYSIOLOGY)[DKA)(201632017)]) 53)
)
Work – accompanied by shortening of cardiac muscle
Work done – external work Factors that influence the CO
Against resistance offered Imparting momentum to I.! Stroke Volume
by peripheral circulation blood flow A.! Pre-load/end-diastolic fiber length
Pressure Volume work Kinetic Energy work 1.! Total blood volume
PVW = Pressure x Volume KE = 1/2 (Mass)(Velocity)2 2.! Ventricular compliance
3.! Venous Tone
Work when there is NO shortening (during isovolumetric 4.! Skeletal muscle pump
contraction phase) 5.! Thoracic Pump
-! Energy broken down B.! Contractility
-! Released as heat 1.! Sympathetic stimulation
-! TENSION HEAT = work done 2.! HR-homeostatic autoregulation
3.! Pre-load
TENSION HEAT = K x Tension x Delta time 4.! Afterload
5.! Left Ventricular Size
Total External Work C.! Afterload
During Rest During Exercise 1.! Ventricular Radius
(3%)
< (10%) 2.! Ventricular Systolic Pressure
II.! Heart Rate
Viscosity Kinetic Energy
ANS
Blood pressure Tension Heat
Frank-Starling’s Law of the Heart = length-tension
Heart Rate Frequency of Work relationship
EDV; Interfilament spacing
Cardiac Output Stroke Volume Contraction; Ca
volume of blood ejected volume of blood ejected release SR
heart/time heart/beat
SV x HR EDV - ESV ESPVR = rel. between pressure & volume during cardiac
5-6L/min cycle; indirect measure of the maximum isovolumetric
pressure & ideal indicator of contractile state of the heart
PHYSIOLOGY)[DKA)(201632017)]) 54)
)
Contractility = intrinsic ability of cardiac muscle to Effects of changes in contractility Constant
develop force at given muscle length Contractility end-systolic Preoload
Contractility Contractility Slope of ESPVR volume Afterload
Stroke Volume
Positive ionotropic effect Negative ionotropic effect Effects of changes in pre-load Constant
•! Stroke Volume •! Parasympathetic Stroke Volume ESV Contractility
•! Ejection fraction stimulation Segment DEF
•! Heart Rate (Staircase •! Heart Failure
phenomenon) •! Myocardial Infarction Width of pressure-
•! Sympathetic •! Pharmacologic volume loop
Stimulation depressants
•! AP/unit time •! CO2 Effects of Afterload Constant
•! SERCA2 •! Acidosis Afterload Blood Contractility
•! Phospholamban- •! Extracellular Na ESV Ejection
phosphorylation •! Ca channel blockers Wall tension Fraction
•! Cardiac glycosides •! cGMP Aortic pressure Stroke volume
•! Extracellular Ca Taller
•!Intracellular Na •! O2
•! ESV •! Extracellular Ca Echocardiography
•! Na-Ca exchange •! cAMP = assess contractility
= changes in ventricular chamber size, aortic diameter &
CO & CVP (Central Venous Pressure) relationship/ aortic blood flow
VR (Venous Return) & RAP (Right Atrial Pressure) rel.
Variable Independent Dependent Ejection Fraction ! ventricular blood ejected during
Axis Y-axis X-axis systole
CVP/RAP CO
Parameter RAP Cardiac Function Vascular Function
CO CVP/RAP Curve Curve
2-4mmHg CO (5-7L/min.) VR
CVP/RAP VR
PHYSIOLOGY)[DKA)(201632017)]) 55)
)
Extrinsic factors affecting the performance of the heart Factors affecting vascular function curve
1.! Preload 1.! Blood Volume
Preload Velocity of shortening; BV Shift RAP & CO Ex.
Force of contraction; Right/Upwards Transfusion
Tension;
2.! Afterload Left/ Downwards Hemorrhage
Afterload; Velocity of
2.! Venomotor Tone
Pressure shortening;
Tone Shift Ex. RAP & CO
3.! Heart rate Right/Upwards Venoconstriction
BV/ Venous BV; CO; RAP; Mean BV; CO; RAP; Mean
compliance NOT AFFECTED Systemic Pressure Systemic Pressure
Venous Compliance Venous Compliance
TPR change CO; VR CO; VR TPR; TPR;
PHYSIOLOGY)[DKA)(201632017)]) 56)
)
HEMODYNAMICS
Ultimate function of the cardiovascular system Characteristics of Blood Vessels
= ensure adequate blood flow to the capillaries Arteries & aorta Transport blood from heart at high pressure
of all organs Arterioles Well-developed smooth muscles
Aorta Thin walls; Higher elastic fiber = more compliant
Vascular system = active role in regulation of Capillaries Monolayer of endothelial cells; site of nutrient
blood pressure & distribution of blood flow and waste exchange
Veins Transport blood back to the heart; major
Factors affecting the Adequacy of blood supply reservoirs of extra blood
$! Blood pressure Venules Collect blood from capillaries, enlarges and
$! Blood flow drains to vena cava
$! Resistance to blood flow
Diameter Thickness
Vena Aorta
cava Vena cava
Aorta
Vein Artery
Artery Vein
Arteriole Arteriole
Venule Terminal
Terminal arteriole
arteriole Venule
Capillary Capillary
PHYSIOLOGY)[DKA)(201632017)]) 57)
)
Relationship between Flow, Velocity and Relationship of Blood Flow, Pressure and Resistance
Cross-Sectional Area of Blood Vessels Factors affecting Blood Flow:
a.! Pressure Difference – pressure gradient between 2 end of
Velocity – distance a particle travels with time vessels which pushed blood flow through the vessel
Flow – rate of displacement of a volume of fluid per *P = Pi – Po
unit time b.! Resistance – impediment to blood flow; friction that impedes
Blood Flow – quantity of blood that passes blood flow
through a given point in the circulation in a given
time /Å+11%Å+)@(ÉÉ+Å+#&+(*Ö)
Ohm’s Law Flow (Q) =
4+1(1':#&+))(4)
Overall blood flow in the total circulation =
5L/min Flow Pressure Difference Resistance
,"Ä)
Velocity =
!Å"11Ç9+&'("#:,)6Å+:)"É)C%Ñ+ Poiseuille’s Law = most
fundamental law that
Flow = Velocity x Area governs flow of Newtonian
fluids through cylindrical
Cross-sectional area of the vessel – sum of the tubes; relationship of blood
cross-sectional areas of blood vessels flow to pressure and
Vessel Cross-sectional Area (cm2) resistance
Capillaries 2500
Venules 250
Small veins 80
Arterioles 40
Small arteries 20
Vena cava 8 Flow Pressure Radius Length Viscosity
Aorta 2.5 Gradient
Constant Flow Constant Radius '! Viscosity and Length – does not usually vary, thus does not
play significant role
Area Velocity Flow Velocity
'! Radius of tube – critical factor in determining flow
)
PHYSIOLOGY)[DKA)(201632017)]) 58)
)
Factors affecting Resistance to Flow in Blood 3.! Patterns of Blood Flow
vessels: $! Laminar/Turbulent
1.! Attributes of Blood Flow Laminar Turbulent
$! Viscosity Sound Silent Noisy
Hct/ Plasma Viscosity Resistance Blood movement Parallel Multidirectional
proteins/Plts Flow Parabolic Eddy currents
Velocity Profile are present
HCT
M >F Velocity of blood in Laminar
PHYSIOLOGY)[DKA)(201632017)]) 59)
)
4.! Factors acting on walls of Blood vessels and Heart $! Distending Force = force that pulls apart a theoretical
Chambers slit in the blood vessels/heart chambers
$! Shear stress = force exerted by blood on the wall
of the blood vessels Distending Force = (Distending Pressure) (Radius)
WℎKHF)LEFKLL
QGLTOLGEë = ) $! Wall Tension = force which opposes the distending
WℎKHF)FHEK
pressure; prevents theoretical slit in the vessel/heart
Viscosity Resistance Shear Flow chambers
Stress rate
Viscosity Shear Shear Flow Law of Laplace:
Stress rate rate Wall tension = Transmural Pressure (Radius of vessel)
PHYSIOLOGY)[DKA)(201632017)]) 60)
)
I.! Arterial System 2.! Mean Arterial Pressure = average of arterial
Muscular Elastin Compliance Resistance pressures measured over a period of time; pressure
wall content driving blood into the tissues average over the entire
cardiac cycle
Elastin content Workload of the heart
(î)lélvåãoçÇî)âotlvåãoç)
Est. MAP = P diastolic +
ï
Pressures in the Circulation:
1.! Arterial Blood Pressure – pressure exerted by the
circulating blood upon walls of the blood vessels; pulsatile MAP determined by about 60% diastole & 40% systole
fashion between systolic and diastolic values Age Hardening Systolic Compliance
a.! Physical Factors: of vessels pressure
Volume of blood Dependent on inflow of blood from heart
and outflow to venous Cardiac TPR MAP
Arterial volume Pressure Output
Arterial inflow >
outflow
Arterial inflow = Pressure is 3.! Pulse Pressure = pulsation or throb in the arteries
outflow constant in wrist/neck
Affected by: SV and Compliance
*|åãìns Constant Vessel Compliance
Compliance = Stroke Volume
*îusllìus
PHYSIOLOGY)[DKA)(201632017)]) 61)
)
Pressure Pulse Wave and Wave Control Intrinsic Tone = intrinsic contractile ability of arteriolar smooth
Transmission of Pulse Pressure = ejection of blood muscle
from left ventricle to the aorta initiating a wave front Controls Vasoconstrictors Vasodilators
of distention or pressure wave that is propagated Neural Sympathetic nerves Nitric Oxide releasing
down the aorta and its branches Hormonal Epinephrine; Epinephrine
Pressure Wave = pulse felt when palpating a Vasopressin Atrial Natriuteric Peptide
peripheral artery Angiotensin II
Compliance Velocity of Transmission Local Internal BP Eicosanoids; K; CO2; H;
Endothelin-I Bradykinin; Adenosine
O2
Pressure Pulse Wave > Velocity of Blood Flow
PHYSIOLOGY)[DKA)(201632017)]) 62)
)
IV.! Capillary System – circulation of blood through b.! Filtration – permeability of capillary membranes are
the smallest vessels of the body; 5% of circulation due to pores, clefts, fenestrations and gaps
Anatomy of Capillary network: Permeability
&! Typical Capillary – thin-walled endothelial cells Hepatic capillaries
&! Intercellular clefts/pores – narrow, water-filled
> Brain
spaces of flat cells of the endothelial wall Venous ends > Arterial End
&! Metarteriole – connects an arteriole to a venule as well
as capillaries Starling’s Forces
&! Precapillary sphincters – site of exit from metarteriole c.! Oncotic Pressure ())= attracts or pulls fluid to
to a capillary; arteriole to a capillary compartment
d.! Hydrostatic Pressure (P)= repels or pushes fluid out
sum of cross-sectional areas velocity of flow of its compartment
cross arrangement of Total Net Filtration = [(Pc) + ()IF)] – [()c) + (PIF)]
sectional area capillaries in Resistance Net Filtration Pressure Pc )IF
parallel
Net Filtration Pressure )c PIF
Transcapillary exchange – solute and solvent movement
across the capillary endothelial walls: Arteriolar resistance Pc
a.! Diffusion – exchange of gases, substrates and waste
products between capillaries and tissue cells Resistance to flow to Pc
Fick’s Law of Diffusion venules
Concentration gradient; Capillary Diffusion Effect on Capillary Hydrostatic Pressure
Surface Area; Capillary Permeability Change in Venous > Change in Arterial
Pressure Pressure
Diffusion Through
Lipid-soluble Capillary endothelium Absorption – fluid movement from interstitial compartment
Lipid-insoluble Water-filled pores, clefts, channels into the intravascular compartment
Large molecules Restricted; Diffusion-limited Capillary Filtration Coefficient – reflection of capillary
Small molecules Flow-limited permeability for a given tissue
Filtration coefficient capillary permeability
Flow-limited – only restriction to net movement across c.! Pinocytosis – transfer of substance across the
capillary wall is rate capillary wall through vesicles that are formed by
Diffusion-limited – capillary membrane permeability is the pinching off of the endothelial membrane
limiting factor to their transport
PHYSIOLOGY)[DKA)(201632017)]) 63)
)
CARDIOVASCULAR REGULATION
Specific needs of tissues for blood flow: Local Blood Flow
Oxygen CO2 removal Vasodilators:
Nutrients (Glucose, AA, FA) H+ Removal Adenosine; CO2; H+; K+; Histamine; Lactic Acid
Hormonal Transport Ion Con’c Maintenance
Vasodilator theory
Determinants of Blood Flow: Rate of O2 Rate of formation
Flow Pressure Difference Resistance metabolism availability of vasodilators
Oxygen Demand Theory – O2 is require to maintain
vascular smooth muscle contraction
Resistance Radius O2 Blood O2
availability Vasodilation flow delivery
Cardiac TPR MAP Local Control of Blood Flow
Output •! Auto-regulation/Myogenic
•! Endothelial Cell-Mediated
Driving Pressure = has no correlation with resistance
•! Metabolic
•! ANS
Determinants of Tissue Blood Flow:
Long term Control of Blood Flow
MAP Blood Flow
•! Humoral Regulation
•! Hormonal Regulation
Smooth Muscle Resistance Tissue Blood
Contraction Flow Blood Flow Response in organ to arteriolar tone
Strong Local Metabolic Strong Sympathetic
Mechanisms of Blood Flow Control Brain Kidney
Control Time Changes Heart Muscle Skin
Acute Seconds to Local constrictions of Skeletal Muscle Splanchnic Organ
minutes arterioles, metarterioles &
capillaries
Long-term Days, weeks & in size and
& months number of
vessels
PHYSIOLOGY)[DKA)(201632017)]) 64)
)
Local Control of Blood Flow Long term Control of Blood Flow
•! Auto-regulation/Myogenic O2 Tissue vascularity
Arterial Blood Flow <1 min. =
Pressure Blood Flow returns
•! Humoral Regulation = regulation by
Sudden stretch Smooth Resistance Blood substances secreted/absorbed
of Small Blood Muscle Flow •! Hormonal Regulation
Vessels Contraction Stimulation !1 "2
Effect Vasoconstriction Vasodilation
•! Endothelial Cell-Mediated Signaling IP3 and DAG cAMP
Rapid flow Shear Nitric Vasodilation Blood pathway
in arteries stress Oxide Flow
Release Hormone Norepinephrine Epinephrine
Released by Sympathetic Adrenal
nerve endings medulla
•! Metabolic Stimulation !1 Site & con’c
Arterial O2 & Blood Blood Pressure dependent
Pressure vessel Flow
Nutrients Constriction Epinephrine effects
Skeletal con’c "2-vasodilation
Rate of Metabolism Blood Flow Muscle
con’c !1-vasoconstriction
PHYSIOLOGY)[DKA)(201632017)]) 65)
)
Regulation of Arterial Pressure )
Renal Blood Flow
Levels of Angiotensin, Aldosterone, ADH
H2O conservation
H2O Output
H2O Intake, Total Blood Volume, Venous
Tone
Blood Volume, Preload, Contractility
Afterload
Heart rate
S
Cardiac Output, TPR
MAP
Factors affecting Basal Tone: Cardiovascular Regulation during Blood Loss & Moderate Exercise
•! Myogenic response
Vessel Response Blood Loss Moderate Exercise
•! Increase pO2
Coronary Dilate Dilate
•! Presence of Ca2+
Cerebral Dilate Dilate
Stress Skin Constrict Dilate
Arterial Venous Preload, CO, Skeletal Muscle Constrict Dilate
Blood Contraction EDV, MAP Splanchnic Constrict Constrict
Volume Renal Constrict Constrict
Others Constrict Constrict
PHYSIOLOGY)[DKA)(201632017)]) 66)
)
Cardiovascular reflex Receptors Stretch/ Cardiopulmonary Peripheral
Baroreceptor Baroreceptor Chemoreceptor
Reflex Reflex Vascular Reflex
Stimulus MAP MAP BAP; Atrial
Pressure
Receptor- CN IX & X Stretch receptor of Receptors in
Afferent heart & aortic body &
Limb pulmonary vessels carotid
Integrating Brainstem
Center
Efferent Sympathetic & Sympathetic Sympathetic
Limb Parasympathetic Nerves Nerves
Atrial pressure (BV) Nerves
Affect to organ: Compensation Organ Blood vessels & Kidneys & Heart Blood vessels &
Heart Sympa; HR BV; Atrial Heart Heart
Pressure Response Parasympathetic Sympathetic; Sympathetic;
Kidney Sympa; RAAS MAP MAP
Dilate Sympathetic; BAP; Atrial
MAP Pressure
*Note: TPR is only changed during metabolic
control Bainbridge reflex:
During Exercise
Metabolism; TPR MAP
Blood Flow
PHYSIOLOGY)[DKA)(201632017)]) 67)
)
SPECIAL CIRCULATION
Regulation of Blood Flow Mechanisms that control blood flow throughout the body:
-! Organ possesses circulatory adaptations I.! Local Control
allowing changes appropriate for causing A.! Autoregulation – ability of tissue to maintain a relatively constant
minimal harm to overall organism blood flow
Organ Percent Arterial Pressure Blood flow
Abdominal organs 21% <60mmHg
Skeletal muscles 20%
above normal value Constant/ Not affected
Kidneys 20%
Brain 14% >140mmHg
Other organs 9-10%
Skin 5-9%
Heart 4% B.! Active Hyperemia – vessels are sensitive to local metabolic needs
Response:
Arteriolar dilatation; Number of perfused capillaries
Types of Capillaries
Continuous Most common; complete
capillaries endothelial lining; all tissues C.! Reactive Hyperemia – temporary occlusion of an artery supplying
except epithelia & cartilage; an organ
diffusion of H2O, small Size and Time of Occlusion Blood flow
solutes & lipid-soluble
Specialized Very restricted permeability; D.! Metabolic
continuous seen in CNS, Thymus, BBB E.! Myogenic = closely to stretch related events that are intrinsic to
capillaries smooth muscles
Fenestrated Gaps/pores in endothelial Law of Laplace T = P (r)
Capillaries lining; rapid exchange of
H2O & solutes bet. plasma & II.! Extrinsic Control
IF; seen in kidney, GI tract A.! Neural
Discontinuous Gaps bet. adjacent NE = principal neurotransmitter at sympathetic nerve terminals
capillaries endothelial cells; permit free Nitric Oxide = mediator of endothelium dependent vasodilator
change of H2O & large response
plasma protein; seen in liver B.! Hormonal
sinusoids, spleen, bone Receptors for vasoactive hormones differ in vascular beds
marrow
PHYSIOLOGY)[DKA)(201632017)]) 68)
)
SPECIAL CIRCULATION
Circulation Cutaneous Coronary Cerebral Skeletal muscle Splanchnic Hepatic Fetal
Body weight 2% 30-40% 15%
Description Minimal nutrient Obtain Least tolerant
& O2 requirement nutrition of ischemia
primarily from
blood in
ventricle
Important Resistance vessel Right & Left ICA, vertebral, Celiac, Sup. &
Vessels (Arterioles/ AV coronary basilar artery, Inf. Mesenteric
anastomoses) artery circle of Willis arteries
Neural Factors Sympathetic Sympathetic Cervical; Sympathetic; Sympathetic
(Cholinergic) & vagal; Sympathetic degree of Basal
(weak) tone
Humoral Sensitive to basal O2; NO; H; Arterial CO2; O2; CO2;
Factors tone CO2; K; K; Adenosine nutrients;
Adenosine metabolic
products
Metabolic Change in No metabolic
factor arteriolar regulator can
resistance account
Autoregulation Myogenic Myogenic
change in mechanism ABSENT
diameter of
vessels
Reactive Reactive Functional
Hyperemia Hyperemia Hyperemia
Other factors Temperature Aortic Arterial pressure; Autoregulation; Physical
pressure; Tissue Pressure; Food factors; O2
extravascular blood viscosity; consumption
compression; squeezing of
heart rate muscles
PHYSIOLOGY)[DKA)(201632017)]) 69)
)
Cutaneous Circulation Temperature effects on Cutaneous Circulation
Higher brain control – primary regulation Temperature Effect
Blushing – response to embarrassment Cold Vasoconstriction
Blanching – cerebral stimulation of sympathetic NS due to Prolonged exposure to cold Vasodilation
fear/anxiety Hot Vasodilation
*Highly Sensitive to vasoconstrictor as E & NE
Countercurrent = cold blood flowing in veins take up heat from adjacent arteries ! results to warm venous and cool
arterial blood
Skeletal Muscle Circulation Splanchnic Circulation
! 30-40% body weight -! includes blood flow to stomach, small intestine, large
Muscle Blood Flow intestine, pancreas, spleen and liver
At rest 5-10mL/min -! 30% Cardiac Output
During exercise 50-fold -! Countercurrent flow – permits solutes to move from
arteriole to venule without having to traverse the entire
villus (80% of O2)
Type of muscle Blood Flow Circulatory Shock – villi suffer ischemic death due to
Slow twitch > Fast twitch substantial O2 shunt from arterioles to venules
Oxidative
Slow twitch Fast twitch ! adrenergic Constriction
> " adrenergic Dilation
Neural Factors
Metabolic vasodilation Blood Flow PNS Blood Flow Glandular
muscle activity secretion
Fight & Flight Vasoconstriction Flow to more
Basal frequency of firing Time crucial areas
Sympathetic vasoconstriction 1-2/second
Maximal vasoconstriction 10/second Autoregulation
Food ATP Vasodilation Blood
Vasoconstriction evoked by SNS (Dose-dependent) Consumption levels Flow
NE > E Peptide hormones (CCK, O2 con’c Blood
gastrin, bradykinin, VIP,) Flow
Skeletal Muscle Predominance
Resting Neural
Exercising Metabolite
PHYSIOLOGY)[DKA)(201632017)]) 70)
)
Coronary Circulation Adenosine Hypothesis
Vascular channels link cardiac vessels and cardiac chmabers: O2 tension coronary blood flow
a.! Arteriosinusoidal channels – small arteries/ arterioles
that lose their arterial property metabolic activity myocardial release
b.! Arterioluminal channels – directly to atria and ventricles of the heart of adenosine
c.! Thebesian vessels – connect capillary beds w/ cardiac
chambers & cardiac veins Diminished Coronary Heart Flow
Myocardial ischemia – prolonged reduction in
Epicardium coronary blood flow results to accumulation of harmful
>Blood flow in Systole substances like K+, lactic acid & H+
Endocardium >Blood flow in Diastole Myocardial Stunning – ischemia followed by perfusion
Aortic pressure – primary factor responsible for perfusion in could cause mechanical dysfunction; too prolonged;
myocardium intracellular Ca2+ overload
Myocardial hibernation – chronic arterial occlusion;
Squeezing effect/Extravascular compression – influences reduction in cardiac contractility
heart’s blood supply
Metabolic activity Coronary Collateral Circulation
Metabolic activity Blood Flow Coronary resistance -! No inter-coronary channels in humans
-! Develop between branches of occluded and non-
occluded arteries
Coronary Blood Flow Cycle Influence of
Left Coronary Artery Systolic reversal extravascular Coronary Steal
Right Coronary Artery No reversal compression "! Vasodilator drugs = increase diameter
"! Reduce the head of pressure
Effect of Heart Rate
Tachycardia time in systole; HR; time in Cardiac Oxygen Consumption
metabolic requirement diastole •! Derives energy by oxidative phosphorylation
Bradycardia time in systole; HR; time in •! Process through 36mol of ATP is derived
metabolic requirement diastole •! Glucose and lactate consumed at equal amounts
•! Total Cardiac O2 consumption
Metabolites causing reactive CO2; H+; K+; Hypoxia; 35-40% Oxidation of carbohydrate
hyperemia Adenosine 60-65% Non-carbohydrate fuel
PHYSIOLOGY)[DKA)(201632017)]) 71)
)
Cerebral Circulation Intracranial Pressure
•! Increase in arterial inflow = induces arterial -! Contained in inelastic, closed skull;
dilatation = increase venous outflow -! Brian parenchyma, CBV CSF
•! Least tolerant of ischemia
Interruption of blood flow Result Monroe-Kellie Doctrine – sum of all intracranial volume
<5 seconds Unconsciousness (Brain, CSF, CBV and other constituents)
>5minutes Irreversible brain death in any of the equal of the
volumes others
Brain
'! 2% of total body weight Factors altering Cerebral Blood Flow
'! receives 15% Cardiac Output Factor Change Result
'! oxidative sources of energy production CO2 CO2 Vasodilation Cerebral
Arteries 2 ICA & 2 vertebral arteries; Basilar Tension Blood Flow
artery; Circle of Willis H+ in Arterial Blood No Change
Veins Leaves the cranium via the IJV; in CSF Vasodilation
Capillaries Blood Brain Barrier
Lymphatics None K+ K+ Arteriolar dilatation *Effect is not
sustained*
Blood Brain Barrier Adenosine Adenosine Vasodilation
'! Passage of H2O soluble substrates from the blood
to the CNS is limited
'! Cerebral capillary endothelial cells limiting Autoregulation
penetration of cerebral parenchyma MAP Effect Result
'! Protects brain from abrupt changes <60mmHg cerebral blood flow Syncope
'! Passive transport across tight cerebral capillaries
>160mmHg permeability of the blood Brian
Cerebrospinal Fluid (CSF) brain barrier edema
•! Fills ventricles and subarachnoid space; formed
mainly in choroid plexus Cerebral Blood Arterial Intracranial
•! Absorbed thru arachnoid villi Flow Pressure pressure
Total CSF volume 150mL
Total daily production 550mL
PHYSIOLOGY)[DKA)(201632017)]) 72)
)
Hepatic Circulation Fetal Circulation
-! 25% Cardiac Output -! depends completely on placenta for O2
-! 15% Total Blood Volume
Placental Blood Flow
Source of Blood Flow 50% Liver
Portal Vein (3/4) Hepatic Artery (1/4) 50% Inferior Vena Cava;
> Ductus Venous blood
Mean Blood Pressure
Portal Vein (10mmHg) < Hepatic Artery (90mmHg) Fetal HgB > Affinity for O2
Autoregulation
Portal Vein (ABSENT) Hepatic Artery (Autoregulate Pulmonary Vascular Closure to Ductus
< via Adenosine) Resistance Arteriosus
Pressure Resistance to LV Closure to
Portal Vein Hepatic Sinusoids Hepatic Veins output Foramen Ovale
(10mmHg)
> (8-9mmHg)
> (5mmHg)
PHYSIOLOGY)[DKA)(201632017)]) 73)
)
GASTROINTESTINAL PHYSIOLOGY
Functional Anatomy
•! Hollow tubes divided into segments Layers of GI Tract
•! Brunner’s gland – blind ending Layer Description
glandular structures that are Mucosa Innermost layer; consists of:
invaginations of the tube Epithelium Enterocytes; Enteroendocrine cells;
•! Pancreas/Salivary glands – attached via Mucin-producing cells – columnar epithelial cells
ducts where secretions empty into gut linked by tight junctions
lumen Lamina propria Loose connective tissue; glands; capillaries and
nerve fibers
Blood Supply Muscularis Thin innermost layer of intestinal smooth muscle;
$! Originates from celiac plexus mucosae folds and ridges
$! Receives 25% Cardiac Output Submucosa Loose connective tissue; some glands; larger nerve
$! Absorbed nutrients to the rest of the body trunks and vessels;
$! Venous drainage does not go directly to Submucosal Plexus
heart, passes thru portal circulation Muscle layer Muscularis externa/propria; Myenteric Plexus
$! Liver – major blood supply of GI Layers:
$! Lymph drainage – important for transport Inner circular
of lipid-soluble substance across GI Outer longitudinal
Serosa/Adventitia Outermost layer; squamous mesothelial cells; part
Structures of the GI System of mesentery; secretes thin viscous fluid
Luminal organs Accessory glands
Mouth & pharynx Salivary glands Regulation of GI Function
Esophagus Pancreas Endocrine/ Stimulated by neural input/factors not Gastrin,
Stomach Liver Hormonal associated with meal; EEC responds to a Secretin,
Small Intestines Gallbladder stimulus CCK
Large Intestines Paracrine Chemical messenger released from sensing Histamine,
Rectum cell, acts on nearby target cell by diffusion Serotonin
Anus Neurocrine Involves the release of neurotransmitter from ENS
nerve terminal; influences motor/secretory
activity of GI tract
PHYSIOLOGY)[DKA)(201632017)]) 74)
)
Innervation of the GI tract: Physiologic Functions of the GI System
1.! Extrinsic Nervous System – innervates the gut with cell bodies
located outside the gut Primary
Parasympathetic Sympathetic Digestion Chemically and mechanically
Cranial – Vagus Nerves T5-L2 breaks down food particle into
Sacral – Pelvic (S2-S4) nutrients; begins after
Direct Innervation Indirect ingestion
Esophagus, stomach, Distal half large Absorption Passage of substance through
pancreas, small intestine; anus intestinal mucosa; absorption
intestines, proximal half caused by large surface area -
of large intestine villi & microvilli
Acetylcholine Neurotransmitter Norepinephrine Motility Functional types of GI
Stimulatory Effect Inhibitory movement
Stimulates secretory Action Inhibits motor & Secretion Comes from glands associated
and motor activity secretory function; w/ tract, formed by gut wall
local blood flow; and intestinal mucosa itself
Induces contraction of
muscularis mucosa Secondary
Maintenance Dietary Fluid Intake: 1.2-2L
2.! Intrinsic Nervous System – has cell bodies that are contained of overall Total Secreted Fluid: 7-8.5L
within the wall of the gut fluid & Total Fluid Absorbed: 8-9L
Enteric Nervous System “Little brain of the gut” electrolyte Total Fluid in feces:
$! Primary neural control; 100M neurons; nervous connections with balance 100mL
parasympathetic and sympathetic nerve fibers Excretion of $! Nondigested
Major Plexuses: waste $! Colonic bacteria
Myenteric Plexus Submucosal materials $! Water
Auerbach Other name Meissners $! Dying/Dead epithelial
Outer Layer Inner cells
Muscular of esophagus- Location Submucosa of $! Heavy metals/ org. ions
rectum intestines only Immune Gut-associated lymphoid
Tonic contractions; Velocity Action Secretory functions tissue (GALT)
of excitatory waves; Intensity activities (against microbial pathogens)
of Rhythmic contractions
PHYSIOLOGY)[DKA)(201632017)]) 75)
)
Types of Digestion Constituents of GI secretions:
a.! Mechanical Digestion 1.! Water
$! Mastication (Chewing) – changes physical state 2.! Inorganic substance - (electrolytes) H+; HCO3-
$! Swallowing (Deglutition) 3.! Organic substance – enzymes, mucin, absorptive
b.! Chemical Digestion – changes in chemical factors, immunoglobulins
composition; results of hydrolysis (Digestive enzymes)
Anatomical Types of Secretory Glands:
Types of Motility '! Mucus/Goblet cells
'! PITS
a.! Propulsive (peristalsis) – propagated movement to
'! Deep tubular glands
caudal
'! Complex glands
b.! Mixing – differs in different parts; peristalsis &
contraction
c.! Segmentation – non-propulsive; mixing & Non-immunologic defenses:
a.! Gastric acid secretions
churning
b.! Intestinal mucin
c.! Peristalsis
Electrical Activity of GI smooth muscles:
d.! Epithelial cell permeability barrier
Slow wave Types Spike Potential
Not one Action True “Antroduodenal cluster unit”
Potential $! More important than pressure
Basic electrical rhythm Caused/ Slow wave potential
Interstitial cells of excited by when it reaches Integrated response to a meal
Cajal RMP Threshold Phases Description Stimuli
NV: -50 to -60 mv
Cephalic Activation of GI tract for its Cognitive;
Does not elicit Causes muscle readiness for a meal; an Olfactory;
contractions contractions increase in excitatory Visual;
Intensity: 5 to 15 mv parasympathetic neural outflow Auditory
Oral Increase in parasympathetic
Frequency of Slow wave neural outflow to gut;
Duodenum > Ileum > Colon > Stomach stimulation of salivary
(12/min) (8-9/min) (6-8/min) (3/min) secretions
Esophageal Moves food from pharynx to
Frequency of slow wave Rate of contraction stomach
PHYSIOLOGY)[DKA)(201632017)]) 76)
)
GI Sphincters Cognitive stimuli = anticipation of thinking about the
Sphincter Muscle Separates Function food; experimented by Ivan Pavlov
Upper Skeletal Pharynx- Prevents air
esophageal esophagus from entering Salivary Glands
Lower Esophagus- Prevents Gland Serous Mucous
esophageal stomach reflux Parotid Only
Pyloric Stomach Digestion Sublingual Partly Mainly
Smooth end Submandibular Mainly Partly
Sphincter of Bile duct- Controls Buccal Only
Oddi duodenum secretion
junction Major types of secretions:
Ileocecal Ileum- Limit reflux of Secretion Enzymes Purpose
cecum colonic Serous Ptyalin/ !- Digesting starch
content amylase
Internal Anal Anus Work in Mucous Mucin Lubricating/surface
defecation protective purpose
External Anal Skeletal Rectum
Saliva
,! 0.5mL/min. (Basal Awake State)
,! maintaining healthy oral tissues
,! neutralization of refluxed gastric contents
,! mucosal growth
,! maximal rate of production: 1mL/min/g
,! HYPOTONIC; ALKALINE
PHYSIOLOGY)[DKA)(201632017)]) 77)
)
Salivary amylase works best at Flow of Saliva Maximal Stimulation
Neutral pH flow Potassium Osmolality Na P S
rate L
> A
NaCl
))
plasma
HCO3 > HCO3 saliva
A L
Composition of saliva: Cl S I
a.! Proteins/enzymes (lipase/amylase) M
> V
K saliva
b.! Glycoproteins (mucin) K A < A
c.! Water; lysozymes; electrolytes
Rate of secretion Isotonicity Deglutition (Swallowing)
*! Events that propel food from mouth to stomach
Blood Flow Metabolism (proportional to *! Initially voluntary then reflex
salivary formation) *! Swallowing center: Medulla, Lower pons
(CN 5,9,10,12)
Neural Control of Salivary Secretion Phases of Swallowing:
Parasympathetic Innervation Sympathetic
Phase Description
Sup. & Inf. Salivatory Origin Superior Cervical
Oral Voluntary; broken down; bolus moved
nuclei CN 7 & 9 Ganglion
toward oropharynx; pressing food against
Marked Increase in Slight hard palate w/ tongue
salivary
Pharyngeal Touch receptors stimulated by swallowing
secretions
reflex; occurs in <1 second; respiration is
Taste & tactile; Stimuli Along surface of inhibited
nervous signals from blood vessel wall
Esophageal Begins w/ relaxation of UES; Respiration
CNS; originates in
resumes;
stomach & upper
a.! Primary Peristalsis – controlled by
small intestines
swallowing reflex (9secs)
b.! Secondary Peristalsis – frequently
Gustatory buds repetitive
Tonicity Appreciation of buds
Chewing Reflex
Mastication (Chewing)
Bolus of food
.! Voluntary behavior
Initiates Reflex inhibition of mastication
.! Controlled by somatic nerves to skeletal
.! Muscles to mouth and jaw Lower jaw drops
.! Lubricates food Stretch reflex of jaw leads to Rebound contraction
.! Chops food to smaller pieces Raises jaw to closure of teeth
Bolus of Food
PHYSIOLOGY)[DKA)(201632017)]) 78)
)
Esophagus Histological Modifications for Digestion/Absorption
$! 18-26cm hollow muscular tube Purposes
$! stratified squamous epithelium
$! no serosa Small Intestines mucosa – modified for increase
$! conduit that moves food from pharynx to stomach absorptive capacity
$! Innervation: Vagus Nerve Villi – epithelial and lamina propria projections to lumen;
a.! Somatic fiber : Striated Muscle Microvilli – mucosal epithelial cell projections
b.! Visceral fiber : Smooth Muscle Absorption: markedly increase surface area
$! Parts: Lacteal – route of absorbed lipid transported into
#!Upper 1/3 - striated muscles lymphatics and circulatory system
#!Middle 1/3 - striated and smooth muscles
#!Lower 1/3 - smooth muscles Fibers – prevent absorption of fats in the intestines
Colonic bacteria – converts undigested polysaccharides
Types of Peristaltic Movements: to short chain fatty acids
Primary Continuation of peristaltic waves from pharynx Lipid droplets – emulsification droplet
Secondary Results from distention of esophagus Bile salts – prevent action of lipid droplet re-aggregation
PHYSIOLOGY)[DKA)(201632017)]) 79)
)
Events in the Gastrointestinal Tract
Organ Function Digestion Absorption Motility Secretion
Mixing Propulsive Salt & Mucus Enzymes Acid HCO3 Bile
H2O
Oro- Mechanical CHO Chewing Swallowing %! %! Amylase
pharyngeal digestion
Esophagus Conduit CHO Peristalsis %!
Stomach Storage; CHON Water Grinding; Peristalsis %! %! Pepsinogen HCl
partial Receptive
digestion relaxation
(storage)
Small Digestion; CHO; Fat; CHO; Fat; Segmentation Migrating %! %! Other Pancreatic %! %!
Intestines absorption CHON; CHON; Myenteric enzymes juice
Nucleic Nucleic Complex
acid acid; H2O;
electrolyte
s
Large Storage; Bacterial H2O; Segmentation Defecation %! %!
Intestines absorption Digestion electrolyte ; Mass
s Movement
Rectum Defecation
Pancreas Other %!
Enzymes
Liver Major %! %!
blood
supply
Con’c of free FA and monosaccharides in intestinal lumen Vitamin K – produced by colonic bacteria and absorbed in
inside micelle are equilibrium large intestines
intracellular FA/ monosaccharide Micelle degrades Vitamin B12 – binds to intrinsic factor before absorbed in
the ileum
Chylomicron – fat droplet after exocytosis Source of water in lumen of GIT – ingestion & secretions of
Thoracic Duct – site of chylomicron entry glands & mucosal epithelial cells
Fat-soluble vitamins Water-soluble vitamins
Vitamins A, D, E, K Vitamins C & B (except B12) Osmosis of water’s osmolality difference due to differential
concentration of Na & contributions of Cl and HCO3
PHYSIOLOGY)[DKA)(201632017)]) 80)
)
Chemical Digestion and Absorption
Carbohydrate Protein Fats
Oral Salivary Amylase (starch)
Gastric Stops Stomach pepsinogen Contractile activity
Pancreatic Pancreatic Amylase (Disaccharides) Pancreatic proteases Pancreatic colipase
binds
Intestinal Brush borders (Monosaccharides) Intestinal villi luminal peptidase Contractile activity
Transport Facilitated diffusion Secondary Active Transport Exocytosis – released
Fructose (GLUT)/ Galactose & Glucose to intersitium
(SGLT/ Sodium-Glucose Transport)
Note Cellulose/Dietary fibers are not broken Amino acids are transported into
down interstitium via facilitated diffusion
PHYSIOLOGY)[DKA)(201632017)]) 82)
)
Stomach Secretion Gastric Mucosal Barrier
Part Cells Substance Released $! Mucus gel layer protecting epithelial cells from damaging effects of
Parietal cell HCl/ intrinsic factor secreted HCO3 & pepsinogen
Body Chief cell Pepsinogen
Frequency of BER:
Epithelial cell Mucus & HCO3 Small Intestine > Large Intestine > Stomach
Fundus
12-20/min 8/min 3-5/min
Antrum G cell Gastrin
frequency of Action Force of contraction
D cell Somatostatin Potential
Enterochronaffin- Histamine
like cell
Excitatory neurotransmitter & frequency of AP
hormones
Basal/Interdigestive Phase Neural & hormonal factors Intensity of contraction
Gastric acid secretion follows circardian rhythm
Constant frequency BER Constant muscle contraction
Morning Evening
Gastric Motility (Gastric Motor Activity)
/!Tightly coordinated by CNS-ENS
Pepsin Secretion /!Fundus spontaneous relaxes food can immediately lodge into
#! Chief cells produce inactive pepsinogen fundus
#! Factors stimulate/inhibit acid secretion /!2 functional units
#! Pepsinogen is activated by pepsin at low pH Proximal part Fundus & body Reservoir function
#! Pepsin breaks down peptides Distal part Antrum & pylorus Grinding & emptying
#! Accelerates protein digestion
#! Irreversibly inactivated Gastric accommodation – expansion in content accompanied by surge
in intraluminal pressure
Basic Electrical Rhythm gastric content intraluminal pressure
$! Produced by pacemaker (Interstitial Cells of Cajal)
$! Responsible for the peristaltic contractions
$! Conducted through gap junctions gastric content Amplitude of Action potential
$! May or may not cause muscle contraction BER
CNS-ENS pathway, 3 types of coordinated pattern:
BER Effect
a.! Propulsion
Threshold Muscle contraction
b.! Grinding
Electrical Threshold Action Potential
c.! Retropulsion
potential
PHYSIOLOGY)[DKA)(201632017)]) 83)
)
Phases of Gastrointestinal control
Phases (based on Stimuli Stimulates HCl Secretion
initiating stimulus)
Cephalic Sight, smell, taste, chewing of food ENS activity; Parietal, G, ECL cells
*Inhibits D cell
Gastric Distention, acidity, amino acids, peptides ENS activity
Protein digestion G cell
Intestinal Distention, acidity, osmolarity, digestive ENS; CCK, Secretin (enterogastrones)
products
Motilin – induces MMC; originates from M cells; released Ileocecal Sphincter = closed to prevent bacterial colonic content
into circulation during interdigestive state; unknown Distention of Ileocecal sphincter
stimulus Terminal ileum Open
Cecum Closed
PHYSIOLOGY)[DKA)(201632017)]) 84)
)
GET Intestinal Motility Reflexes
Liquid > Solid Gastro-ileal Triggers relaxation of ileocecal valve to
permit passage of chyme to cecum
Smaller > Bigger Gastro-colic Triggers mass movement in colon
Hot food > Cold food Colonocolonic Distention of one part causes relaxation
of other parts
CHON > CHO > FA Orthocolic Morning urge to defecate
PHYSIOLOGY)[DKA)(201632017)]) 85)
)
HEPATOBILIARY PHYSIOLOGY
Liver Central veins – drain the lobules & merge to form hepatic veins
$! 2% Total Body Weight into vena cava
$! Hepatocyte – major cell type Blood flow vascular resistance
$! Hepatic lobule – functional unit of liver; plates that
radiate from the central vein
1050mL blood Portal vein to liver sinusoids/minute
Hepatic sinusoids – capillaries surrounded by hepatocytes + 300mL blood Hepatic artery to sinusoids/minute
supplied by branches of portal vein & hepatic artery 1350mL blood (27% Resting Cardiac Output)
Fasting Sinusoids are collapsed High Lymph Flow – very permeable pores in hepatic sinusoids &
Postprandial More recruited sinusoids liver sinusoids epithelial cells
3.! Kupffer cells (reticuloendothelial cells) – macrophage Transforming Growth Factor-" - cytokine secreted hepatic cells;
main terminator of liver regeneration
4.! Space of Disse (perisinusoidal space) – thin layer of Growth factor -" Liver regeneration
loose connective tissue beneath sinusoidal endothelium
and separating endothelium
Biliary System
Canaliculus – drains bile from liver to biliary ductules (lined by
5.! Stellate cells – serves as storage sites for retinoids;
cholangiocytes)
synthesis of excessive collagen
Portal Triad – periphery of each hepatic lobule
Vascular resistance
.! Hepatic Artery (HA)
Artery > Vein .! Portal Vein (PV)
.! Bile Duct (BD)
Hepatic Vascular and Lymph System:
Hepatic Portal Vein – drains to small intestine Functions:
Hepatic arteries – bring oxygenated blood to liver from 1.! Metabolic
descending aorta 2.! Detoxification
3.! Excretion of protein-bound lipid-soluble waste products
PHYSIOLOGY)[DKA)(201632017)]) 86)
)
Carbohydrate Fat Protein Metabolic reactions:
Storage of large amount Oxidation of FA Deamination of amino Phase I Phase II
of glycogen acids Oxidation, Glucoronic acid
Conversion of galactose Synthesis of large Formation of plasma Hydroxylation, Sulfate
& fructose to glucose quantities of proteins & urea for Cytochrome p450 Amino acid
cholesterol, removal of ammonia Glutathione
Gluconeogenesis phospholipids & Interconversion of
Chemical compounds lipoproteins amino acids and Bile
from intermediate synthesis of ,! Excretory fluid important lipid digestion
products compounds ,! Medium in metabolic waste products are exported
from
Storage of Vitamins ,! Concentrated solution of biological detergents
Vitamins Storage prevent deficiency for that aids in solubilization of the products
Vitamin D 3-4 months ,! Micellar solution with major solutes
Vitamin A 10 months 10 : 3 : 1
Vitamin B12 < 1 year Bile Acid : Phospahtidylcholine : Cholesterol
,! Secretion – drives the concomitant movement of
Iron as Ferritin – hepatocytes contain apoferritin capable of combining water and electrolytes across tight junctions
reversibly with iron ,! Bile salt export pump (BSEP) - majority of bile
Vitamin K – required by metabolic processes; used in coagulation flow secretion of bile acids across the apical
! Prothrombin, Factors VII, IX and X membrane of hepatocytes via ATPase transporter
,! Gallbladder – storage site of bile
First Pass Metabolism (Biotransformation) Albumin Oncontic pressure Ascites
'! A process where absorbed substances in intestines are metabolized by
liver before making to systemic circulation
'! Limit entry of toxic substances Regulation of Bile Acid Synthesis
Bile acid Bile acid Synthesis of
Excretion uptake flow to liver 10-fold
Small water-soluble Large water-soluble catabolites bound to plasma
catabolites proteins Bile Acid Synthesis
Excreted thru Taken by basolateral membrane transporters '! Produced by hepatocytes
kidneys metabolizing at level of microsomes & cytosol; '! End products of cholesterol metabolism
excreted into feces Cholesterol 7 !-hydroxylase – rate-limiting step of
bile acid synthesis
Levels
1.! Physical – involves Kupffer cells, phagocytic cells Secondary Bile acids – yielded after primary bile acids
2.! Chemical – endowed w/ broad array of enzymes; more soluble & less are acted upon by colonic bacteria
susceptible Glycine/Taurine – conjugated with bile acids
PHYSIOLOGY)[DKA)(201632017)]) 87)
)
Bile acids
Key Transporters of Hepatocytes Primary Secondary
Name Basolateral Canalicular U Substrate/Function Chenodeoxycholic Ursodeoxycholic
P
NTCP T Conjugated Bile acids Cholic Deoxycholic
OATP Yes No A Bile acids & xenobiotics Lithocolic
K
E
Conjugated bile acids – retained in the intestinal
BSEP S Conjugated Bile acids
E lumen until actively absorbed
MDR3 C Phosphatidylcholine
MDR1 No Yes R Cationic Xenobiotics
E Apical Sodium-Dependent Bile Salt Transporter
ABC5/ ABC8 T
Cholesterol (ASBT) – actively absorbs conjugated bile acids into
cMOAT/ I Sulfated lithocholic acid & the terminal ileum
MRP2 O conjugated bilirubin
N
Lithocolic acid – preferentially sulfated rather than
Enterohepatic Circulation of Bile Acids conjugated with glycine/taurine
Basolateral transporters (either Na+-dependent/independent)
'! Takes up actively reabsorbed conjugated bile acids that travel the portal Bile Modification of Ductules
blood back to hepatocyte Cholangiocytes – modify composition of bile
Glucose & amino acids – reclaimed using specific
10%/day or 200-400mg – bile acid that escapes uptake and lost in stool transporters
Glutathione – broken down on surface of
Fecal Bile Acid Loss Hepatic Bile Acid Synthesis cholangiocytes
Cl- = exchange with HCO3-; reducing risk of Ca2+
precipitation
Active Secretion Passive Secretion Cl-HCO3 exchange Ca2+ precipitation
Bile acids Water
Phosphatidylcholine Glucose
Conjugated bilirubin Calcium Major Transport Processes of Cholangiocytes that
Xenobiotics Glutathione secrete an Alkaline-Rich Fluid
Amino acids & urea Assimilation of Bile flow
lipids (Postprandial
Inhibits reduction of bile acids’ cholesterol bile acid period)
return to gallbladder degradation production
CCK Bladder Bile flow to
Bile diluted at this site contraction common bile duct
Ingestion Secretin HCO3- Insertion of Aquaporin
of meal response secretion H2O channels
PHYSIOLOGY)[DKA)(201632017)]) 88)
)
Gallbladder – muscular sac lined with high resistance epithelial Bilirubin Formation & Excretion
cells Conjugated bilirubin – hydrolyzed to unconjugated bilirubin by
Period bacterial glucoronides
Postprandial Bile enters the ducts & conveyed toward the Urobilinogens – colorless tetrapyroles reduced by normal gut
small intestines bacteria from unconjuagted bilirubin
Between Bile outflow blocked by constriction of Stercobilins – orange derivatives of bilirubin excreted normally
meals Sphincter of Oddi; redirected to gallbladder in the feces
Urobilin – escapes from hepatic uptake and filtered across renal
Mechanism of Bile Concentration in Gallbladder glomerulus
%! Na+ ions actively absorbed in exchange of protons and bile RBC destruction Bilirubin
acids
%! Single micelle = only one osmotically active particle
%! Bile remains isotonic Ammonia Handling
%! Addition bile acids = incorporated to mixed micelles Ammonia (NH3)
1! metabolites that arises from protein catabolism and
bacterial activity
Stimuli to hepatic secretion of bile and gallbladder emptying 1! toxic to CNS
1! only converted in the liver to urea (Urea Cycle)
CCK Gallbladder contraction
Sphincter of Oddi relaxation Sources of Ammonia
Secretin Stimulates liver ductal secretion 50% Colonic
Bile acids Stimulates hepatic parenchymal 40% Kidney
secretion of bile Liver
Vagal stimulation Causes weak contraction of gallbladder 10% Metabolic process in muscles
(Ach) Glutamine release in senescent RBC
OATP transporter – takes up bilirubin-albumin complex as it Urea – readily filtered in glomerulus & reabsorbed by kidney
reaches the liver tubules; enters colon either excreted/ metabolzied to ammonia
UDPGT – catalyzes bilirubin conjugation with glucoronic acid by colonic bacteria
PHYSIOLOGY)[DKA)(201632017)]) 89)
)
RENAL PHYSIOLOGY
Renal Functions: Functions of Mesangium :
$! Excretory – metabolic waste products -! Alters capillary surface area
$! Regulatory – balance between intake & output -! Give structural support to glomerular capillaries
,! Acid-base balance -! Secrete extracellular matrix
,! Body fluid osmolality -! Exhibit phagocytic activity
,! Volume -! Secrete prostaglandin
,! Electrolytes’ concentration -! Increase glomerular arteriolar resistance
,! Arterial blood pressure secretion of extracellular matrix
$! Endocrine – production of EPO, Renin & Calcitriol
$! Metabolic – production of glucose via gluconeogenesis phagocytic activy
Prostaglandin secretion
Anatomy Contraction of
Part Renal Cortex Renal Medulla mesangium Glomerular Arteriolar Resistance
Location Outer Inner
Alteration of capillary surface area
Staining Darker Lighter
Identification Presence of Renal Multiple Medullary
corpuscles Pyramids Renal Tubules
Divisions Glomeruli; CT; Loop of Henle; Macula densa – specialized group of epithelial cells in
Cortical CD Medullary CD TALH; comes contact w/ afferent & efferent arterioles
Nephrons – functional unit of kidney (1.2M/kidney) Juxtaglomerular apparatus – consists of macula densa,
extraglomerular mesangial cells & juxtaglomerular cells
Renal Corpuscles/Glomerulus – made up of glomerular '! Component of tubuloglomerular feedback mechanism;
capillaries surrounded by Bowman’s capsule involved in autoregulation of renal blood flow & GFR
a.! Glomerular capillaries – tuft of capillaries supplied '! Renin secretion; ADH & Aldosterone sensitive
by the afferent arteriole & drained by efferent
b.! Bowman’s capsule – formed by podocytes Types of nephorn
Visceral cells – face outward at the vascular pole Nephron Cortical Juxtamedullary
Bowman’s space – space between visceral and Site found Outer cortex Deep of cortex
partietal layer Function Reabsorption Osmotic gradient
c.! Mesangium – important component of the renal & secretion generation for H2O absorp.
corpuscle
PHYSIOLOGY)[DKA)(201632017)]) 90)
)
Three processes of Urine formation:
Generation of Hypertonic Medullary 1.! Glomerular Filtration – ultrafiltration of protein-free plasma in the
Interstitium glomerulus
Cortical 2.! Tubular reabsorption – regulated transport of substaces out of
< Juxtamedullary tubular urine to be returned in capillary blood
Presnece in Kidney Mass 3.! Tubular secretion – transport of substance from capillary blood into
Cortical (75%) > Juxtamedullary (25%) tubular urine
Osmotic Gradient Generation
Cortical Amount of urine = Amt. Filtered – Amt. Reabsorbed + Amt. Secreted
< Juxtamedullary
Hydrostatic Pressure Four ways Kidneys handle substance
Glomerular > Peritubular
capillaries capillaries A.! Excretion = Filtration
PHYSIOLOGY)[DKA)(201632017)]) 91)
)
Properties of the Filtration barrier: Pressure Afferent end Relation Efferent end
Endothelial Fenestrated; permeable to water; & small solutes; PGC 60mmHg > 58mmHg
cells RBC, WBC, plateletes; expresses negatively charged
PBS -15mmHg = -15mmHg
ion; synthesizes vasodilator Nitric Oxide &
vasoconstrictor endothelin )GC -28mmHg > -35mmHg
Basement “charge-selective barrier”; gel-like structure formed
)BS 0mmHg = 0mmHg
membrane from collagenous & non-collagenous glycoprotein
called proteoglycans PUI 17mmHg 8mmHg
Podocyte Interdigitate to cover the basement membrane;
>
separated by making the barrier “size-selective
Filtration Absorption
filter”
Arterial end Venous end
Filtered substances
1.! Neutral molecules Net ultrafitration Pressure gradient
2.! Positively-charged molecules – filtered much more readily
Arrangement in Resistance
than negatively-charged
parallel
3.! Low molecular weight substances – not freely filtered
PGC can be altered by:
Dynamics of Ultrafiltration
1.! Afferent arteriolar resistance
Effect on Filtration Pressure
2.! Efferent arteriolar resistance
Promotes PGC Movement of fluid from GC to BS
3.! Renal arteriolar resistance
Opposes PBS
Opposes )GC Size PGC & GFR
Does not influence )BS Con’c of protein is very low Afferent Efferent
<
Net Ultrafiltration Pressure = Kf x (PGC - PBS - )GC) Afferent > Efferent
PHYSIOLOGY)[DKA)(201632017)]) 92)
)
Factors affecting )GC:
Resistance Afferent end Size Efferent end PGC & GFR a.!
Constrict Normal Arterial Plasma oncotic pressure
< )GC GFR
Dilate > Normal
Normal > Constricts b.! Filtration fraction – fraction of renal plasma flow
Normal Dilate that is filtered by glomerular capillaries
< Filtration Fraction GFR RPF
PHYSIOLOGY)[DKA)(201632017)]) 93)
)
Glomerular Filtration Rate & Clearance: Renal Blood Flow
$! Rate at which plasma is filtered by glomerulus/unit $! Average RBF = 1.2L/min
time $! 20% of Cardiac Output
$! Sum of filtration rates $! 8% of total body oxygen consumption
$! Index of kidney function; evaluates the severity & $! maintain hyperosmolar oxygen consumption due to
course of kidney disease metabolic cost
$! Proportional to body size $! Greater cortical blood flow permits high rate of
$! Decrease in age filtration in glomerulus for regulation of body fluid
$! Lower in females volume & solute concentration
$! Normal value: 125mL/min or 180L/day $! Renal O2 consumption varies in proportion to renal
tubular Na reabsorption
Inulin – ideal substance that can be used to measure GFR; Blood flow GFR
because it is freely filterable, not reabsorbed, produced nor
metabolized/stored; not clinically used because it has to be
infused Autoregulation = phenomenon whereby RBF & GFR are
maintained relatively constant as Arterial BP changes
Creatinine – used to measure GFR; overestimates filtration between 80-180mmHg
rate but since measurement in serum creatinine is also
overestimated (can be cancelled out) Mechanisms:
Creatinine GFR 1.! Myogenic – pressure-sensitive mechanism that
responds to changes in arterial pressure
Amount filtered = Amount secreted Arterial Renal AA Smooth Ca influx Pressure
BP muscle
õuopsúùûü) †)|åãìns) contracts
GFR =
îãtlntúùûü
Renal Clearance
$! ability of kidneys to handle solutes & H2O 2.! Tubuloglomerular feedback-NaCl mechanism –
$! rate at which substance is excreted; estimate of GFR changes in NaCl concentration in tubular fluid
$! Renal artery = single input source to kidney GFR NaCl in formation &
$! Whereas renal vein & ureters constitute the 2 output is fluid at MD release of ATP GFR
routes GFR Flow rate at NaCl
is LH reabsorption NaCl
Para-aminohippuric acid = also a good estimate of renal formation & release GFR
plasma flow; but needs to IV infused; of ATP & adenosine
PHYSIOLOGY)[DKA)(201632017)]) 94)
)
Effects of Decreased NaCl concentration in MD cells: Substance Filtered Reabsorbed Excreted Filtered
1.! load
Renin Conversion EA PGC Water 180 178.5 1.5 99.2
release of AI to AII constriction Na+ 25,200 25,050 150 99.4
2.! Cl- 18,000 17,850 150 99.2
Resistance to blood flow PGC HCO3- 4320 4318 2 99.9+
K+ 720 620 100 86.1
Ca2+ 540 530 10 98.2
ATP & Adenosine Dilatation
Glucose 800 799.5 0.5 100
Urea 56 28 28 50.0
Filtered Load
Glucose > HCO3- > Na+ > H2O/Cl- > Ca2+ > K+ > Urea
Major Hormones Influencing GFR & RBF
Vaso- Hormone ECFV Others Effect on GFR Effect on RBF
Sympathetic nerves
Constrictors
Angiotensin II
Prostaglandins
Natriuretic peptides No change
(ANP, BNP)
Dopamine Renin release
PHYSIOLOGY)[DKA)(201632017)]) 95)
)
Tubular Reabsorption Proximal Tubule
1.! Passive Transport '! reabsorbs 67% of fluid filtered
Diffusion Na+, K+ channels by glomerulus
Facilitated Diffusion GLUT transporters (Uniport)
Solvent Drag NaCl movement
Trans (2/3) > Para (1/3)
2.! Active Transport – moves solute against
electrochemical gradient and requires energy derived
from metabolism
Primary Active Transport – coupled with energy
source
Na+-K+-ATPase pump
Secondary Active Transport – indirectly to energy
source such as ion gradient (SGLT1, SGLT2)
Endocytosis for protein absorption
Part Reabsorbed w/
Transport maximum for glucose – limit to a rate at 1st half HCO3-
which solute can be transported due to saturation of 2nd half Cl-
specific transport system when tubular load exceeds
capacity to carrier proteins; 375mg/min
Loop of Henle
Reabsorption of Filtered water and solutes from tubular '! reabsorbs 25% filtered Na+
lumen: '! 15% of filtered water
1.! Transcellular route – through cell membrane
2.! Paracellular route – through junctional and Thick Ascending Limb (TALH)
intercellular space '! diluting segment
3.! Ultrafiltration (Bulk Flow) – mediated by '! imp. for recycling of K+
hydrostatice and colloid osmotic forces
NaCl movement
Trans (50%) = Para (50%)
PHYSIOLOGY)[DKA)(201632017)]) 96)
)
Distal Tubule Tubular Secretion
Thiazide – blocks NaCl '! Means for excreting products of metabolism
co-transporter '! Responsibility of the Proximal Tubule cells
'! Eliminates exogenous substances such as drugs,
5% filtered NaCl pollutants, organic compounds
PHYSIOLOGY)[DKA)(201632017)]) 97)
)
Tubule Permeability Transcellular Transporters Para- Reabsorbed Tubular Fluid
H2O Solutes Apical Basolateral cellular Osmolality
Proximal 1 half
st P P 2’ Na+-H+ antiporter 1’ Na+-K+ Na H2O , Na+,
Tubule ATPase HCO3-, H+,
Na+-glucose/ pump Pi, Lactate,
amino acid/ Glucose,
lactate/Pi Amino acids
cotransporter Isoosmotic
2 half
nd P P 2’ Na+-H+ antiporter 1’ Na+-K+ NaCl Na+, Cl-;
Cl-anion ATPase
exchanger pump
2’ K+-Cl-
transporter
Loop of Thin P Im O Aquaporin-1 H2O
Henle Descending water channel Hyperosmotic
Thin Im P Passively NaCl NaCl
Ascending
Thick Im P 2’ Na+-K+-2Cl 1’ Na+-K+ Ca+, Na+, Cl-,
Ascending cotransporter ATPase K+, Ca+, K+,
Na+-H+ antiporter pump Mg2+ Mg2+
Distal Proximal Im P; Im 2’ Na+-Cl- co- 1’ Na+-K+
to urea transporter ATPase
pump Hypoosmotic
Late P P; Im PC Epithelial Na+ 1’ Na+-K+ Na+, H2O,
[ADH] to urea Channels (ENaC) ATPase K+
[Aldosterone] pump
Collecting Cortical IC H+-ATPase pump HCO3-
Duct Medullary P P even 2’ Urea Transporter Na+, H2O,
[ADH] to urea urea
PHYSIOLOGY)[DKA)(201632017)]) 98)
)
Hormone Nephron Site of Action Effect on H2O & Effect on H2O & Action
PT TALH DT CD NaCl reabsorption NaCl excretion
Sympathetic Epinephrine & Norepinephrine
Angiotensin II Most powerful Na+- retaining substance
Adlosterone Principal cells in Increases
Cortical CD; Secreted stimulation of Na+-
in glomerulosa cells K+ ATPase pump
ADH Most important in Insertion of
regulating H2O vesicles containing
rebsorption Aquaporin 2
channels
Dopamine Catecholamine Stimulated by
released from increase effective
dopaminergic nerves circulating volume
in kidneys
ANP/BNP Formed in cardiac Inhibits ADH
atria & cardiac
ventricles
Urodilatin Secreted by DT & CD Stimulated by rise
in BP & ECV
Uroguanlyn Produced by GI More pronoucned
neuroendocrine cells when given orally
hyperosmolarity dehydration hypotension hypovolemia
Obligatory Urine Volume
$! Maximum urine concentrating
Effectivity ability = 1200mOsm/L to
Urodilatin ANP BNP 1400mOsm/L
> > $! Normal 70kg must excrete
600mOsm/day
Urine Concentration and Dilution $! Minimum volume of urine =
Functions of: 0.444L/day
Loop of Henle Countercurrent multiplier
Vasa Recta Countercurrent exchanger
ADH Alters permeability of late DT/CD
PHYSIOLOGY)[DKA)(201632017)]) 99)
)
Countercurrent Mechanism
'! Interaction between the flow of Segment Renal Urea Handling Regulation
tubular filtrate through loop of Henle Glomerulus Filtered freely
and flow of blood through vasa recta PT 50% reabsorbed Unrelated to H2O
'! Solute concentration ranger from tALH Recycled urea enters passively
300-1200mOsm TALH
DT Impermeable
Steps: Cortical CD
1.! Single effect – Na+ is pumped out
Medullary CD Under ADH level 50% reabsorbed
of TALH w/ maximum
gradient/difference of 200mOsm
2.! H2O flows out tDLH raising
Urea
osmolality to 400mOsm
2! Results from protein breakdown in
3.! Equilibration of tubular fluid &
the liver
interstitium
2! Permeable in MCD under ADH
4.! Fluid shifts along loop
2! Major osmole in urine
2! 40-50% of the osmolarity of renal
Antidiurteic Hormone/ Vasopressin
medullary interstitium
'! 9-amino acid peptide secreted from
Posterior pituitary
'! Synthesized in Hypothalamus
'! Most important in water conservation
Vasa Recta
'! Decreases Urine output
+! critical in maintenance of the corticocapillary osmotic gradient
'! Transports solute-free-water
+! hairpin structure
Plasma osmolality +! allows blood flow to reach inner medulla but not wash out osmotic
ADH gradient
Urine osmolality +! highly permeable to H2O & solutes
+! ability to maintain the medullary interstitial gradient
+! maintenance of hyperosmotic interstitium
PHYSIOLOGY)[DKA)(201632017)]) 100)
)
Formation of Concentrated Urine Factors affecting Urinary Con’c & Dilution:
H2O restriction High H2O intake 1.! Osmotic gradient
Antidiuresis Water diuresis a.! Length of LH
ADH b.! Rate of Active NaCl reabsorption in TAL
H2O reabsorption 2.! Protein Content of Diet
Tubular Osmolality Protein Con’c ability
Interstitial fluid
Urea permeability 3.! Medullary Blood Flow
Urea diffusing out Blood flow Interstitial osmolality Con’c ability
Urine con’c Concentrated Diluted
Factors Maximal ADH level; Absent ADH;
Normal NaCl tubular Normally functioning
reabsorption; Adequate tubular segments
delivery of tubular fluid; (tALh, DT, CD, TALH 4.! Osmotic Permeability
Hyperosmotic medullary – most important) H2O permeability H2O reabsorption
interstitium
PHYSIOLOGY)[DKA)(201632017)]) 101)
)
Muscle Muscle Type Innervation
Type Causes During filling During micturation
Detrussor Smooth Parasympathetic Inhibited Stimulated
Internal urethral Smooth Sympathetic Stimulated Inhibited
sphincter Contraction
External urethral Skeletal Somatic motor Stimulated Inhibited
sphincter
PHYSIOLOGY)[DKA)(201632017)]) 102)
)
FLUID AND ELECTROLYTES
Osmosis = H2O moves intra to extra Control of Osmolality
Total Body Water in Different Hypertonic Solution All solutes contribute to
Age Groups ECF ECF ICF osmolality (mOsm/kg)
Age group X body weight osmolality volume volume
Infants 0.7 Hypotonic Solution Effective Osmoles – restricted
Adult male 0.6 ECF ECF ICF only to the ECF
Adult female 0.55 osmolality volume volume
Elderly male 0.5 Isotonic Saline Osmolality H2O
Elderly female 0.45 ECF osmolality ECF ICF volume
unchanged volume unchanged
Electrolyte ECF QC ICF
Na+ 145 12 Total Osmolallity = All effective osmoles + all
> ineffective osmoles
Control of ECF Osmolality:
1.! Osmoreceptor-ADH System
Ca2+ 5 > 0.001 Total Osmolality = 2Na+ + Glucose/18 + 2.! Thrist Mechanism
Cl- 105 5 BUN/2.8
> Estimation of Osmolality = 2 x (Plasma Na)
HCO3 25 > 12
pH 7.4 > 7.1 Substance added
K+ 4 150 NaCl H2O Isotonic Saline
< Plasma osmolality 0
P 2 < 100
Plasma Na 0
PHYSIOLOGY)[DKA)(201632017)]) 103)
)
Osmoreceptor-ADH System Thirst Mechanims
High Plasma osmolality Low '! Located in anterolateral hypothalamus
Stimulate Hypothalamic osmoreceptor Inhibited '! Respond only to effective osmoles
ADH release '! Relieved by act of drinking
'! Completely satisfied only when plasma osmolality,
H2O retention blood volume and blood pressure are corrected
Urine output
Sodium and ECF Water
Perspiration Water Balance Osmolality Na+
Positive
Constriction Arterioles Dilation
Blood pressure Negative
ADH cAMP PKA H2O reabsorption ECF fluid = directly proportional to total amount of Na+
Control of ECF Volume
Na+ Balance Volume ECF Volume
Aquaporin Channel Membrane Present
Positive Expansion
2 Apical membrane
3&4 Basolateral membrane Negative Depletion
PHYSIOLOGY)[DKA)(201632017)]) 104)
)
Volume Sensors:
Vascular Sensor Difference Osmoregulation Volume Regulation
Pressure Trigger Sympathetic & ADH Sensed Plasma Effective Circulating
Cardiac atria (ANP) osmolality Volume
Ventricular Sensors Hypothalamic Carotid Sinus, Afferent
myocyte (BNP) osmoreceptors arteriole, Atria
Carotid sinus, JXA Effectors ADH RAAS, Sympathtic NS,
(Renin), Aortic arch Thirst ANP, ADH, natriuresis
Affected Urine osmolality Urine Na+ excretion
Na+ salts = most abundant solutes in ECF; major & intake
determinant of ECF osmolality
Potassium
Hypovolemia Differences Hypervolemia )! Major intracellular cation
Contraction Volume Expansion )! Needed for cell growth/division
Sympathetic Nerves )! Excitability of nerve muscle cells, contractiliy of
cardaic, skeletal and smooth muscle
ADH stimulation
Tubule K+ % absorbed
H2O permeability
PT Passive reabsorption 67%
Renin (RAAS) TALH Recycling to lumen 20%
DT Principal cell K+ secretion
ANP & Urodilatin & Intercalated K+ absorption Variable
CD cell
H2O & Na+ excretion
Na+ reabsorption
Factors keeping K+ constant
Receptor Effect
Alpha K+ release to cell
Beta K+ uptake to cell
PHYSIOLOGY)[DKA)(201632017)]) 105)
)
Factors Physiologic Pathophysiologic Reabsorption of Calcium
Constant K+ Epinephrine; Acid-base balance; Tubule Transcellular QC Paracellular
Insulin; Cell lysis; Exercise; PT 20% > 80%
Aldosterone Plasma osmolality LH 20% Not reabsorbed
Increasing K+ Plasma K+; Tubular flow rate; >
ADH; Acid-base balance; DT 100% actively > None
Aldosterone Glucocorticoids
Acronyme Channel Area
H2O uptake Tubular flow K+ secretion TRPV 5/6 Ca2+- permeable epithelial Apical
channels membrane
Glucocorticoids K+ secretion Calbindin-Ca2+ complex Within cell
PMCa1b Ca2+-ATPase pump Basolateral
NCX1 3Na+-1Ca2+ antiporter membrane
Types of Apical K+ channels in Late DT and CCD:
Channel Conductance Responsible for Phosphate/ Inorganic Phosphorus
ROMK Basal K+ secretion 3! important component in DNA, RNA, ATP and
intermediates of metabolic pathways
MAXI-K Flow stimulated K+ secretion
Site Distribution
Bone 86%
Calcium ICF 14%
#!Bone formation, cell division, growth, blood ECF 0.03%
coagulation Bound to proteins 10%
Site Distribution
Bone 99% Phosphate Excretion
Ionized Calcium 50%
Bound to plasma proteins 45% PTH level
Phosphate Loading Depletion
Parathyroid Ca2+ Phosphate Volume Expansion Contraction
hormone excretion
pH Acidotic Alkalotic
Calcitriol Ca2+ Phosphate
Hormones Glucocorticoids Growth hormone
excretion
PT: mainly transcellular via Na+-Pi symporters
Calcitonin Ca2+ Phosphate
NPT2 = most important transporter
excretion
Pi-inorganic anion transporter = exit of Pi in basolateral m.
PHYSIOLOGY)[DKA)(201632017)]) 106)
)
ACID-BASE BALANCE
Acid-base Balance – maintained and regulated by renal and pKa = negative logarithm of the dissociation constant
respiratory systems which modify extracellular fluid pH by
changing bicarbonate pair (HCO3 & CO2); difference in Extracellular buffers Description
quality between input and output of acids/base Bicarbonate Most important buffer of ECF
due to high con’c; major ECF
Acid Proton donor Hydrogen ion donor buffer; maintain
Base Proton acceptor Hydrogen ion acceptor Phosphate pK is 6.8;
Protein Most plentiful in the body, most
Acid Tendency to discharge H+ powerful buffer because pK of
Strong Strong proteins
Weak Less Calcium In bone is significant ECF buffer
bicarbonate
Base Removal of H+
Strong Strong Intercellular buffer Description
Weak Less Organic & Inorganic Most important buffer
Phosphate
State Arterial pH Hemoglobin in RBC Major buffer for H+ in rbc
Acidosis Deoxyhemoglobin More powerful than OxyHgB
(Haldane Effect)
Alkalosis
Chloride Shift – process of exchanging bicarbonate
Compensation – normal body process tending to return the formed in RBC w/ chloride ion from plasma makes
arterial pH to normal possible CO2 to buffer RBC
Buffer – minimizes changes in pH when an acid/base is Effective buffering range = pKa +/- 1
added to it; consists of a sol’n with weak acid & strong base
Titration curve of bicarbonate buffer system = sigmoidal
pH H+ con’c State Linear midregion (pH = 5.1-7.1) = area where large
amount of acids/bases can be added without much
Acidosis
change in pH
Alkalosis pH of solution is within +/- 1.0 pH units of pKa
PHYSIOLOGY)[DKA)(201632017)]) 107)
)
Volatile acids – refers to carbon diozide which can be
Major System Regulator excreted by lungs
pCO2 Respiratory System
HCO3 Renal Non-volatile/Fixed acid – refers to acid excreted by the
kidneys/ metabolized acid in the body
Difference Hemoglobin QC Plasma Protein
Quantitatively 6x more 6x less Processes involved in Renal Regulation of Acid-Base
> Balance:
Con’c 2x more > 2x less /!Secretion of H+ ions
Histidine residue 3 1 PT DT
> Filtered HCO3- 90% 10%
Occurs Result of Na pump Intercalated cell
Imidazole group of Histidine = only amino acid residue Transporter Na+-H-linked H-ATPase
providing buffer at physiological pH responsible transporter pumps
Facilitated by Carbonic anhydrase
Isohydric change = condition that causes H+
concentration to change as it causes the balance of buffer /!Reabsorption of Filtered HCO3-
system to change at the same time
PT (90%) > DT (10%)
Hydrogen regulation – chemical buffering by ECF & ICF
buffers within a fraction of second HCO3- lost = H+ gain
Regulation Method Rate
Respiratory Alteration of breathing 1-12mins - days
Factors affecting HCO3- reabsorption:
rate of CO2 removal
pH
Renal Excreting an Hours - several
acid/alkaline urine days pCO2 HCO3- reabsorption
Alveolar CO2 H+ pH K+
ventilation ELFV
pH H+ Alveolar H+ pH
ventilation /!Production of HCO3- = since urine cannot excrete free
H+ without urine buffer, thus HCO3- excretion leads to
HCO3- production in kidneys
PHYSIOLOGY)[DKA)(201632017)]) 108)
)
Phosphate = major urinary buffer in its travel from plasma to Renal Net Acid Secretion – represents the amount of
urine; urinary excretion follows phosphate intake (cannot new HCO3- generated by kidneys and added to the
increase response to acid load) body stores
Ammonia – more important quanitatively; major mechanism Net Acid Excretion = T.A. + NH4 – urinary HCO3-
by kidney; increases urinary H+ excretion HCO3- lost = Loss of OH- = Gain of H+
Renal Ammoniagenesis = stimulated by acidosis
Ammonia synthesis = controls urinary acid excretion State NH4+ & Urinary HCO3- excretion
titrable acid excretion
Collecting duct = most acidic region of the kidney; where Acidosis
most ammonia produced migrate
Alkalosis
Process of Ammonium excretion:
Process Site
Possible fates of H+ secreted in nephron
Ammonium formation Proximal tubule % Distribution
Ammonium reabsorption TALH
98% Filtered HCO3-
Ammonium trapping Collecting Tubule
1% Buffered by NH3 to NH4+
1% Buffered by PO4 to form titrable acids
pH H+ secretion
Rest Free H+
pCO2 H+ secretion
Anion Gap – difference between cations (Na) and
K+ Renal Ammonic Anions (Cl- & HCO3-)
Production
Aldosterone/ H+ Secretion Anion Gap = Na – (Cl- + HCO3-)
Mineralocorticoids Anion Gap = Unmeasured Anion – Unmeasured Cation
UA – UC = Na – (Cl- + HCO3-)
NaOH = added to the acid urine until pH turns to plasma (7.4)
Titrable acid = amount of NaOH equal to net H+ added to Normal Anion Gap = 8-12mEq/L
weak buffers in tubular fluid
Normal anion gap acidosis – also termed as
“Hyperchloremic” acidosis
PHYSIOLOGY)[DKA)(201632017)]) 109)
)
Conditions causing Normal Anion Gap Metabolic
Metabolic acidosis Anion gap Acidosis:
Normal Anion Gap Cl- HCO3- Unaltered $! Diarrhea
con’c con’c $! Early renal insufficiency
High Anion Gap HCO3- No change Altered $! Acetaolamide
con’c in Cl- con’c $! Renal Tubular Acidosis
$! Saline
Conditions causing High Anion Gap Metabolic acidosis :
M Methanol Diarrhea
U Uremia HCO3- Cl- = Normal Anion gap
D Diabetic Ketoacidosis
P Paraldehyde Saline
I Ischemia; INH Cl- HCO3- = Normal Anion gap
L Lactic Acidosis
E Ethanol
S Salicylates pH pCO2 Conditons
Metabolic Acidosis
Computing Anion Gap
Respiratory Acidosis
Na+ (140) > Cl- + HCO3- (105 + 24)
Metabolic Alkalosis
Henderson-Hasselbach Equation Respiratory Alklalosis
pH = pKa + log [HCO3-]/ 0.03 x PCO2
PHYSIOLOGY)[DKA)(201632017)]) 110)
)
ARTERIAL BLOOD GAS READING
pH pCO2 HCO3- Conditons
7.35-7.45 N 35-45 N 22-26 N Normal Acid-Base
<7.4 <35 22-26 N Normal/ Compensated Metabolic Acidosis
<7.4 >45 22-26 N Normal/ Compensated Respiratory Acidosis
>7.4 <35 22-26 N Normal/ Compensated Respiratory Alkalosis
>7.4 >45 22-26 N Normal/ Compensated Metabolic Alkalosis
<7.35 35-45 N 22-26 N Uncompensated Metabolic Acidosis
<7.35 <35 <22 Partly Compensated Metabolic Acidosis
<7.35 >45 22-26 N Uncompensated Respiratory Acidosis
<7.35 >45 >26 Partly Compensated Respiratory Acidosis
<7.35 >45 <22 Combined Respiratory & Metabolic Acidosis
PHYSIOLOGY)[DKA)(201632017)]) 111)
)
HEMOSTASIS
Hemostasis – the control of bleeding
Requires: Life Cycle of Platelet
$! Platelets Origin: Bone Marrow ! Pleuripotent
$! Blood vessels Hematopoietic Stem Cell ! Myeloid Stem
$! Clotting factors Cell ! Megakaryocyte ! Platelet
Lifespan: 7-10 days
Structural layers of blood vessels: Sequestration: Spleen (1/3 Total Plts)
1.! Tunica Interna – innermost layer Elimination: Macrophages of Spleen and Liver
a.! Endothelium
b.! Sub-endothelium Platelet Histology
•! Basement membrane Plasma Contains Phospholipids,
•! Connective tissue (collagen) membrane glycoprotein, arachidonic acid
•! Cells (Fibroblasts) Marginal Maintains platelet discoid shape
2.! Tunica Media – middle layer primarily composed of microtubule band
circularly arranged smooth muscle Tubular systems Have 2 types
3.! Tunica Externa – outermost layer containing Granules Has alpha, delta and Lambda
connective tissue primarily for support granules
PHYSIOLOGY)[DKA)(201632017)]) 112)
)
Steps in Platelet Plug Formation:
Tubular system Function a.! Platelet Adhesion
Surface opening Function as release sites 4! Platelet contact w/ collagen tissue
Canalicular of granules content 4! vWF secreted by platelets & endothelial cell
Dense tubular Production sites of 4! Platelet adheres to blood vessel’s collage via:
system Prostaglandin & GPIa Directly
Thromboxane A2 GP1b vWF bridge between collagen & platelet
GPIIb & GPIIIa Bridge bet. collagen, fibrinogen & platelet
Granules are 3 types namely:
Granule Contents b.! Platelet Activation
Alpha ! Platelet-derived factors 4! Platelet is activated once binds w/ collagen
Fibrinogen 4! Releases mediators (ADP, Serotonin)
von Willebrand’s Factor 4! Synthesizes Thromboxane A2
Factors 4, 5, 8 4! Induction of changes in:
Thrombospondin Metabolism Production of more mediators
"-thomboglobulin Shape Change from discoid to spherical cell w/ numerous
Delta ( Calcium cytoplasmic projections
Serotonin Cell Increased glycoprotein expression; rearrangement of
Storage Pool of Nucleotides membrane phospholipid creates ideal site for coagulation
(ADP/ATP) reactions
Lambda . Lysosomal enzymes
Mediator Action
I.! Primary Hemostasis ADP Alters surface configuration of circulating
Vascular spasm – manifests inferent response platelet, promoting aggregation
of vasoconstriction Thromboxane A2 Potentiates platelet adhesion & aggregation
Mechanisms:
a.! Local Myogenic response c.! Platelet Aggregation
b.! Local Hormonal response 2! Mediators induces aggregation
%! Endothelin = induces transient 2! Fibrinogen serves as bridges for platelet aggregation
vasoconstriction 2! Bind to previously activated platelet & positive feedback is
%! Thromboxane A2 triggered
%! Serotonin 2! Triggers platelet contraction stregthening plugs formed
2! Blood vessel contracts to decrease blood flow and pressure
PHYSIOLOGY)[DKA)(201632017)]) 113)
)
Ionized Calcium and plasma protein fibrinogen –
necessary for platelet aggregation
PHYSIOLOGY)[DKA)(201632017)]) 114)
)
Thrombin generated by extrinsic
Factor Name Active Form Pathway pathway recruits intrinsic pathway via:
I Fibrinogen Serine Protease Fibrin Both -! Factor 11
II Prothrombin Serine Protease Both -! Factor 8
III Tissue Factor Serine Protease Cofactor Extrinsic -! Factor 5
IV Calcium Serine Protease Cofactor Both -! Platelet
V Labile factor; Proaccelerin Serine Protease Cofactor Both
VII Stable factor; Proconvertin Serine Protease Extrinsic Positive Feedback established by
VIII Anti-hemophilic factor Serine Protease Cofactor Intrinsic intrinsic pathway::: Cyclic activation of
IX Christmas Factor Serine Protease Intrinsic Thrombin-F11-8-5
X Stuart Prower Factor Serine Protease Both
XI Plasma Thromboplastin Serine Protease Intrinsic Extrinsic Pathway – initiates events
antecedent but the recruited intrinsic pathway is
XII Hageman Factor Serine Protease Intrinsic responsible for the efficient coagulation
XIII Fibrin Stabilizing Factor Transglutaminase Both
Clot Retraction
Prekalikrein Serine Protease Intrinsic
,! Contraction after few minutes a
High Molecular Weight Kininogen Serine Protease Cofactor Intrinsic clot is formed
,! 20-60 minutes
Usual Coagulation Process in Human Body ,! Squeezes out most of the fluid
Clot formation content
Extrinsic (15mins) > Intrinsic (1-6mins) ,! Clot retracts – edges of broken
blood vessel are pulled together
Clot Formation Initiation
Pivotal Role of Thrombin:
Extrinsic = usual > Intrinsic 0! Conversion of Fibrinogen to fibrin
pathway 0! Activations of Factors 3, 5, 11
Thrombin Generation 0! Cleaving of F8 from vWF
Extrinsic < Intrinsic = often recruited 0! Activation of Platelets
by extrinsic
Tissue Repair
/!Stimulate wound healing through secretion of platelet derived growth factor
/!PDGF – mitogenic both to vascular smooth muscles and fibroblast
PHYSIOLOGY)[DKA)(201632017)]) 115)
)
Additional Features of Clotting System Anti-Fibrinolytic System – inhibitors of plasmin
Factors Role •! Alpha-2-antiplasmin – faster inhibitor
Co-factors Accelerate enzymatic reactions involved •! Aplha-2-macroglobulin – slower inhibitor
in coagulation process
! F3-5-8, HMWK, Ca2+ & Phospholipid Anticoagulation system – limits the clot formation at the
Factor 12 Recruited by extrinsic pathway starting site of injury; prevents massive thrombin generation in the
at factor 11 absence of a substantial procoagulant stimulus
! Def. w/ F12, Prekallikrein & HMWK A.! Tissue Factor Pathway Inhibitor (TFPI)
are not associated w/ abnormal %! Endothelial cells – secretes TFPI
hemostasis %! TFPI inhibits thrombin
Calcium Reducing calcium in blood specimens
used for laboratory test can prevent B.! Throbomodulin-Protein C
coagulation %! Steps:
a.! Citrate deionizes calcium •! Thrombin binds to an endothelial cell receptor known
b.! EDTA precipitates Calcium as thrombomodulin
Plasma Ca2+ in humans, never low •! Eliminates thrombin’s clot producing effect
enough to cause clotting abnormalities •! Bound to thrombomodulin activates protein C
•! Activated Protein C (w/ protein S as a co-factor)
Fibrinolytic System – dissolves the clot after it is formed inhibits:
t-PA/u-PA F5A Anti-coagulation
Plasminogen !!!!!!!! Plasmin F8A Anti-coagulation
Plasminogen Activator Inhibitor Pro-fibrinolysis
Steps:
•! Plasminogen activator is activated by several %! Protein C & S – also Vitamin K dependent proteins
pathways produced by the liver
•! Converts plasminogen to plasmin Deficiency in Protein Clot formation/
•! Plasmin dissolves fibrin clot to produce fibrin C&S hypercoagulable state
degradation product (FDP)
•! FDP inhibits fibrin polymerization Half Life
Factor 2-7-9-10 < Protein C & S
Several Types of Plasminogen Activators
Vitamin K deficiency/ Warfarin Treatment
Intrinsically generated Extrinsically generated
F12A Tissue Plasminogen Activator Protein C & S Normal F2-7-9-10
Kallikrein Urokinase
PHYSIOLOGY)[DKA)(201632017)]) 116)
)
Anti-thrombin III- Heparin Endothelial cells play an important role in stages of
•! Heparin is secreted by endothelial cells hemostasis:
•! Binds to anti-thrombin III !! Pro-coagulation
•! Anti-Thrombin III-Heparin Complex inactivates •! Induces vascular spasm
thrombin & F9-10-12 •! Induces platelet
-! Prevents spread of clotting mechanism away from site of !! Anti-coagulation/ Fibrinolytic Effects
injury •! Binds, activates, cleaves thrombin
-! Most important physiologic anti-coagulant •! Activates Protein C ! Thrombomodulin expression
-! 90% of antithrombin activity is derived from AT-III •! Activates Antithrombin III ! Heparin secretion
•! Activates plasminogen ! tPA secretion
Role of platelet
A.! Maintenance of Vascular Integrity Test Overview Reflects
+! Adhere to the vessel wall and releases Platelet Tourniquet test Point between the systolic Vascular
Derived Growth Factor (PDGF) and diastolic blood fragility
+! PDGF – nurtures the endothelial cells which helps pressure for 5mins
maintain the normal vascular integrity :: (+) 10-20 more petechiae
per square inch
B.! Initial arrest of bleeding by platelet plug formation Bleeding time Standard-sized incision Platelet
.! Platelet adhesion (10mm long & 1mm deep) count &
.! Release reaction Time from skin incision till function
.! Aggregation bleeding cessation
Prothrombin Tissue factor is added Extrinsic
C.! Pro-coagulation time (PT) plasma specimen pathway
*! Stabilizes hemostatic plug by contributing to fibrin
Activated Activator added to plasma Intrinsic
formation
Partial Time from phospholipid till pathway
*! Displays specific plasma membrane receptors which
Thromboplastin clot formation is known as
bind to the clotting factors
Time (aPTT) prothrombin time
*! Displays platelet factor also functions as a cofactor in
clot formation cascade
PHYSIOLOGY)[DKA)(201632017)]) 117)
)
Liver – production site all clotting factors Hypercoagulable State/ Thrombophilia (Thrombosis)
Vitamin K – essential for production of Factors 2-7-9-10, = disorder of hemostasis wherein there is increased
Protein C & S tendency for clot formation
PHYSIOLOGY)[DKA)(201632017)]) 118)
)
Hemostasis & Its Major Deficiency in Main Mechanism Example
Components Component, Defect
favors Bone Marrow Failure Aplastic Anemia
Fibrinolytic System
1! Plasminogen Reduced Bone Marrow Infiltration Metastatic Carcinoma
1! Plasminogen Activators Platelet
1! Plasmin Production Impaired Platelet Chemotherapy/
Anti-Coagulation System Thrombophilia Production Radiotherapy
1! Tissue Factor Pathway (Thrombosis) Ineffective Megakaryocyte Megalobastic anemia
Inhibitor (TFPI) Decreased Immune mediated Drug-induced
1! Thrombomodulin Platelet destruction
1! Anti-Thrombin III Survival Infections HIV
1! Heparin Non-immune Splenomegaly
Coagulation System Defective Defective Adhesion Bernard-Soulier Syndrome
1! Platelet Platelet Defective Aggregation Aspirin therapy
1! Clotting Factors Abnormal Function Defective Secretion Storage Pool Disease
Anti-fibrinolytic System Bleeding Low production Von Willebrand’s Disease;
1! !-2-antiplasmin Reduced Hemophilia A; Liver
1! !-2-macroglobulin Clotting Disease
Factors Increased Consumption Disseminated Intravascular
Abnormal Bleeding Coagulopathy (DIC)
Fibrinolytic > Antifibrinolytic Mechanisms of Drugs for Treatment/Prevention of Thrombosis
Anticoagulation > Coagulation
"! Thrombolytics
#! Substitute for endogenous plasminogen activator
Thrombophilia #! Stimulate plasminogen activator
Coagulation "! Anti-coagulants
> Anticoagulation #! Block the pathway production of clotting factors
Antifibrinolytic > Fibrinolytic #! Stimulate/simulate the natural anitcoagulation system
"! Antiplatelet
#! Block platelet pathway, receptor, signal transduction &
membrane glycoprotiens
PHYSIOLOGY)[DKA)(201632017)]) 119)
)
GENERALITIES OF THE IMMUNE SYSTEM
Immunology – study of the immune system and its
response to microbial pathogens & damaged tissues Innate Type of Adaptive
Immunity
Immune system – collection of cells, tissues, and Microbes & damaged React Against infectious &
molecules that mediate resistance to infection host cell only non-infectious
Classes of microbes Recognize Specific antigen
Immune response – coordinated reaction of the Adaptive Enhances Innate
immune system cells to infectious microbes Powerful defense before Function Must be stimulated by
adaptive microbes; uses cells of
Immunity – state of resistance to disease innate immunity
Epithelial barrier; Barrier Humoral immunity –
Antigen (Ag) – any molecule that can bind to -! NK cells B cells
components of specific immune system -! Phagocytes Cell-mediated
-! Complement system immunity – T cells
Antibody (Ab) – family of defensive proteins the body
makes after antigen stimulation Does not react against Reaction Does not react against
host self-antigens
Immunoglobulins – antibodies when secreted by
plasma cells Rate of microbes elimination
Innate Immunity > Adaptive Immunity
Anamnestic response – pertains to immunologic
memory Specialized & effective defense
Innate Immunity < Adaptive Immunity
Cytokines – protein substances secreted by cells that Finer specificity
are affecting the behavior of nearby cells Innate Immunity Adaptive Immunity
<
Role of Immune System
)! Defense against infections Active Immunity Passive
)! Defense against tumor Introduced by Description Transfer Ab/ lymphocyte
)! Recognizes and responds to tissue grafts & newly infection/ vaccination Limited lifetime of
introduced proteins transffered Ab
)! Can injure cells & induce pathologic inflammation Resistant; long-lived Rapidly confer immunity
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Type of Adaptive Humoral Cell-mediated Pathogen recognition
Immunity receptors – receptors of
Microbe Extracellular Phagocytosed Intracellular pathogen-associated
Responding lymphocyte B-cells (Antibodies) Helper-T-cells Cytotoxic-T-cell molecular pattern
Effector Secretes Antibodies; Activates Kills infected
Block infection & macrophages to cells & eliminate Macrophages – has
eliminate extracellular kill microbes reservoir receptors that are
Recognizes Molecules including Microbial protein antigens nonclonally distributed;
proteins, nucleic acid, mediated by recpetors
lipids & carbohydrates encoded in the germline
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Phases of Adaptive Immunity: Lymphocytes
.! Antigen Recognition 7! Only cells that produce specific receptors for antigens
$! Naïve antigen-specific lymphocytes locate & 7! Key mediators of adaptive immunity
recognize microbial antigens 7! Distinguished by surface proteins “CD”
.! Lymphocyte Activation CD (Cluster of Differentiaton) = delineate surface
$! Signal 1 = Ag-binding to Ag-receptors proteins that define a particular cell type/ stage of cell
-! Initiate all immune responses differentiation & recognize antigens
$! Signal 2 = other signals
-! Requirement for microbe-dependent second Cell types B cell T cell NK cell
signals ensures that lymphocytes respond to Mediators of Humoral Cell-mediated Innate
infectious agents and not to non-infectious Synthesis Bone Bone marrow Bone
substances Maturation marrow Thymus Marrow
$! Clonal expansion = differentiation from naïve
lymphocytes to effector lymphocytes Function Capable of Recognizes peptide Kills
producing fragments of protein infected
Cell type Differentiates into
Ab; antigens host cells
B cell Secrete antibodies
T cell Kills infected host cells
T helper cell types TH1 TH2
.! Antigen Elimination
Secretes IL-2; #-IF IL-4; IL-5
Naïve cell CD 4+ CD 8+ Immunity Cellular Humoral
Cell type T-helper cell T-cytotoxic cell
MHC MHC II MHC I Major Histocompatibility Complex – specialized peptide
display molecules
Cells found All nucleated cells B cells & T cell
Function Promote Ab Kill cells
Antigen-Presenting Cells (APCs) – specialized cells displaying
production/ harboring
antigens
macrophage killing microbes the
of ingested microbes cytoplasm
Generative Lymphoid organs – site in which lymphocytes
mature
.! Contraction
Apoptosis – process of cell death; majority of
Cells Mechanism
effector lymphocytes die
.! Memory T cell Site of infection ! eliminates microbes
Memory lymphocyte – survive for years after the B cell Stays in organ ! secretes Ab ! eliminates microbes
infection & able to respond rapidly to repeat
encounter w/ microbe
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Maturation of Lymphocytes Antigen-Presenting Cells
'! Synthesis: Bone Marrow Type Functions
'! Maturation: Bone Marrow/Thymus Dendritic "! Initiation of T cell response;
'! Mature lymphocytes enter circulation and cells "! dendrite-like processes;
peripheral lymphoid organs "! capture protein antigens of microbes
'! Naïve Lymphocytes express receptors for Ag "! Antigen-bearing Dendritic cells – display
! Reside in/ circulate between peripheral portions of Ag for recognition by T lymphocytes
lymphoid organ "! Respond to microbes by producing surface &
! survives days-months waiting to respond to secreted proteins that activate naïve T cells
Ag "! Provide Second signals for T cell proliferation &
'! Differentiation into effector cell & memory differentiation
cells (initiated by antigen recognition) "! Called “Professional APCs”
Effector cells Function Macrophage "! Initiation & effector phase of cell-mediated
B cell Secretes antibodies immunity;
T helper Secretes cytokines to "! serves as professional APC;
activate B cells & "! capable of displaying protein antigens to T cells
macrophage Follicular "! Resides in germinal centers of lymphoid follicles;
T cytotoxic Kills infected host cells Dendritic "! Display Ags that stimulate differentiation of B cell;
cells "! Does not present Ags to T cells
'! Effectors lymphocytes are short-lived & die
as Ag is eliminated but some may migrate Effector Cells – cells that eliminate microbes
to special anatomic site & live for longer Type Subtypes
period T cells Helper T cell & Cytotoxic T cell
'! Memory cells – generated from progeny of Macrophage Cells of Mononuclear Phagocyte System
antigen-stimulated lymphocytes; survive for Granulocytes Neutrophils & Eosinophils
long periods; do not perform effector
function unless stimulated by antigen Tissues of the Immune System
'! Stimulation of memory cells – gives rise Lymphoid Organ Function
to secondary immune response Generative/ Primary/ Site where T & B cells mature & become
Antibody-producing plasma cells – develop in Central competent to respond to Ags
response to microbes in the peripheral Peripheral/ Secondary Where Adaptive Immune Response to
lymphoid organs microbes are initiated
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INNATE IMMUNITY
Receptors used by innate immunity to react Most important transcirption factors activated by TLR signals:
againts microbes Transcription Factor Function
#! Phagocytes Nuclear factor kB Promotes expression of various cytokines &
#! Dendritic cells (NF-kB) endothelial adhesion molecules
#! Lymphocytes Interferon response Stimulates production of type I interferons,
#! Epithelial & endothelial cells factor-3 (IRF-3) cytokines & block viral replication
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0! Phagocytes 0! Dendritic Cells
6! Colony-stimulating factors – produced by many 6! Respond to microbes by producing cytokines that
cell types in response to infections; act on marro to recuit & initiate adaptive immune system
stimulate proliferation & maturation of neutrophil 6! Important bridge between innate & adaptive
precursors; stimulated by cytokines immunity
Type Neutrophils Monocytes
Ingest microbes Blood & tissues Blood & tissues 0! Natural Killer Cells
Survival rate Shorter Longer 6! Recognizes infected & stressed cells, respond by
Response time Faster Slower killing the cells & secreting the macrophage-
activating cytokine (IFN-#)
Recruitment to site of Infection (SICK): 6! Express various receptors for molecules on host
)! Selectin-mediated rolling cells
)! Integrin-mediated firm adhesion 6! Express inhibitory receptors that recognizes normal
)! Chemokine-mediated motility host cells & inhibit activation of NK cells
6! Cytokines – enhances the abiltiy of NK to protect
Transcription Factors against infections
Factor Function 6! IL-12 – one of the NK-activating cytokines
Nuclear factor Promotes expression of various 6! Expresses receptors for the FC portion of IgG
kB (NF-kB) cytokines & endothelial adhesion antibodies
molecules; stimulates production of 6! Responses of activated NK cells:
cytokines, enzymes & other proteins -! Discharge of protein towards the infected cells to
Interferon-# A powerful activator of the microbicidal induce apoptotic death
functions of phagocytes -! Synthesize and secrete IFN-# to activate
Opsonization – process of coating microbes for efficient macrophage and become more effective at killing
recognition by phagocytes phagocytosed microbes
Phagolysosomes & lysosomes produces the following: Complement System = collection of circulating &
Enzymes activated Function membrane-associated proteins important in defense
Phagocyte oxidase Converts O2 to superoxide anion againts microbes
& free radical
Nitric Oxide Catalyzes arginine to NO Functions of Complement in host defense:
Synthase 2! Elimination of mcirobes
Lysosomal Protease Break down microbial protein 2! Stimuli for the development of humoral response
Inflammation – protective host response to infections 2! Help dispose waste products after apoptosis
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Pathway Alternative Pathway Classical Pathway Lecithin
Other name By-pass pathway/ Properdin pathway Specific pathway Mannan-Binding Lectin
Activating Substance LPS (bacterial capsule); Cobra venom Immune complex Mannose group on
factor; IgA aggregates; Microorganisms (Ag-Ab complexes) microbial cell
Immunity Innate Humoral (Adaptive) Innate
Immunoglobulin involved IgA IgM; IgG
Important electrolyte Mg2+ Ca2+
Recognition Unit C3, Factor B, Factor D, Factor P C1q, C1r, C1s Opsonin, MBP, MASP-1
C3 Convertase C3bBb C4b2a
C5 Convertase C3bBb3bP C4b2a3b
Membrane Attack Complex C5b6789
End Result Cell Lysis
Action Description
Paracrine Act on adjacent cells
Autocrine Act on cells that produce them
Endocrine Active away from site of secretion
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C-reactive protein (CRP) – binds to phosphatidylcholine
Cytokines Function on microbes & coats the microbes for phagocytosis
TNF, IL-1 & principal cytokines involved in recruiting
Chemokines blood neutrophils & monocytes to sites of Acute phase response – typer of protective response of
infection CRP
IL-12 activate NK cells; produced in response to
LPS & many phagocytosed microbes Infection CRP Acute phase response
IFN-# Produced by T cells; considered a cytokine
in both innate & adaptive
Innate Immunity stimulating Adaptive Immunity
Type I Inhibit viral replication & prevent spread )! Innate response generate molecules that function as
Interferon of the infecton to uninfected second signals
)! Activates T cells & B cells
TNF con’c Promotes thrombosis Blood )! Microbes/ IFN-# produced by NK cells stimulate
pressure dendritic cells & macrophage
)! Production of 2 types of second signals
Type of 2nd signal First Second
Microbe Response Cell responsible Dendritic cell & macrophage
Extracellular Combated by phagocytes, Action Expresses Secrete cytokine
bacteria/ fungi complement system & acute phase surface molecule IL-12
proteins (costimulators)
Intracellular Mediated by phagocytes & NK cells Effect of T cell Binds to T cell Stimulates &
bacteria/ viruses receptors differentiate T
Blood-borne Complement system & Antibodies cells into effectors
microbes Result Ag recognition to Cell-mediated
activate T cell immunity
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ADAPTIVE HUMORAL IMMUNITY
Adaptive immunity – recruited when Type of Humoral Cell-mediated
innate immune system fails to Adaptive
control/eliminate pathogen & antigen- Immunity
presenting cell Microbe Extracellular Phagocytosed Intracellular
Responding B-cells (Antibodies) Helper-T-cells Cytotoxic-T-cell
Humoral Immune Response lymphocyte
•! Division of adaptive immune response Effector Secretes Antibodies; Activates Kills infected
responsible for the protection of Block infection & macrophages cells &
extracellular spaces through production eliminate to kill eliminate
of antibodies extracellular microbes reservoir
Recognizes Molecules including Microbial protein antigens
Phases of Adaptive Immune Response proteins, nucleic
"! Recognition of Antigen acid, lipids &
"! Activation of Lymphocytes carbohydrates
"! Effector Phase of Antigen Elimination
"! Decline/Return to Homeostasis
"! Maintenance of Memory Chain Light (L) Heavy (H)
Molecular weight 23 kDa 53-75 kDa
I.! Antigen Recognition Amino acid 220 (214-220) 446 (440-450)
Antigen Receptors – found on surface of residues
lymphocytes & responsible for antigen Disulfide bond L chain to H chain Between 2 H chains
recognition Types/Classes /,. #,!,µ,(,'
Immunoglobulins/ B-cell Receptors Variable 1 1
)! Glycoproteins on surface of B cells Constant 1 3 or more
)! Membrane-bound antibodies
)! Can recognize antigen in native Constant and variable sequence regions
conformation Terminal Carboxy (C) Amino (N)
Epitopes/ Antigen Determinant – part of Region Constant Variable
antigen recognized by antibodies L-chain ° °
¢)
)(CL) ¢)
)(VL)
H-chain ï °
Domains – compact repeating segments of £)
(CH1, CH2, CH3) £)
(VH)
folded immunoglobulin molecule
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Basic immunoglobulin structure Cross-linking – antibodies bound to an Ag may still bind to
-! Composed of 4 polypeptide chains structurally similar antigen
-! 2 identical light chains (L)
-! 2 identical heavy chains (H) Affinity – strenght in which one antigen-binding surface of an
-! held together as tetramer (LH)2 by disulfide bonds antibody binds to one epitope
-! Y-shaped configuration Avidity – the summation of strength of bindings
VH & VL portion – site of Immunoglobulin where Ag Affinity maturation – low affinity of antibody increases as
binds repeated exposure
VH & VL = similar sequence Exposure Affinity
CH = consists of equal thirds CH1, CH2, CH3
CL = closely resembles 3 domains of constant region of
heavy chain Affinity
Primary exposure < Secondary exposure
Intra-chain disulfide bond – same position in each
Antigen-binding surface
domain of both L-H chains
Each domain = 110 amino acid residues Avidity > Affinity
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IMMUNOGLOBULINS
Isotypes IgM IgG IgA IgE IgD
Heavy chain µ # ! ' (
Pentamer Monomer Dimer Monomer Monomer
# of Ag binding site 10 2 4 2 2
Molecular weight 900,000 100,000 385,000 200,000 180,000
% Total Ab in serum 10% 75%-80% 13% 0.002% <1%
Normal Value 20-140 640-1430 70-300 0.01-0.04 <8.0
Serum half life 5 days 23 days 6 days 2 days
Crosses placenta Yes
Fixes complement C1q C1q Mast cells &
Fc binds to Phagocyte basophils
Function Main antibody of Main blood Ab of Secreted in mucus, Ab in allergy Component
primary response secondary response; colostrum, tears, saliva and parasitic of surface
Excellent neutralizes toxins, Prevents attachment of infection membrane
complement opsonization bacteria & virus Ag-sensitive of B cells
Oldest; 1st Ab Longest half-life Main in secretions means of Synthesized
development Smallest; most prevalent Activation of B cells eliminating by Ag-
5L2H2 units joined Activation of classical occurs in MALT intestinal sensitive
by J chain & complement pathway parasites lymphocyte
Types disulfide bonds; IgG1 & IgG3 – activate sIgA: IgA1 & IgA2
Natural complement
isohemagglutinins IgG2 & IgG4 –
of Blood ABO predominant w/ CHO Ag
Conditions with Leukemia, Multiple Leukemia, Nephrotic Leukemia, Nephrotic Ataxia-
LOW value myeloma, inherited syndrome, syndrome, Ataxia- Telangectasia
immune diseases Macroglobulinemia Telangectasia
Conditions with Macroglobulinemia, Multiple myeloma, Multiple myeloma, RA, MM, asthma, Multiple
HIGH value Early Hepatitis, IM, Multiple sclerosis, SLE, Liver cirrhosis, parasitic myeloma
RA, Nephrotic Chronic hepatitis, AIDS, Chronic Hepatitis infection,
syndrome, autoimmune disease atopic
parasitic infection dermatitis,
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Serum Half-life T cell-receptors
)! Transmembrane glycoproteins on the surface of T cells
IgG > IgA > IgM > IgE > IgD
)! Do not recognize & bind antigens directly but recognize
Abundance in serum epitopes bound to MHC complex
IgG IgA IgM IgD IgE )! Have only 1 binding site
> > > > )! Have no secreted forms
Binding sites )! Have 2 types
IgM IgA IgG IgD IgE 7! TCR 1/ Gamma-delta receptor (#()
> > = = 7! TCR 2/ Alpha-beta receptor (!") – make up
Molecular Weight majority of TCR & TCR1’s function
IgM > IgA > IgE > IgD > IgG
Major Histocompatibility Complex (MHC)
Size of bound peptide 8! Genetic locus involved in rejection of foreign & non-
self Ag
MHC I < MHC II
8! MHC Antigens - encode for cell surface proteins
Cell distirbution 8! Human Leukocyte Antigens (HLA) system – in
MHC I MHC II humans
> 8! Highly polymorphic in nature
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Dendritic cells – captures antigens entering the body and Antigen Presentation of dendritic cells
concentrate in peripheral lymphoid organs )! Antigen capture by dendritic cells
Population Type Classical Plasmacytoid )! Activation of dendritic cells
Distribution Tissues & Lymphoid Tissues & Blood )! Migration of DC
Produces TNF, IL-6, IL-12 & Type 1 )! Maturation of migrating DC
IL-23 Interferons )! Mature DC presenting antigen to naïve T cell
T cell response For most antigens Against viruses )! Antigen presentation
Chemoreactant Chemokine Receptor 7 (CCR7) – has CLIP = Classs II invariant chain peptide; makes MHC class
affinity to lymphatic epithelium & stromal cells chemokine II inaccessible
Cross-presentation – occurs when virally-infected cells
Tapasin = bridging protein that links the newly ingested by dendritic cell to CD8+ T cell undergo processing
synthesized MHC Class I molecule w/ TAP to capture & transport of the antigen to the cytosol; Ag eventually
actively-pumped peptide enters ER, binds to MHC class I & presented to T cells
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)! Differentiation of T Lymphocytes to Effector Cells
Interleukin-2 (IL-2) Differentiation of Naïve T cells
5! Binds to and acts on the same T cell T cells Stimulate Ag Action
5! First cytokine to be secreted by Ag- Phagocyte- IL-12 Potent activator of macrophage
stimulated T cell TH1 mediated IFN-#
5! Stimulate survival & proliferation of T killing of
cells microbes
Phagocyte- IL-4, Stimulates production of IgE &
Clonal Expansion – T & B cells begin to independent; IL-5 activates eosinophils
proliferate within 1-2 days eosinophil IL-4, Promote expulsion of parasites
mediated IL-13 & inhibit entry of microbes by
Postulates of Clonal Selection Hypothesis TH2 immunity stimulating mucus secretion
3! Lymphocytes bear single type of IL-4, Inhibits microbicidal activities
receptor w/ unique specificity IL-13, of macrophage suppressing TH1
3! Foreign molecule & lymphocyte IL-10 cell-mediated immunity
receptor = capable of binding that Macrophage Synthesis of extracellular
molecule w/ high affinity leading to activation matrix proteins for tissue repair
lymphocyte activation TH17 IL-1, IL-6, IL-23 & TGF-"
3! Differentiated effector cells – will bear IL-17, Principal inflammatory
receptors of identical specificity to those IL-22 mediators; help protect againts
of parental cell extracellular bacteria & fungi
3! Lymphocytes w/ receptors specific for Regulatory TBF-" Suppresses T cell response &
ubiquitous self-molecules are deleted at T help prevent autoimmune
early stage of lymphoid development response
TFH (Follicular T helper IL-6 Provides help to B cells in
III.! Differentiation of Lymphocytes
cells) lymphoid follicles for high-
)! Differentiation of B Cells to Effector Cells
affinity Ab production
B cell !Plasma cell ! Secrete antibodies
B cell presents Ag to T helper cells ! Helper T cells is activated;
IgM & IgD - 2 membrane-bound antibodies
expresses CD40L, secretes cytokines ! B cells activated by CD40
expressed by naïve b cells
engagement ! B cell proliferation & differentiation
B cell expresses Type II complement receptor
! binds to C3d ! production of 2nd signal for
B lymphocytes
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Type T cell dependent T cell independent IV.! Decline of Immune Response – once
B cell activation Protein antigens Polysaccharides, lipids & immune response is over, system return
elicited by non-protein molecule to homeostasis
T cell Mediated Not mediated ,! IgG binds to Ag in tissues & blood
Switching Isotype switching Minimal class switching ,! Immune complex formation
Affinity maturation Present Little to none ,! B cell may bind to antigen portion &
Memory B cell Present Limited Fc portion of Ig
Production ,! Recognized by FcyRII receptors
,! Receptors deliver inhibitory signals
B cell Efector Functions that will shut off antigen receptor-
induced signals (Antibody feedback)
Opsonization Antibodies coat microbes & promote
phagocyte ingestion
V.! Memory Cells – fraction of progeny of
Neutralization Prevents microbes from gaining entry to cells
the activated T & B cells do not have
Antibody-dependent Mediated w/ monocyte-macrophages, natural
effector function & becomes memory
cellular cytotoxicity killer cells & neutrophils; recognize & bind to
cells circulating the blood & reside in
antibody-coated cells
tissues
IgE & mast cell- Elicited during helminthic infections & allergic
mediated reactios diseases
Complement Via classical pathway; IgM & IgG
activation
Protection of Passive transfer of IgG in placenta & IgA in
neonate breast milk
Immediate Hypersensitivity
Hypersensitivity – injurious/pathologic immune '! Production of IgE Ab due to strong response elicited
reactions due to by allergens
+! Uncontrolled response to foreign antigen leading to '! Production of IL-4 & IL-13
tissue injury '! IgE binds to high-affinity Fc receptors
+! Immune response directed to self-antigen '! Cross-linking of the bound IgE by antigens leading to
(1)!Rapid release of granule contents of mast cells
Mast cell mediators (2)!Synthesis & secretion of lipid mediators
8! Include vasoacitve amines (histamines) (3)!Synthesis & secretion of cytokines
8! Proteases & Cytokines '! Release of mast cell mediators
8! Arachidonic acid metabolites
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Late phase response – may follow immediate hypersensitivity in the ensuing Antivenin – for snake bites
hours/days due to eosinophils that migrate in inflamed areas
Uses of Monoclonal Antibodies
Stimulatory Hypersensitivity – mediated by non-complement fixing antibodies; !! Graft rejections suppression
antibodies that react w/ cell surface component or receptor and switches on cell !! Lymphomas & solid tumors
chemotherapeutic regimens
Passive Immunization – administration of immunoglobulin prepared from !! Direct anti-infective agents
individuals w/ known high levels of antibodies specific to infectious agents !! Interfere w/ activity of pro-
inflammatory mediators
Intravenous Immune Globulin Replacement – replacement in some individuals such as TNF-!
who innately do not have antibodies/ have low levels of antibodies
Hypersensitivity Types
Type Type I Type II Type III Type IV
Other name Immediate Antibody-mediated Immune Delayed Type
cytotoxic Complex
Immune IgE IgG/IgM IgG/IgM TH1 cells TH2 cells CTL
reactant
Antigen Soluble Cell-/matrix- Cell- Soluble Soluble Soluble antigen Cell-associated
antigen associated surface antigen antigen antigen
antigen receptor
Effector Mast-cell Complement, Antibody Complement, Macrophage IgE production, Cytotoxicity
Mechanism activation FcR’ cells, alters phagocytes activation eosinophils
(phagocytes, signalling activation,
NK cells) mastocytosis
Example of Allergic Some drug Chronic Serum Allergic Chronic Graft rejection,
reactions rhinitis, allergies utricaria sickness, contact asthma, poison ivy
asthma, arthus dermatitis, chronic allergic contact
systemic reaction tuberculin rhinitis dermatitis
anaphylaxis reaction
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ADAPTIVE CELL-MEDIATED IMMUNITY
Cell-mediated Immunity – division of adaptive immunity which T-cell Receptor Complex
is responsible for the protection of the body against infections #! comprised to T cell-receptor non-covalently
due to intracellular microogranisms linked w/ CD3 protein & Zeta proteins
#! Responsible for antigen recognition but signal
Phases of Adaptive Immune Response transduction after Ag recognition is facilitated
"! Recognition of Antigen to initiate T cell activation
"! Activation of Lymphocytes
"! Effector Phase of Antigen Elimination Co-receptors
"! Decline/Return to Homeostasis '! Found on T cell surfaces
"! Maintenance of Memory '! Recognize the MHC molecules
'! Serves as signal transduction along w/ CD3 &
I.! Antigen Recognition Zeta proteins to help T cell activation
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II.! Lymphocyte Activation
Lymphocyte Activation – takes place when Accessory Molecules involved in T cell activation
antigen recognition (1st signal) is accompanied by Accessory Function Ligand name Expression
co-stimulation (2nd signal) Molecule
CD3 Signal None
Ag-recognition ! Co-stimulatin ! Cytokines released Transduction
(TCR complex)
CD28 – receptor of T cells Zeta Signal None
Microbial encounter Protein expression Protein & Transduction
(TCR complex)
CD4 Signal Class II MHC APC
B7-1 (CD80)B7-2 (CD86) – expressed by Antigen
Transduction
Presentign Cells
CD8 Signal Class I MHC APC; CTL
B7 costimulators & cytokines – enhances T cell Transduction target cell
differentiation; specially when CD40 ligand CD28 Signal B7-1; B7-2 APC
(CD40L/CD154) binds w/ the CD40 on APC Transduction
(costimulator)
CTLA-4 – inhibitory receptor; recognizes B7-1 & B7-2 CTLA-4 Signal B7-1; B7-2 APC
PD-1 – inhibitory receptor; expressed by activated T Transduction
cell; recognizes other ligands in various cells; inhibits (inhibitor)
responses to some chronic viral infections PD-1 Signal B7-1; B7-2 APC
Transduction
Cytokines – large group of proteins that function as (inhibitor)
mediators of immunity & inflammation; produced by LFA-1 Adhesion CAM-1 APC;
dendritic cells & macrophages in innate response Endothelium
VLA-4 Adhesion VCAM-1 Endothelium
Interleukin-2 (IL-2)
7! Binds & acts on same T cell
7! Increase the expression of IL-2 receptors Amount of Interleukins 2 secreted
7! 1st cytokine produced by activated CD4 T cells CD 4+ T cell CD 8+ T cell
7! small amount secreted by CD8 T cells >
7! function mainly to enhance survival &
proliferation of T cells
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Biologic actions of selected T cell cytokines Types TH1 TH2 TH17
Cytokine Principal Action Cellular Source Secretes IL-2; #-IF IL-4; IL-5 IL-17; IL-22; IL-
IL-2 Survival, proliferation & CD4+ & CD8+ T 6; IL-1; IL-23
differentiation of effector cells
& regulatory T cell Cells Macrophage; Mast cells Macrophage;
IL-4 B cells switching to IgE CD4+ T cells; responsible NK cell Dendritic cell
mast cells Activated Bacterial & Helminthic Inflammation
IL-5 Activation of Eosinophils CD4+ T cells; during viral infection
mast cells infections
IFN-# Activation of Macrophage CD4+ & CD8+ T Immunity Cellular Humoral
cells; NK cells Function Stimulate Activated Host defense
TGF- " Inhibition of T cell CD4+ regulatory T phagocyte- T cells againts some
activation; differentiation cells; other cell mediated themselves bacteria, fungi;
of regulatory T cell types ingestion & inflammatory
killing of disorders
General Properties of Cytokines microbes
Property Mechanism
Produced TCR signal & costimulation III.! Clonal Expansion & Differentiation of T helper Cells
transiently in induce cytokine gene -! specialization of adaptive response; “cross-regulation”
response to antigen transcription where differentiation is directed toward one subset
Act on autocrine/ T cell activation induces depending upon the type of infection & inhibition of
paracrine expression of both cytokines & other cell populations
high affinity receptors for
cytokines Naïve CD4+ T cell ! Activation ! TH1 cell/TH2 cell/ TH17
Pleiotrophism Many different cell types may
express receptors for a particular IL-4 & IL-13 – promoes parasite expulsion from mucosal
cytokine organs & inhibit entry of microbes in TH2 cells
Redundancy Many cytokines use same
conserved signaling pathway IV.! Memory T cells – expanded pool of antigen-specific
lymphocytes that develop from progeny of TH
lymphocytes & CTLs
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V.! Decline of Immune Response – effector cells die by Immune Tolerance – lack of response to antigens upon
apoptosis after elimination of microbes, returning to exposure of lymphocytes to these antigens
basal resting state/ homeostasis a.! Immunogenic response – activation, proliferation &
differentiation of lymphocytes into effector cells
CD4+ Cells Activates Effector Function b.! Tolerogenic response – lymphocytes are either
Cell-mediated Macrophage Macrophage activation & killed/ inactivated
immunity killing of phagocytosed c.! Immunologic ignorance – antigen specific
microbes lymphocytes will not produce any reactions
Humoral Antigen- Antibody secretion;
immunity specific B neutralization & Tolerance Mechanisms
Lymphocyte elimination of antigen Central T cell Cell death (negative selection) &
generation of regulatory T cells
CD8+ T cell effector function Peripheral T cell Inactivation of T cells (anergy)/ death
)! Engagment of TCR by peptide (activation induced cell death)/
)! MHC complex caused release of perforin & granzymes suppression by regulatory T cells
complexed w/ serglycin Central B cell Changes in receptor
)! Granzyme – delivered into cytosol of infected cell & specificity(receptor editing)/ killing
targets BID & pro-caspase 3 (negative selection)
)! Truncated BID (tBID) disrupt mitochodrial membrane Peripheral B cell Inactivation of T cells (anergy)
)! Activated caspase 3 cleaves ICAD releasing caspase-
activated DNAse (CAD) Autoimmunity – inappropriate immune attack againts
)! Release of cytochrome c into cytosol activates apoptosis body’s own proteins or antigens; mediated by
& CAD induces DNA fragmentation autoantibodies & self-reactive T cells; characterized by
breakdown of immune tolerance
Receptors B cell receptor T cell receptor Disease Attacked
Surface B cell T cell Multiple sclerosis Myelin sheath
Binding site Depends on Ig (2-10) 1 Myasthenia gravis Cholinergic receptors on skeletal
Recognize Ag Can Cannot muscles
Recognizes Antigen Peptides bound Rheumatoid arthritis Joints & synovial membranes
to MHC Type I DM Insulin-producing cells of
Secreted forms Yes None pancreas
SLE Various tissues & organs like
Molecular Mimicry – some infections produce peptide skin, joints & kidneys
antigens that are similar to & cross react w/ self-antigen
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Adaptive Humoral Immunity Cell medaited Immunity Protozoal evasion of immune
Immunity Type response
Antigen B cell receptor T cell receptor Strategy Example
Recognition Escape into Trypanosoma
Lymphocyte T cell dependent (proteins); T cell Clonal expansion of T cell via cytoplasm cruzi
Activation independent (polysaccharides, CD40L ! costimulation following
lipids, non-protein molecules) phagocytosis
Antigen Opsonization, Neutralization, Macrophage activation; Prevention Leishmania
Elimination Antibody-dependent cellular release of granulozymes and of spp.
toxicity, IgE & Mast cell mediated secretions complement
action, complement activation activation
Return to Apoptosis of effector cells Apoptosis of effector cells Gene Trypanosoma
Homeostasis switching of spp.
Memory Progeny of T cell & B cell become Antigen-specific lymphocytes antigenic
memory cells (progeny of TH lymphocytes variation
& CTLs) Immuno- Trypanosoma
suppression spp.
Host Response to Pathogens Viral response to evade immunity
Bacterial strategies to avoid Immunity Strategy Example
Strategy Example Antigeni variation Influenza virus
Encapsulated organisms Streptococcus pneumoniae, Polymorphism Adenovirus; Rhinovirus
inhibiting phagocytosis Haemophilus influenzae Latency Herpes virus Family
Toxin-mediated killing of Staphylococcus spp. Inhibition of Ag presentation Herpes virus Family
phagocytes Inhibition of proteasomal EBV, CMV
Neutralization of Staphylococcus spp. activity
opsonizing IgG Block of TAP transport HSV
Survival within Mycobacterium tuberculosis Removal of MHC Class I CMV
phagocytes Mycobacterium leprae Infection of lymphocytes Cytomegalovirus
Inhibition of Staphylococcus spp. Prevention of complement Herpes Simplex virus
complement activation Streptococcus spp. activation
Polymorphism Streptococcus pneumoniae, Block cytokine activation of Pox virus
Salmonella typhi effector cells
PHYSIOLOGY)[DKA)(201632017)]) 140)
)
Host Response to Pathogens
Organism Bacterial Protozoal Viral
Immunity Extracellular Intracellular
Humoral Complement activation, Antibody Complement & antibody Interferon production of infected cell;
lysozymes attack production & during extracellular Antibodies in plasma block entry of
polysaccharides; blockage of stage of infection virus, activation of complement &
antibodies block entry, entry recruiment of NK cells
neutralizes toxins
Cell- Phagocytosed bacteria Granuloma Phagocytosis NK cells: cytotoxic & participates in
mediated undergo processing & formation; ADCC
Helper T the antigens are Stimulate Stimulate cytokine Secrete interleukin, recruit &
presented to T helper cytokine production activate macrophage
cells production
Cytotoxic Directly lyse Destroy infected cells directly lyse infected cells
infected cells
Strategies +! Encapsulated organisms inhibiting +! Escape into cytoplasm +! Antigenic variation
phagocytosis following phagocytosis +! Polymorphism
+! Toxin-mediated killing of phagocytes +! Prevention of +! Latency
+! Neutralization of opsonizing IgG complement activation +! Inhibition of Ag presentation
+! Survival within phagocytes +! Gene switching of +! Infection of lymphocytes
+! Inhibition of complement activation antigenic variation +! Prevention of complement activation
+! Polymorphism +! Immunosuppression +! Block cytokine activation of effector
cells
PHYSIOLOGY)[DKA)(201632017)]) 141)
)
SENSORY PHYSIOLOGY
Sensory system – provides information coming from the B.! Intensity
external and internal environment Weber-Fechner Law or Steven’s Power Law
Intensity of stimulus Magnitude of receptor
Sensory receptors – detect or receive the sensory stimuli potential
which are converted into electrical signals and are
conveyed to CNS via sensory pathways Stimulus intensity is encoded by:
$! Frequency coding
Adequate stimulus – refers to the particular type of Firing frequency of Magnitude of receptor
stimulus to which a receptor is most sensitive sensory neuron potential
PHYSIOLOGY)[DKA)(201632017)]) 142)
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Receptive field – spatial region where application of stimulus Size of body NO CHANGE in Topographic
causes a sensory neuron to respond part representation in sensory cortex
Sensory unit – made up of primary afferent neuron &
receptors Threshold Sensitivity
Significance of adaptation
Two-point discrimination – spatial or tactile ability to
Duration Stimulus
distinguish 2 stimuli being 2 separate units
Duration AP frequency
Two-point discrimination threshold – closest distance that 2
stimuli can still be distinguished meow
Duration Amount of information
reaching the brain
Factors affecting 2-pt discrimination:
Size of Sensory unit Better 2 point
E.! Other mechanisms of encoding pattern of activity
receptive field present discrimination ability
9! Temporal Coding Pattern – same neuron carries 2
different types of sensory information
Discharge of neuron 2-point discrimination
9! Spatial Pattern Coding – activity of several neurons
innervating receptive field required to elicit a sensation
9! Feature detectors – Neurons within brain that
Sensitivity integrate information from a variety of sensory fibers
Thigh < Arm and fire to indicate presence of a complex stimulus
2-point discrimination threshold
Sensory Receptor – part of neuron or a special cell that
Thigh > Arm are adapted to respond to a particular stimulus but may
respond to other stimuli at a higher threshold
PHYSIOLOGY)[DKA)(201632017)]) 143)
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Classification of receptors: According to rate of adaptation
According to complexity Type Slowly adapting Rapidly adapting
Simple Free nerve endings Receptors Tonic/Static Phasic/Dynamic
Complex Covered with layers of connective tissue
AP fired Continuous at rate
Special Receptor & afferent neuron separated by a
synapse Response At or near the Only when change is
initial level of firing taking place;
According to source of stimulus regardless of Important for body
Receptor Stimuli stimulus’ duration balance & movement
Exteroreceptor From outside the body Found in Joints & Muscles
Enteroreceptor From within the body Maintenance Steady posture Future position
Proprioreceptor Position of the limbs or force of Examples Merkel’s disc, Meissner’s &
muscle contraction Ruffini’s endings Pacinian corpuscles
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Types of Fibers
Types Fiber Axon diameter Propagation velocity Afferent cutaneous/muscle nerve Efferent nerve
A! M 12-20um 80-120m/sec 1a: All intrafusal fibers Motoneurons to skeletal muscle
1b: Golgi tendon organ
A" M 6-12um 35-75m/sec Mechanoreceptors
A( M 1-6um 5-30m/sec Fast pain: thermoreceptors
A# M Motoneurons to intrafusal fibers
B M Preganglionic sympathetic
C unM <1um 0.5-2m/sec Slow pain: thermoreceptors Postganglionic sympathetic
PHYSIOLOGY)[DKA)(201632017)]) 145)
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Cerebral cortex – consists of 6 layers
System Dorsal Column Anterolateral Layers Ends
Submodalities Touch-pressure, Position Pain, Temperature, Crude- Layer 1-4 Non-specific thalamic
sense, Vibration, Kinesthesia touch nuclei ends
Location in Dorsal column Anterolateral column Layer 4 Specific nuclei of
spinal cord thalamus ends
Type of fibers Large myelinated Small myelinated
Small unmyelinated Stereognosis – ability to identify
Somatotrophic Strictly maintained Present but not strictly objects depending on touch, pressure &
organization throughout the pathway maintained large cortical component
Level of Medulla Spinal cord
decussation Vibratory Sensation Touch receptors
Brianstem Ventral posterior lateral Ventral posterior lateral Receptor Detects
termination nucleus & posterior nuclear nucleus & posterior nuclear Pacinian High frequency
group of thalamus group of thalamus corpuscles signals
Brainstem reticular formation Meissner’s Low frequency
Cerebral Primary & Secondary somatic sensory cortices & somatic corpuscles signals
termination sensory associaton area
Dorsal column pathway degenerates in
SI SII persons with poorly controlled:
Located Post-central gyrus Superior wall of Sylvian fissure :! Pernicious Anemia
Brodmann’s area 3,1,2 :! Diabetes Mellitus
Function Position, sense, discriminate Elaboration of sensory data & :! Vitamin deficiency
size & shape involved in learning through
tactile discrimination Proprioception – refers to position
Representation Sensory homonculus of fibers Representation not complete senses, rate of change of position and
from various parts of body movement
Proprioception
Size of cortical receiving area Numbers of receptors in part of body Subtypes Description
Static Conscious perception of
Sensory pathway – set of sensory neurons arranged in series carrying signals orientation of different
from the dorsal root into spinal cord to brain parts of body
Dynamic Rate of movement sense or
Sensory Homonculus – detailed localization of fibers from various parts of the kinesthesia
body
PHYSIOLOGY)[DKA)(201632017)]) 146)
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Specific Tactile-touch, Itch & tickle Synthetic Synthetic Proprioception Temperature Pain
somatic pressure, sense sense
sense vibration Vibration Stereognosis
Description Ability to Position senses, Unpleasant
identify objects rate of change sensation
depending on of position & usually
touch, movement associated
pressure & with tissue
large cortical damage
component
Stimulus Mild repeated Pattern of Cold Warm Intense
local sensation rhythmic (10- (30- mechanical
brought by pressure 38°C) 43°C) deformation,
mechanical/ temperature
chemical agents extremes
Sensory Cutaneous Unmyelinated Touch Skin tactile Nerve endings Nociceptors
receptors mechanoreceptors free nerve receptors receptors, Deep
(Meissner’s, endings & rapidly (Meissner’s receptors, slow
Pacinian, Merkel’s adapting & adapting spray
& Ruffini’s mechanoreceptors Pacinian) endings
corpuscles)
Sensory Group II Small A! fibers A( & C C A( & C fibers
nerve fibers (A" & A( fibers) unmyelinated C fibers fibers
fibers
Pathway Lemniscal & Lateral Dorsal Dorsal Lemniscal, Lateral Ascending
Spinothalamic spinothalamic column column Spinocerebellar spinothalamic nociceptive
tract tract pathways;
End in
spinal cord
& brainstem
Specific Ventrobasal nuclei Parietal lobe VPL nucleus of Ventrobasal Reticular
cortical of thalamus & posterior to thalamus, nuclei of system in
areas postcentral gyrus the postcentral postcentral thalamus, thalamus &
gyrus gyrus, postcentral postcentral
cerebellum gyrus gyrus
PHYSIOLOGY)[DKA)(201632017)]) 147)
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Temperature
Receptor Receptive Speed of Encoded Sensation Fibers Response Cessation of firing
Field Size Adaptation temperature
Pacinian Large Very rapid Vibration Warm 30°-45°C 47°C
corpuscle Cold 10°-25°C 40°C but fires
Meissner’s Small Rapid Speed of stimulus again at 45°C
corpuscle application
Merkel’s disk Small Slow Location of stimulus Pain Sensation
Ruffini’s Large Slow Magnitude Temperature Description
corpuscle Stimulation of pain receptors
<15°C
Mr. R = Slow (Mr. = Merkel; R = Ruffini)
31°-36°C Comfort zone; sensation of thermal
Ms. P = Fast (Ms. = Meissner’s; P = Pacinian)
neutrality
Pathways Orientation Description
>45°C Stimulation of pain receptors
Lemniscal Dorsal Detailed localization, spatial
form & temporal pattern of
Thermal neutrality – detects thermal changes until
tactile stimuli, vibratory
0.5°C
sensation & proprioception
Spinothalamic Anterolateral Poorly localized, gross tactle
sensations Adaptation
Temperature Description
Frequency of receptors <20°C No adaptation occurs
20°-40°C Adaptation occurs; sensation within
Cold receptors (4-10X) > Warm receptors
this range gradually fades to one of
Pacinian Meissner’s thermal neutrality
> >40°C No adaptation occurs
Transient Receptor Potential (TRP proteins) – ion channels in
Velocity of Heat Conduction
plasma membrane of axon terminals causing receptor to
depolarize by inward flux of Na+ when activated temperature Metal > Skin
changes Conduction of Colder Sensation
Stimulus-causing receptor potential:
-! Ion channels protein (TRP) Metal > Wood
-! Temperature extremes
-! Chemical ligands Capsaicin – colorless irritant commonly found in spicy
Skin sensation – depends on current skin temperature food like chili
PHYSIOLOGY)[DKA)(201632017)]) 148)
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Proprioception Substance P Histamine Slow Pain
Subtypes Description
Static Conscious perception of orientation of CGRP Vasodilation
the different parts of the body with CGRP Bradykinin
respect to each other
Dynamic Rate of movement sense or kinesthesia Bradykinin Prostaglandins
PHYSIOLOGY)[DKA)(201632017)]) 149)
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Types of Pain
Type Description Pathway Effect
Fast/ Initial pain Discrete, well-localized, A( fibers; Spinothalamic tract; Evokes withdrawal reflex &
pinprick sensation topograpically represented in sympathetic response
cortex
Slow/Delayed pain Poorly-localized, dull, C fibers; Spinoreticulothalamic Produces emotional perception,
burning sensation system; collaterals pass through nauseam profuse sweating,
reticuar formation lowering of blood pressure &
generalized reduction in skeletal
muscle tone
Visceral pain Poorly-localized, stimulated Sympathetic nerves to spinal Carries activity related to
by distention, intestinal colic nerves then to spinal cord by percepton of visceral pain from
& traction of mesentery dorsal root ganglia; primary upper respiratory & GI tract;
visceral nociceptive afferent fibers involves ANS & vagus nerve
teminate on secondary neurons in
dorsal horn
Projected pain Directly stimulating fibers within a pain pathway
Labeled line Encode location of pain Stimulation anywhere along
mechanism the pathway result in same
perception
Phantom limb Activation of sensory pathway at either Causes of pain include: spontaneous activity of DRG cells;
phenomenon site of amputation/ within CNS sprouting of damaged sympathetic post-ganglionic axons;
producing pain that appear to come up-regulation of adrenoreceptors in primary afferent
from severed limb neuron
Radiating pain Orginates at local site spreading to distant sites
Referred pain Originates from visceral Common pathway shared by Somatic nociceptive afferent
organs that is referred to visceral & somatic pain fibers activation – reflex excitation of
sites on skin !-motoneurons in prolonged
contraction of skeletal muscles
causing splinting pain
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Central termination Effects of Pain
Type Termination Description Type Effect
Subcortical Thalamus Retiuclar system, Short-term Beneficial by helping a person to avoid
hypothalamus, conditions that may bring tissue damage
periaqueductal gray, Long-term Lead to abnormal physiologic/pyschologic
brainstem, spinal cord responses:
Cortical Cerebral cortex Postcentral gyrus Stimulation of sympathoadrenal system,
urinary retention & ileus, stress hormones
Splinting pain – perception of pain being from the muscles release, respiratory alkalosis, MI, protein
rather than in visceral structures catabolism, dysrhythmias, hyperglycemia,
PHYSIOLOGY)[DKA)(201632017)]) 151)
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Axon Reflex: Components of Endogenous Analgesic System (EAS):
$! Spread of action potentials in a stimulated nociceptive Pathway Opioid- Non-opioid analgesic
fiber toward peripheral axonal branch point mediated EAS pathway
$! Causes release of sensitizing & vasodilatory Secreted Brainstem & Brainstem & raphe
neuropeptides such as CGRP & Substance P from Spinal cord nuclei from spinal cord
! stimulate release of histamine from mast cells Secretions Endogenous “Stress-induced
causing changes in capillary permeability & edema opioid peptides, analgesia”; Serotonin &
formation Enkephalin & catecholamines
$! Responsible for hyperalgesic responses & participate in Dynorphin, B-
visceral pathologic functions like asthmatic-like endorphin
constrictions of pulmonary airway Effect Inhibit neural Inhibits nociceptive
activity in neurons by secreting
Modifications of Pain Perception nociceptive enkephalins
Modification Description pathway
Counterirritants Inhibition in central sensory
pathways by diffuse noxious B-endorphins – from hypothalamus & pituitary gland binds
inhibitions & gate control theory opiate receptors to inhibit neural activity
Endogenous Descending control system that
analgesic regulates transmission of nociceptive Opiates:
system information leading to supression of 3! Prevents release of excitatory neurotransmitter in
excessive pain afferent terminal
Gating in dorsal Collateral fibers from dorsal column 3! Produces inhibitory post-synaptic potential (IPSP)
horn produces presynaptic inhibition of 3! Stimulates the descending analgesic pathway
lateral spinothalamic tract
TENS & Acupuncture – pain-relieving procedures that
Spinal pain “gate” – refers to modulation of nociceptive utilize spinal pain “gate”
information transmitted from dorsal horn of the spinal cord;
activates dorsal horn inhibitory interneurons to block
nociceptive-related activity from being transmitted by
closing the gate
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HEARING & VESTIBULAR PHYSIOLOGY
Sound – produced by compression and
decompression waves that are transmitted Division Part Description/Function
in air or in other elastic media such as Pinna Helps direct sounds into auditory canal;
water External role in sound localization
Ear External Transmits sound pressure waves to
Sound frequency – measured in cycle per auditory canal tympanic membrane
second/ Hertz Tympanic Separates external from middle ear
membrane
Decibel (dB) – unit of sound pressure level Middle Ossicles (Incus, Linked together by eardrum, bones
Ear Malleus, Stapes) amplify the force of sound vibrations
Normal human ear – sensitive to pure
Stapedius & Protective function, preventing strong
tones with frequencies that range between
tensor tympani sound waves from causing excessive
20-20,000Hz
stimulation of auditory receptors
Membranous & Complex, continuous series of spaces in
Sound pressure level
Inner Bony labyrinths temporal bone,
Eardrum (10X) > Auricle Ear Cochlea ï
Spiral shaped organ consists of 2 )turns
£
Auditory canal > Auricle from broad base to a narrow apex
Organ of Corti Neural apparatus responsible for
Loud sound – initiates reflex contraction of transduction of sound & converts
the middle ear muscles called tympanic mechanical energy to electrical energy
reflex
Resting Membrane Potential End of Fibers
Middle ear muscles: Stapedius & Tensor
tympani Inner hair cell Outer hair cell Inner hair cell > Outer hair
(-40mV)
< (-70mV) (90%) cell
Cochlear fluid
Fluid Perilymph Endolymph K+ effect Neural information about
Part Bony labyrinth, Membranous acoustic signal
Inner hair cell < Outer hair cell
scala vestibuli, labyrinth, Inner hair > Outer hair
scala tympani scala media cell cell
Endolymph
Frequency K+ Na+ Positive
potential
Basilar membrane > Apex
(+80mV)
PHYSIOLOGY)[DKA)(201632017)]) 153)
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Amplifications from outer ear to inner ear: Vestibular Apparatus:
)! Organ pipe resonance – increases air pressure by 10x Compostion Part
)! Ratio of surface area of large tympanic membrane to 3 semicircular canals Horizontal, superior, posterior
smaller oval window provides 30x increase 2 otolith organs Utricle, saccule
)! Mechanical advantage of lever system formed by
ossicles 3x Ampulla – swelling found on each semicircular canal
where it joins the utricle; contains sensory epithelium
Results of these 3 mechanisms = amplification of a sound
wave by 800x before it sets liquid in inner ear in motion Ampullary crest – ridge that is covered by epithelium
where vestibular hair cells in innervated by primary
Sound transduction afferent fibers of the vestibular nerve
,! Stereocilia deflected toward kinocilium
,! Opening of K+ channels within cell membrane Calcium carbonate crystals – found inside gelatinous
,! Depolarizing hair cell mass in the macula
,! Opening of channels causes inward flow of potassium
,! Release of neurotransmitter glutamate ***Otolith increases specific gravity of otolith membrane
,! Synapses at base of the cell by 2x the endolymph
,! Glutamate depolarizes adjacent afferent neuron
,! Generation of Action Potential Otolith Utricle Saccule Semicircular
canals
K+ influx!Depolarization!Glutamate release!AP generation Acceleration Horizontal Vertical Angular
PHYSIOLOGY)[DKA)(201632017)]) 155)
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PHYSIOLOGY OF VISION
Optics of Vision Types of Lenses
Velocity of light = 300,000km/s Lens Convex Concave
Velocity Light passing Not refracted Not refracted
Air Liquid/Transparent through center
> solid Light passing Strike angulated surface Enter the lens ahead of
through edges interface center
Refractive Index = Benting of rays Towards the center Away from center
|sãåçové)åè)ão§•v)op)tou Ray to center Converge Diverge
|sãåçové)åè)ão§•v)op)lìxlvtpçs Focal point Present Absent
Diopters Positive Negative
Refractive Index of Air= 1 Focal point – single point where parallel light rays pass through equal
curvature
Interface perpendicular to light beam:
9! Light rays still travel in straight path Types of Convex Lenses
9! Decrease in the velocity Type Convex Convex 2 Convex Concave
9! Shorter wavelength Sphere Cylindrical Cylinders Cylinder
Refraction All edges Passing through Crossed at right
Refractive index Velocity towards 2 edges but not angles (Light rays
center ray at top nor bottom pass on sides)
Refractive index Wavelength Light Single point Single plane Single point Single
focus plane
Refraction – bending of light rays at an Coming of Focal point Focal Line Focal point Diverge
angulated interface rays
Perpendicular – direction in which light
Focal Length of a Lens = distance beyond a convex lens at which parallel
travels due to light rays bend to the plane
rays converge to form a focal point
of the wave front
Difference in velocity - causes angulation Divergent Rays
Focal Length Convex Convexity Focal
Wave front striking Effect
Diverging light rays Parallel light rays length
angulated surface >
First Velocity Convexity of lens in diverging rays
Last Same Velocity Diverging light rays Parallel light rays
>
PHYSIOLOGY)[DKA)(201632017)]) 156)
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Formation of Image by Convex Lens The Eyes
Light rays passing through center of the lens come to a Layer Part Description
point focus on opposite side of the lens directly in line Outer Conjunctiva Covers posterior of lids & anterior of
with point source and center of lens layer sclera; dilutes infectious material
(Fibrous) Cornea Avascular; many pain fibers without
Image = upside down with respect to original object pigmentation
2 lateral sides of image = reversed Sclera Dense, white, collagenous outer
protective coating of the eye
Refractive Power of Lens Iris Flat surface w/ pupil; contains
-! Ability of lens to bend light rays sphincter and dilator muscles
-! Measured in diopters (convergence power, optical Pupil Centrally situated round aperture
power, focusing power) Ciliary body Produces aqueous humor
Middle Aqueous Circulates in anterior chamber &
Cylindrical lenses – axis should be stated aside from its layer humor maintains a constant pressure
strength (Uveal) inside the eye
Choroid Vascular posterior segment between
Retinal Image – image focused on the retina is inversed
retina & sclera
and reversed with respect to the object
Chorio- Nourished outer 1/3 of retina &
Reversed/Inverted image – considered by brain as
capillaries inner 2/3 of retina
normal
Retina Contains macula, interneurons,
pigments, fovea, photoreceptors,
Refractive interfaces of the eyes
Inner optic discs
Refractive indices Between
layer Macula Has highest con’c of cones; sharpest
1.003 Air & anterior cornea
(Neural) visual acuity
1.376 Posterior cornea & aqueous humor
Fovea Point of sharpest vision;
1.336 Aqueous humor & anterior lens
Lens Focuses light, transparent,
1.386 Posterior lens & vitreous humor
biconvex, avascular without
1.336 Vitreous humor & Retina
innervation; highest protein in body
Vitreous Clear, avascular, gelatinous body,
Refractive power Caused by
humor fills space between lens & retina
2/3 Anterior surface of cornea & air; due
Extraocular 4 Rectus: Medial, Lateral, Inferior &
to big differences
muscles Superior
1/3 Lens; due to difference in curvature
2 Oblique: Superior & Inferior
PHYSIOLOGY)[DKA)(201632017)]) 157)
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Pupillary size – CN3; determined by balance of Interneurons – synaptic connections within the retina
•! Constriction – parasympathetic activity Cells Bipolar cells Horizontal cells Amacrine cells
•! Dilatation – sympathetic activity Synapse Outer layer of Inner layer of
retina retina
Depth of focus – greatest with extremely Interconnect Photoreceptor & Photoreceptors & Ganglion cells &
constricted pupils as central rays are always ganglion cells bipolar cells bipolar cells
focus
Pigment layer of retina:
Flow of Aqueous humor: Melanin
Posterior chamber ! Pupil ! Anterior chamber -! prevents light reflection throughout the eyeball
! Trabecular meshwork ! Canal of Schlemm ! -! phagocytosis of photoreceptor outer segments
Episcleral vessels ! Systemic circulation -! maintenance of outer blood-retina barrier
-! stores vitamin A
Retina:
Fovea – pit-like depression in middle of the Four major functional segments
macula where visual targets are most focused .! Synaptic body – connects horizontal & bipolar cells
.! Nucleus
Foveal receptors synapse – on only one bipolar .! Inner segment – contains cytoplasm with organelles; synthesis
cell; synapses on only one ganglion cell sites of photopigments; funnels photons into outer segment
.! Outer segment – light sensitive photosensitive pigments; with
Peripheral vision discs infolded shelf of cell membrane
-! Mediated by both rods & cones ;! Rods – rhodopsins
-! Receptive field of ganglion is larger than fovea ;! Cones – color pigments
-! Visual angle more than 10 degrees away from
center of fovea Transduction site – phototransduction is a cascade of chemical &
Receptive Field electrical events to detect, amplify & signal response to light
Peripheral > Fovea
Optic nerve/Optic disc – retinal ganglion cell axons cross the retina as
retinal fiber layer; corresponds to the blind spot
Vitamin A – important precursor of
photosensitive chemicals in rods and cones Blind spot – absence of photoreceptors
PHYSIOLOGY)[DKA)(201632017)]) 158)
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Photoreceptors
Photoreceptor Rods Cones
Sensitivity
PHYSIOLOGY)[DKA)(201632017)]) 159)
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Phototransduction B.! Photon absorption
Light Negativity of Hyperpolarization Segment Outer Inner
photoreceptor Channel cGMP-gated cation K+ channels
membrane potential channels
Gate Close Open
Light intensity Size of receptor potential Changes Decrease Na+ influx K+ efflux
Light intensity Saturation of response (Hyperpolarization)
Photon sensitivity
Photoreceptors Glutamate release Rods Cones
>
Rate of Photon Absorption
More glutamate release if Presynaptic terminal Cones Rods
Depolarized Hyperpolarized
>
>
Cone responses – do not saturate even at the brightest
Less glutamate release if Presynaptic terminal levels of natural light
Hyperpolarized > Depolarized
C.! Rhodopsin
%! G protein-coupled light receptor
A.! Dark current – presence of ionic current which flows %! Molecule made out of either:
into the outer segment & out of inner segment Retinal Aldehyde of retinol
Na-K pumps Removes Na+ & imports K+ Opsin Transmembrane protein
Na-Ca exchanger Removes Ca2+
Indirect light-regulated Influx of Na+ in outer %! Metarhodopsin II – activated form of rhodopsin
cGMp-gated channel segment %! 11-cis retinal – unstable form; exists in dark
Nonlight regulated K+ Efflux of K+ in inner segment %! Bleaching - separation of all-trans retinal & opsin
channel
PHYSIOLOGY)[DKA)(201632017)]) 160)
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D.! Guanosine monophosphate E.! Termination of light-activated
$! Second messenger Mechanism Description
$! Links light activated events of disk membranes Closure of cGMP- Leads to decrease in Ca2+ with
to electrical events to outer membrane gated channels replenishment of cGMP channel opening
$! Dark Rhodopsin kinase Phosphorylates light-activated rhodopsin
GTP ! Guanylyl cyclase ! cGMP ! Opening of & is recognized and bound by cytosolic
cGMP-gated cation channels protein, arrestin
PHYSIOLOGY)[DKA)(201632017)]) 161)
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Univariance – property of response when light hitting the J.! Temporal Summation
cone on fringe of its absorbance generates large response $! Synapse of distal axon of bipolar cell with dendrites of
sufficiently high light intensity ganglion cell & amacrine cells form a junction
$! Amacrine cells – responsible for temporal summation
Cone photopigments – more likely to absorb photons $! Located in inner plexiform layer
when wavelengths are at their peak absorbance $! Sensitive again to even weak stimulus after preceding
bright stimulus
Fine spatial discrimination – not compatible with the $! Amacrine cell synapse – inhibitory reciprocal action
use of multiple cones due to wavelength-dependent for temporal processing of bipolar cell response
differences & eye’s ability to focus light and also small
objects may stimulate only single cones K.! Form sense – determines acuity of vision; aids in
Part Fovea Peripheral portions discriminating between seeing 2 stimuli separately as 2
of retina instead of fusing them into 1
Cones M&L S, M & L
Fine spatial Able Unable Minimum visual angle – to see light as 2, each beam should
Discrimination stimulate one cone with one cone in-between unstimulated
Color Discrimination Limited Able
Diffusion Phenomenon – cones at center of a light beam
H.!Purkinje shift/Dark Adaptation receives highest energy while peripheral cone receives less
2! Occurs at the transition between primary use of energy
photopic and scotopic Energy received
Light intensity Rods Color Center > Periphery
PHYSIOLOGY)[DKA)(201632017)]) 162)
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M.!Contrasts of Visual Image Clinical Correlation:
$! Visual signal in primary cortex is concerned with Disease Description
contrasts in the visual scene Emmetropia When parallel light rays from distant
Sharpness Intensity Stimulation (Normal Vision) objects are in sharp focus on retina
of contrast difference Myopia Images from distant objects focused in
(Nearsightedness) front of retina due to eyeball that is too long
N.! Stereopsis – known as depth perception; Corrective: Concave
important in judging distance of objects up to Hyperopia Images are focused at back of retina due to
60meters (Farsightedness) an eyeball that is too short
Corrective: Convex
Images on 2 retinas are not exactly the same Astigmatism Visual image in one plane focus at different
Image on right hand side distance from that of plane at right angles;
Right eye Left eye results from excessive curvature of cornea
> in one planes
Image on left hand side Corrective: Spherical & Cylindrical lens
Right eye Left eye Presbyopia Lens grow larger & thicker and becomes
< less elastic due to progressive denaturation
of lens protein
Horopter – points in space which project on Upper segment: Far seeing
corresponding points in 2 retinas Lower segment: Near seeing
Panum’s area – also known as Fusion area; Corrective: Bifocal lens
Panum’s area Inside Outside
Interpretation We see single We see double Disease Defect
images images Trichromacy Normal color vision; presence of 3 cones
Deuteranomalous Deficient green cones/M cones
Visual Pathway Protanomalous Deficient red cones/ L cones
2 retinas ! nerve signals leave through optic nerves ! Trianomalous Deficient blue cones/ S cones
cross to opposite side ! join the fibers from opposite Dichromats Total loss of one color pigment
temporal retinas ! optic tract fibers synapse in dorsal Deuteranopes Loss of green pigment
lateral geniculate
Protanopes Loss of red pigment
Tritanopes Loss of blue pigment
Geniculocalcarine fibers – pass via optic radiation
Monochromat Has only 1 color pigment; lacks ability to
(geniculocalcarine tract) to primary visual cortex
distinguish wavelength of spectrum
(calcarine fissure area of medial occipital lobe)
Achromat Total loss of cones/ Rod monochromat
PHYSIOLOGY)[DKA)(201632017)]) 163)
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ENDOCRINE PHYSIOLOGY
Endocrinology – study of hormones Diffusability
Hormones – produced by glands & secreted directly into Endocrine Exocrine
blood stream >
Endocrine Endocrine Endocrine cells
System glands/organs w/ non-endocrine General classification of hormones:
organs (hormone- $! Protein hormones
producing) $! Derivatives of amino acid Tryptophan
Examples Pituitary, thyroid, Hypothalamus, (Serotonin, Melatonin)
pancreas, adrenals, heart, liver, $! Derivatives of amino acid tyrosine
parathyroid, gonads kidney, GI tract •! Epinephrine/Norepinephrine
•! Thyroxine & Triiodotyronine
Non-endocrine Cells produced Effect $! Steroid hormones
organs
Hypohalamus Oxytocin, ADH Thyroid Hormone receptor – acts as transcription factor
Heart ANP Na excretion Inactive Preprohormone peptide sequence – composed of
hormone, a signal peptide composed of 15-30aa at amino N-
Liver IGF-1 terminal (+/- copeptides)
Kidney EPO RBC produced 1:1 ratio = Active hormones: Co-peptides
Calcitriol Calcium con’c Specificity of protein hormones = gained from primary amino
acid sequence & posttranslational modifications
GI tract Gastrin Gastric acid
CCK Gallbladder Hormone & Protein Binding
contraction $! Steroid & Thyroid Hormones – transported in blood
bound to plasma proteins produced in liver
Secretin Pancreatic
$! Free hormone
enzymes
,! biologically active; form of action on target organs
GLP-1 VIP
,! feedback control & clearance by cellular uptake &
metabolism
Chemical Nature of Hormones determines: $! Concentrations of bound hormone, free hormone &
$! Synthesis, storage, release transport protein = should be in equilibrium
$! Transport in blood $! Protein binding serves as:
$! Half-life & mode of clearance %! Prolongs circulating half-life on hormone
$! Cellular mechanism of action %! Bound hormone = “Reservoir” & serves as buffer in
acute changes in hormone secretion
PHYSIOLOGY)[DKA)(201632017)]) 164)
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Classification Protein Hormones Tyrosine-derived Hormones Steroid Hormones
Thyroid Hormones Cathecolamines
Description Peptide hormones = <100aa Iodinated tyrosine Co-packaged with
Polypeptide = >=100aa residues via ether ATP, Ca2+, &
linkage Chromogranins
Solubility Hydrophilic Hydrophobic Hydrophilic Hydrophobic
Circulation Unbound to other proteins Bound to Transport Circulate unbound Bound to Transport proteins
proteins
Clearance in High rate Slow rate High rate Slow rate
blood
Half-life Short T4 = 7 days Short (1-2 minutes) 20-100minutes
T3 = 18hours
Signaling Cell membrane receptors Thyroid hormone Cell membrane Intracellular receptors
receptor (nucleus) receptors
Easily digested Yes No Yes Fairly
Method of giving IM, intranasally, Orally IM Orally
sublingually
Examples GHRH, GnRH, TRH, CRH, T3, T4, Epinephrine, Aldosterone, Cortisol,
ADH, Oxytocin, GH, FSH, Norephinephrine, Androstenedione,
LH, TSH, ACTH, Prolactin, Dopamine Dehydroepiandrostene-
PTH, Calcitonin, Glucagon, dione, estrogen, Vit. D,
Insulin, Somatostatin, progesterone, testosterone,
Synthesis Nucleus Thyroid Follicle Adrenal medulla & From cholesterol
Neurons
Storage Secretory vesicles Thyroglobulin Secretory vesicles
PHYSIOLOGY)[DKA)(201632017)]) 165)
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Hormones Protein Hormones Steroid Hormones
Synthesis )! Nucleus ! undergoes excision of introns, splicing of exons, )! Steroidogenic cells – obtain cholesterol from
capping of 5’ end, addition of poly(A) at 3’ end cholesterol-rich lipoproteins
)! Mature Messenger RNA ! Entry to cytoplasm for translation )! Conversion of cholesterol to pregnenolone
(synthesis of inactive preprohormone peptide sequence) on )! Modification to several steroidogenic enzymes
polyribosomes within RER )! Hormone storage in steroid-producing
)! Signal peptide interacts with RNA protein to direct growing endocrine cells (Low)
peptide chain through a pore within cis-RER )! Steroid hormones ! undergo modifications
)! Prohormone – undergores posttranslational modification in Golgi after release of steroidogenic cells ! secretion
apparatus of precursor & second cell converts to
)! Addition of carbohydrate moiety estrogen
)! Package of prohormone in secretory vesicles
)! Final cleavage of prohormone into separate active hormones &
copeptides in secretory vesicles for secretion via Exocytosis
Secretion & 9! Stimulus secretion coupling – mechanism of secretion in 9! Excretion of hormones – involves inactivating
Elimination response to stimulus modifications followed by
9! Regulated exocytosis – requires energy, Ca2+, intact glucoronide/sulfate conjugation in liver
cytoskeleton & presence of coat proteins 9! Modifications ! Increase water solubility !
9! Endocytosis & Lysosomal Degradation of hormone receptor decrease affinity for transport proteins
complex – removal from blood 9! Excreted by kidneys
PHYSIOLOGY)[DKA)(201632017)]) 166)
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Endocrine axis-driven feedback loop – involves 3-tiered
Receptors Cell surface Intracellular
configuration
Hormones Protein Steroid hormones; Thryoid
Tier Organ Releases Action
hormones; hormones; Vit. D
catecholamines 1 st Hypothalamic- Releasing Influenced by
neuroendocrine hormones circardian rhythym
Method Generation of Crosses cell membrane !
neurons
2nd messenger interacts to nuclear/cytosolic
receptors ! binds to hormone 2 Pituitary gland Tropic Stimulates/inhibits
nd
system !
series of response element ! activates/ hormones hormone secretion
interaction repress transcription & 3 rd Peripheral Hormones Specific actions
formation of mRNA ! Endocrine
controls/alters cellular function glands
Stress – overrides circadian rhythm; changes patterns of
Feedback Control of hormone Production hormones response/secretion
Feedback Circuits – root of most control mechanisms in
physiology Peripherally produced hormones – play a minor role in
More common regulation of feedback within endocrine axis-driven
feedback loop
Negative feedback > Positive feedback Defects at level Disorder
Hypothalamus Tertiary Disorder
Response-driven feedback loop – responding to non- Pituitary gland Secondary Disorder
hormonal stimuli Target endocrine organs Primary Disorder
Secretion of hormone ! stimulated/inhibited by change in
level of specific extracellular parameter ! alteration changes Feedback Type Description
physiology of target organs ! change in parameter & Long-loop Peripheral gland hormones can exert
inhibits further hormone secretion long-loop control on both hypothalamus
& ant. pituitary
Negative-feedback loop – confers stability by keeping a Short-loop Tropic hormones exerts negative
hormone/substance within normal range feedback on synthesis/release of
Hormone 1! acts on target organ ! increase in circulating hypothalamus releasing/ inhibiting
hormone 2 ! changes inhibits secretion of hormone 1 hormones
Ultrashort- Hypophysiotrophic hormones may
Primary feedback loop – involves feedback inhibition of loop inhibit their own synthesis & secretion
pituitary tropic hormones & hypothalamus releasing Episodic/Pulsatile secretions of hormones
hormones by peripherally produced hormones -! Hormones are secreted with short half-lives are secreted
in pulse; Pulses can be frequent as every 5-10 minutes
PHYSIOLOGY)[DKA)(201632017)]) 167)
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HYPOTHALAMUS & PITUITARY GLAND
Pituitary Gland (Hypophysis) Hypophysiotrophic – stimulatory to hypophysis;
Part Anterior Pituitary collections of parvicellular neuronal cell bodies in
Other name Adenohypophysis Neurohypophysis hypothalamus
Neurosecretory Parvicellular Magnocellular
cells Anterior Pituitary Secretion – controlled by chemical
Neuronal Direct agents carried in portal hypophyseal vessels from
connection hypothalamus to pituitary (Hypophysiotrophic
Systemic Hypothalamo- Direct hormones)
circulation Hypophysial portal
vessels Cell types Hormones
Somatotrophs Growth hormone (30-40%)
Anterior Pituitary gland – epithelial component: Lactotrophs Prolactin
$! Pars distalis – 90% adenohypophysis Gonadotrophs LH, FSH
$! Pars tuberalis - wraps around the stalk Thyrotrophs TSH
$! Pars intermedia – regresses & absent in adult human Corticotrophs Adrenocorticoptrophin ACTH (20%)
Acidophilic Basophilic
IGF-1 – measured instead of GH to detect GH excess;
Hormone GH, Prolactin FSH, LH, TSH, ACTH
relatively long circulating half-life
Chronic Stress
Posterior pituitary gland – neural part
Median eminence – superior end of neurohypophysis GH, TSH, FSH, LH
funnel shaped swelling Prolactin
Infundibulum – extends from median eminence to pars
nervosa
Disease Pituitary Dwarfism Achondrodysplasia
Pituitary stalk – made up by infundibulum & pars Trunk/Limbs Proportional Unproportional
tuberalis
Order of Damage (1st to last)
Parvicellular neurons ! secrete hormones from axonal 1.! GH, prolactin
termini at median eminence ! enter a primary plexus of 2.! FSH, LH
fenestrated capillaries ! located in pars distalis by 3.! TSH
hypothalamophypophyseal portal vessels ! diffuse out of 4.! ACTH
vasculature & bind to specific receptors
PHYSIOLOGY)[DKA)(201632017)]) 168)
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Hormones Somatotrophic Insulin-like Prolactin FSH/LH TSH ACTH
Hormone Growth Factor
Description Secreted every 20-30 29aa; 13 !-glycoprotein subunit (common to 3) Synthesized as
mins homologous of "-FSH & LH "-TSH part of POMC
insulin
Synthesis GHRH ! G-protein ! Made in liver, Secreted by Secreted by
adenylyl cyclase ! kidney, muscles, gonadotrophs thyrotropes
increased cAMP ! bone, cartilage;
opens Ca2+ channel ! acts via tyrosine
increase intracellular kinase receptor
Ca2+ ! release of GH
Effects (! Promotes growth; (! Growth- Development of Regulates function of Stimulates (! Stimulates
(! stimulates IGF-1 promoting mammary glands; gonads hypertrophy, adrenal
secretion; actions of milk synthesis hyperplasia, cortex;
(! Protein synthesis GH; survival of (! Promotes
(! Anti-insulin effects; (! GH synthesis thyroid growth &
(! Somatostatin & secretion epithelial cells, survival of 2
release; via long-loop zones in-
(! Diurnal rhythm; utero
Pulsatile; (! Diurnal
Stimulated "! Deep, slow-wave "! Sleep "! Gonadotropin- "! Thyrotropin- "! Corticotropin-
by sleep; "! Exercise; stress releasing releasing releasing
"! Hypoglycemia "! Pregnancy hormone hormone hormone;
"! Increased plasma of "! Breast "! Low estrogen/ "! Low T4/T3 "! Low levels of
aa stimulation progesterone, levels cortisol
"! Decreased FA con’c "! Dopamine testosterone "! Stress
"! Moderate to antagonists "! Positive feedback
vigorous exercise "! Serotonin on high estrogen
"! Neurogenic & "! Primary
Physical stress hypothyroidism
Inhibited by +! IGF-1 +! Release of +! High estrogen/ +! High thyroid +! High cortisol
+! Hyperglycemia Dopamine testosterone levels level
+! Somatostatin +! Dopamine +! Progesterone +! Stress
+! IGF-1 agonists (males)
+! Obesity (Bromocriptine) +! Inhibin (FSH)
+! Low aa levels +! Prolactin
(inhibiting GnRH)
PHYSIOLOGY)[DKA)(201632017)]) 169)
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Releasing Factors Target cell of Hormone released Target of Ant. Pituitary Hormones
by Hypothalamus Hypothalamus by Ant. Pituitary
GHRH Stimulates Somatotroph GH Multiple tissue; Liver produces IGF-1
TRH Stimulates Thyrotroph TSH Thyroid follicles ! Thyroid hormones
CRH Stimulates ACTH Fasciculata & Reticularis ! adrenal cortex (MCR2) !
Corticotrophs corticosteroids
GnRH Stimulates Gonadotroph FSH Ovarian Follicular cells to Sertoli ! spermatogenesis
LH make estrogens/progestins Leydig ! testosterone
Prolactin Inhibits Lactotroph PRL Mammary glands ! initiates & maintains milk
inhibiting factor production
Somtostanin (SIF) Inhibits Somatotroph Inhibits GH
Hormones secreted in
pulsatile manner
Insulin
Parathyroid Hormone
Growth Hormone
PHYSIOLOGY)[DKA)(201632017)]) 170)
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Neurohypophyseal Hormones Arginine Vasopressin (AVP)/ Anti-diuretic hormone (ADH)
<! Reabsorbs water at cortical & medullary collecting ducts
ADH & Oxytocin Synthesis, Storage & Release: in kidneys
;! Nonapeptides (9 amino acids) – similar structure <! Increases water permeability leading to concentrated
;! Synthesized by magnocellular bodies of neurons in urine
supraoptic nuclei (SON) & paraventricular neurons <! Stimuli for ADH secretion:
(PVN) hypothalamus ,! Plasma Hyperosmolarity
;! Magnocellular bodies project down hypothalamo- ,! Decreased circulating blood volume
hypophyseal tracts terminate in pars nervosa
;! Posterior pituitary – extensively vascularized & Oxytocin -Acts primary on uterus & breasts
fenestrated %! Uterine smooth muscle contraction
;! Synthesized as preprohormones Period Effect
;! N-signal peptide – cleaved as peptide transported in Pregnancy Sensitive to oxytocin ! increased in
ER when they become prohormones receptors
;! Neurophysin – harbours structure of oxytocin/ADH During Increase oxytocin secretion
& cosecreted peptide Labor Fetus descent ! SON & PVN stimulation !
;! Prohormone packaging in ER & Golgi in a sufficient oxytocin release to enhance labor
membrane-bound secretory granule within SON &
PVN %! Milk Ejection Reflex
;! Axonal termini in pars nervosa – secretory •! Causes myoepithelial cell contraction ! squeezes milk
granules conveyed intraaxonally through fast ATP- out of alveoli
dependent transport mechanism •! Sucking of breast stimulates oxytocin release
;! Prohormone – produces equimolar amounts of •! Hypophysectomy – does not disrupt synthesis &
hormone & neurophysin secretion of this hormones; but initially decreases after
;! Secretory granules – stored in axonal termini in procedure
pars nervosa
•! Secretion of hormones can potentially return to normal
;! Released in pars nervosa in response to stimuli that
levels
detects dendrites in SON & PVN
•! Lesion in pituitary stalk ! lead to loss of neuronal cell
;! Stimuli ! Depolarization of neurons ! AP
bodies SON & PVN
propagation ! increases Ca2+ intracellular !
results in stimulus-secretion response ! exocytosis
Pineal Gland & Melatonin
of ADH/Oxytocin
.! Synthesizes melatonin from serotonin
.! Inhibited by light & stimulated by darkness
.! Transmit information that nighttime has arrived
.! Involved in sleep induction
)
PHYSIOLOGY)[DKA)(201632017)]) 171)
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THYROID PHYSIOLOGY
Thyroid Gland
$! produces prohormone T4 & active T3 Iodide Intrathyroid Wolf Chaikoff
$! only endocrine that can be easily palpated intake iodide levels effect
$! stored in extracellular site within thyroid gland Iodide TSH Thyroid Gland
$! act by binding to nuclear receptors intake enlargement
$! Anatomy
$! Right & Left lobes – connected by isthmus Iodide Deficiency ! causes thyroid hormone deficiency
$! Blood supply: Superior, Inferior thyroid arteries
$! Drainage: Superior, Middle, Inferior thyroid veins Iodide Deficiency Disorders
$! Innervation: Sympathetic vasocmotor Deficiency Description
$! Histology Low dietary intake
$! Thyroid Follicles Low iodine levels in soil Mountainous areas
9! Single layer of follicular cells Low consumption of seafood Economic restraints
9! Rich capillary supply Inadequate utilization Presence of goitrogens
9! Filled with colloid (glucan) in food
9! Apical: lumen of the follicle
9! Basolateral: Outermost side NIS – Sodium-Iodide Symporter; secondary active transport
$! Colloid – composed of thyroglobulin coupled by Na/K- ATPase pump
$! Thyroglobulin
9! Secreted & iodinated by thyroid epithelial cells Pendrin – Chloride/Iodide Symporter; tranports iodide out of
9! Has tyrosyl group where iodine will bind follicular cell to the lumen
9! Contains T4 & T3
$! Parafollicular cells – another cell type found in Megalin – endocytoses T4/T3 from the follicular lumen into
thyroid glands; source of calcitonin the follicular cell
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Thyroid Hormone Synthesis & Secretion
Steps Movement TPO involvement TSH effects Features
Iodide Trapping Increases NIS activity ! Increase iodine ! increase NIS
No follicular cell iodine to plasma iodine
Movement to Movement of iodide to leave cell via pendrin & secretes Pendrin
Pendrin Basal to thyroglobulin
Oxidation Apical TPO Oxidation of Iodide to Iodine via TPO TPO
Iodination Movement Minor Stimulates iodination of thyroglobulin into MIT/DIT in NADPH
(Synthesis) follicular lumen
Conjugation TPO Stimulates conjugation of iodinated tyrosines to form TPO
T4/T3 linked to thyroglobulin catalysed by TPO
(Thyroid Perosidase)
Endocytosis Apical to No Stimulates endocytosis from colloid into follicular cells Megalin
Proteolysis Basal No Stimulates lysis of iodinated thyroglobulin forming T4 Lysosomes
Movement & T3/rT3 in lumen of endolysosomes
Secretion (Secretion) No Stimulates secretion of T4/T3 into circulation MCT
Hyperplasia No Exerts growth-factor effect ! stimulating hyperplasia
within the gland
PHYSIOLOGY)[DKA)(201632017)]) 173)
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C.! Factors Affecting TBG levels Different Types of Deiodinases
TBG TBG Type Type I Type II Type III
Organs Liver, Kidney, Brain, Placenta Deactivating
•! Pregnancy •! Steroid usage Found Thyroid Pituitary, deiodinase T4 to
•! Hepatitis •! Nephrotic inactive rT3
•! Chronic Heroin Abuse syndrome Effects Peripheral Intracellular T3 Prevents the T4
•! Oral estrogen therapy conversion of T4regulation of overproduction
! T3 TSH secretion
TBG Total T3/T4 Free T3/T4 by thyrotropes
No change Increased Hyperthyroidism Hypothyroidism Hyperthyroidism
No change
Effects of TSH
Immediate Intermediate Long term
Nucleus (THR) Affinity Endocytosis of colloids; Protein synthesis; Sustained TSH
T3 T4 Formation of colloid droplets; Expression of stimulation !
> NADPH (for peroxidase); numerous genes hypertophy &
Occupancy of THRs Proteolysis of thyroglobulin & (NIS, Tg, TPO, hyperplasia of
T3 T4 release of T3 & T4 Megalin) follicular cells
>
Regulation of Thyroid Hormone
Thyroid Hormone Receptor Family Hypothalamus – stimulates release of TSH via TRH
Type THR A THR B Pituitary – regulates synthesis & secretion of thyroid hormones via
Chromosome 17 3 TSH release
T3 Affinity High High "-chain – unique to TSH & confers specificity of hormone
THR TR!, TR!1 TRB-1 TRB-2 TSH – once secreted, acts as thyroid follicle cell via specific receptor
Tissue Cardiac, Brain, Pituitary, T3/T4 TSH TRh
Distribution Skeletal Liver, Cochlea,
Kidney Retina
PHYSIOLOGY)[DKA)(201632017)]) 174)
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Metabolic & Developmental Effects Physiologic effects of Thyroid Hormone
State Hypothyroid Hyperthyroid T4/T3 ! Enter the cell (Diffusion/ Carrier-mediated
Thyroid Hormone levels transport) ! Cytoplasm, & binds to cytosol,
microsomes, mitochondria & nucleus
BMR
Thermogenesis Hormone Responsive Tissues
Responsive Unresponsive
Proteolysis Pituitary, Intestines, Liver, Heart, Spleen, testes,
Lungs, Kidney, Skeletal Muscles Adult Brain
Catecholamine Normal Normal Unresponsive tissues ! Contains thyroid hormone
Serum Glucose Normal Normal receptor that are not able to increase BMR
Serum Cholesterol
Autoregulation – exceeds 2mg/day; suppresses
ANS -! Expression of B NADPH oxidase and inhibits NIS & TPO genes
adrenoreceptor
Thyroid Storm – an Acute Thyrotoxic Crisis; occurs
End-Organ Effects in hyperthyroid patients; provoked by stress of
System Effects infections, surgery & trauma
Basal oxygen consumption & heat
General production Effect on newborn
metabolic BMR, Na+-K+-ATPase activity; Cholesterol Mother Newborn
oxidation & biliary secretion Hyperthyroid ! Hypothyroid
Respiratory Minute ventilation, respiratory rate Hypothyroid ! Hyperthyroid
Thyroid Dysfunctions
heart rate, stroke volume, cardiac output,
Disease Description
Cardiovascular systolic BP, positive ionotropic effect
Hyperthyroidism Excess thyroid hormone
Diastolic BP, peripheral vascular
(Thyrotoxicosis)
resistance
Hypothyroidism Deficient thyroid hormone
Nervous Growth of cortex; axons & dendrites
(Myxedema)
proliferation; myelination, synaptogenesis,
reduces catecholamine levels (NE) Goiter Diffuse enlargemnt (prolonged
TSH elevation)
Others Normal tooth, skin & appendage growth,
normal endochondrial ossification, linear bond Thyroid nodule Focal thyroid enlargement
growth & epiphyseal maturation Euthyroid Caused by altered transport/
metabolism of thyroid hormone
PHYSIOLOGY)[DKA)(201632017)]) 175)
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Thyroid Autoimmunity Hyperthyroidism
Antigens Description Types Affected T3/T4 TSH TRH
Thyroglobulin Ab cross react w/ Primary Thyroid gland
acetylcholineesterase in eye; found in
fat Secondary Pituitary
TSH-Receptor Ab may be stimulating/blocking in Tertiary Hypothalamus
nature; common in Grave’s Disease
Thyroid Microsomal Ag; Ab identified to Hypothyroidism
Peroxidase precipitate it (deGroot) Types Affected T3/T4 TSH TRH
Condition Hypothyroid Hyperthyroid Primary Thyroid gland
T3/T4
Secondary Pituitary
TSH
Tertiary Hypothalamus
Intolerance Cold Heat
Effect on bowel Constipation Diarrhea
Other effects Slow speech Tremor
Thyroid Hormone Deficiency in Infants (Cretinism)
Iodide Deficiency Disease (IDD) – world’s most prevalent;
produces stillbirths, cretinism & goiter
Types Description
Congenital Lack of thyroid gland
Production Failure Genetic gland defect
Endemic Iodine lack in diet
PHYSIOLOGY)[DKA)(201632017)]) 176)
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CALCIUM & PHOSPHATE REGULATION
Calcium Distribution in body: Patient Total Ca2+ Ionized Ca2+
Distribution Description Hyperalbuminuria Normal
99.3% Bones, teeth (Hydroxyapatite)
Hypoalbuminuria Normal
0.6% Soft tissues
0.1% Extracellular fluid
Negligible ICF (ER & mitochondria) Acute Effects
H+ Ionized Ca2+ Condition
Circulating Plasma Calcium exists in 3 forms Acidemia
Distribution Form
Alkalemia
50% Free ionized Calcium (Active)
45% Protein(Albumin)-bound
5% Complexed with anions Hypocalcemia Effect Hypercalcemia
Ionized Calcium
Circulating Plasma Phosphate exists in 3 forms Shift to more negative threshold potential Shift to less negative
Distribution Form Nerve excitability
84% Free ionized Phosphate (Active)
10% Protein(Albumin)-bound Muscle excitability
6% Complexed with anions
Calcium Phosphates
Total Plasma Ca2+ = Free ionized + Protein-bound
$! Nerve impulse $! Forms high-energy
Ca2+ Biological $! Blood coagulation phosphate
functions $! Enzymatic co-factor $! Phosphorylation of lipids,
Total Plasma Calcium Range: 8.5-10.5 mg/dl
$! Muscle & myocardial cofactors, 2nd messenger,
Plasma ionized calcium: 4.2-5.2mg/dl
contraction proteins
Laboratory Assays for Calcium
Phosphorus distribution in body:
Assay Content
$! Majority in bones & teeth
Plasma Total Measures both ionized Ca2+ + $! Majority in ICF than ECF
Ca2+ Albumin-bound
$! Small amounts in plasma
Plasma Ionized Measures only free ionized
Ca2+ Ca2+
PHYSIOLOGY)[DKA)(201632017)]) 177)
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Processes that regulate circulating Ca & P in body: 3 receptors of parathyroid gland
Regulation Entry Exit Receptors CaSR VDR Phosphate
GI Dietary absorption -! (Ca-sensing) (Vit. D receptor) receptor
Bone Resorption Formation Action Ca2+ Vit. D PO4
Renal Reabsorption Excretion
PTH production Inhibited Inhibited Stimulated
& secretion
Ionized Calcium Phosphate
Factors affecting PTH production & secretion:
Factor Effect
Calcium Stimulates PTH synthesis & secretion
Phosphate Plasma phosphate directly stimulates PTH
Parathyroid Hormone
secretion ! fall on ionized Ca2+ ! stimulate PTH
•! produced & secreted by chief/principal cells
Vitamin D Inhibits PTH gene transcription ! PTH synthesis
•! Half-life: <5 minutes
•! Pulsatile secretion
•! Acts on osteoblast iCa-PTH response curve – shifted to RIGHT (set point is higher)
•! Single chain of 84 amino acids •! PTH secretion ! small alterations in Ionized Ca2+ ! Total
Terminal Amino acids Ca2+ concentration kept constant ! PTH secretion rises
N-terminal 1-33; active part (Response curve = Steep)
C-terminal 34-84; •! Familial benign Hypercalcemic Hypocalciuria (FBHH) –
inherited inactivating mutation in CaSR gene leading to less
PTH receptors – mediate systemic actions of PTH & sensitive CaSR ! slightly higher than normal blood calcium
found in osteoblasts in bones; proximal & distal range ! asymptomatic
convoluted tubules of kidney
Feedback loops in Calcium Control
PTH actions – major regulator of Ca2+ & PO4 PTH – acts via PTH receptors in kidneys & bones
PTH Plasma Ca2+ Organ Method Effect
Ca2+ reabsorption; Vit. D production
PTH Bone resorption/ Renal Kidney Direct
Tubular reabsorption PO4 reabsorption
PTH stimulating renal 1,25
Bone Direct Bone resorption
VitD synthesis
PTH Plasma phosphate Intestines Indirect Via Vit. D which enhances Ca2+
reabsorption in intestines
PHYSIOLOGY)[DKA)(201632017)]) 178)
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Vitamin D – circulates in blood bound to Vitamin D-binding Passive Diffusion (via paracellular pathway)
protein (DBP); must undergo hydroxylation Part
Source Vitamin D form Description Proximal tubule 70%
Skin Precursor 7- Converted to cholecalciferol Thick ascending limb 20%
cells dehydrocholesterol (Vit. D3) upon UV radiation DCT 9%
Diet Vit. D3 Animal source: liver, fish, Collecting Duct <1%
(Cholecalciferol) dairy products
Vit. D2 Plant source SI absorbs Ca2+ by 2 mechanisms:
(Ergocalciferol) Mechanism Paracellular Transcellular
Passive absorption Active absorption in
Synthesis of Vitamin D throughout SI duodenum
"! Dehdyrocholesterol (Precursor) ! UV light Effect NOT controlled by ! Ca2+ enters via Ca
"! Becomes Cholecalciferol (Vitamin D3) Vitamin D channel
"! In liver. Hydroxylated to 23(OH)D – storage form Predominant; non- ! Ca2+ bound to
"! 25(OH)D ! transported to kidney where it is hydroxylated saturable calbindin
by 1-! hydroxylase ! 1,25-(OH)2-D (active) ! Enteroctes extrudes
"! 25(OH)D ! may be hydroxylated to 24,25-(OH)2D which Ca2+ via Ca2+ & Na+-
is less potent Ca2+ pump
Phosphate = apical membrane of small intestine via Na/Pi
Actions of Active Vitamin D cotransporter
Effect Small Kidney Bone
intestine Vitamin D effect
Calcium Ca2+ Ca2+ Ca2+ Effect Direct Effect Indirect Effect
absorption absorption absorption Bone Bone resorption Bone formation
Paracellular & Transcellular Bone Mobilizes Ca2+ out of bone; More Ca2+
Transcellular pathway in Formation both osteoblast & osteoclast available to
pathway PCT have Vit. D receptors mineralize osteoid
Phosphate Phosphate Phosphate Inhibits
absorption absorption Phosphate
absorption
Vitamin D Inhibits
Vitamin D 1-
hydroxylation
PHYSIOLOGY)[DKA)(201632017)]) 179)
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Calcitonin Bone cells
,! secreted by parafollicular cells Type Osteoblast Osteoclast Osteocyte
,! Calcitonin release stimulated by 1,25(OH)2D & gastrin Origin Primitive Hematopoeitic Osteoblast
,! Actions on bones ! targets osteoclast decreasing bone mesenchymal stem cell
resorption Function Bone Bone Mechano-
Calcitonin Effect formation resorption sensors
Deficiency DOES NOT produce HYPERcalcemia Life span 3 months 2 weeks 20 years
Excess DOES NOT produce HYPOcalcemia Receptors PTH, Vit D, Calcitonin
Sex steroids
Parathyroid Hormone Related Protein (PTHrp) Osteoid – matrix of proteins synthesized by osteobaslts
made of type I collage; provide sites of nucleation of
•! Single chain polypeptide 140-aa
hydroxyapatite crystals
•! Paracrine actions
Hydroxyapatite crystals – Ca10(PO4)6(OH)2
•! Role in alveolar bone resorption for normal tooth
development
Effects of Hormones on Bone
•! Regulates differentiation of keratinocytes & growth of hair
Bone Formation Bone Resorption
follicle
Stimulants PTH (Form=Resorb) PTH (Resorb>Form)
•! Regulate endochondral bone formation
Vitamin D Vitamin D
GH/IGF-1 IL-1/IL-6
Bone Remodeling
Insulin TNF-A/TNF-B
Types Cortical Trabecular Estrogen/Androgen Excess T3/T4
Other names Compact Spongy, Cancellous, Transforming GF-B Excess Cortisol
Medullary Inhibitors Excess Cortisol Estrogen/Androgen
Total bone mass 80% 20% Calcitonin
Distribution Outer layer Interior of bones Transforming GF-B
Function Strength for Calcium turnover;
weight constantly being formed Pulsatile PTH ! PTHR
bearing by & resorbed by
Osteocatabolic Osteoanabolic
long bones osteoblast & osteoclasts
RANKL Osteoblast
Bone turnover Composition of Bone Differentiation
Cortical < Trabecular Extracellular Cellular Osteoclast Apoptosis
Total Bone Mass Osteoid; Osteoblast, Differentiation
Component Mineral Osteoclast,
Cortical > Trabecular Bone Resorption Bone Formation
component Osteocytes
PHYSIOLOGY)[DKA)(201632017)]) 180)
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Bone Remodeling Bone Resorption
•! Osteocytes within mineralized bone ! acts •! Osteoblasts – expresses factors inducing differentition & activation of
as mechanoreceptors to sense mechanical osteoclasts from cells of monocyte/macrophage lineage
stress •! Release of M-CSF ! induces earliest osteoclast precursor
•! Respond by increasing PGE2 production differentiating process
•! PGE2 reaches osteoblast lining cells •! M-CSF acts in concert with RANKL to promote osteoclastogenesis
•! Osteoblast – initiates recruitment & •! RANKL binds to receptor RANK on osteoclast precursor membrane to
differentiation of osteoclast induce osteoclastogenesis
•! Osteoclasts – resorb an area of mineralized •! Osteoclasts attached to endosteal & periosteal surfaces of bone &
bone settles down sealing to bone via integrins
•! Process reverses formation as osteoblast •! Ruffled border – created by infolding of osteoclast’s plasma
precursors are recruited to site & membrane
differentiate into active osteoblasts •! Acidification ! dissolves hydroxyapatite crystals forming shallow
•! Osteoblasts lay new organic matrix & depression
mineralize it •! 2 weeks of bone resorbing, osteoclasts receive different signal from
•! New bone ! replace reabsorbed mature neighboring osteoblast
bone •! Osteoprotegerin (OPG) – acts as soluble decoy for RANKL !
•! Compensation ! coupling of formation & proosteoclastic signal from osteoblast is terminated
resorption
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PHYSIOLOGY)[DKA)(201632017)]) 181)
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ENDOCRINE PANCREATIC HORMONES
Pancreas – retroperitoneal organ associated with GIT Biphasic pattern of glucose stimulation by beta cells
Function Description •! 95% reserved pool
Exocrine 80% Made up of acinar tissue secreting •! 5% secretory granules in releasable pool
digestive juice into duodenum
Endocrine 1-2% Made up of islets of Langerhans Insulin – crosses basal lamina of B cell & neighboring
scattered & distributed throughout fenestrated capillaries to reach blood stream
glandular substance (acini) Phase Time Rate Description
Acute/ 5-15 Rapid Initial burst of insulin secretion
Islets of Langerhans – functional unit of endocrine Early mins & result of secretion of preformed
pancreas; made up of clusters of hormone-secreting insulin secretory granules
endocrine cells Chronic/ 2-3 Slow More gradual & sustained insulin
Cell types Distribution Secretions Late hours secretion as result of synthesis of
new insulin molecules
B cells 60-75% Insulin, C-peptide, amylin
A cells 25% Glucagon, GLP-1, GLP-2 C-peptide – co-secreted in inherent amounts of insulin;
D cells 10% Somatostatin used as measurement to provide information regarding rate
F cells 1% Pancreatic polypeptide of insulin secretion
Reason for C-peptide measurement:
Central portion (B cells) – receives arterial blood nearer the $! Not extracted/degraded by liver (No 1st pass effect)
surface (A & D cells) receive blood containing secretions $! Can be distinguished between endogenous &
from inner cells exogenous source of insulin
Half Life
Neural inputs – sympathetic & parasympathetic nervous
C-peptide > Insulin
system
Form Chains Disulfide Synthesis
bonds Insulin secretion
Preproinsulin A,B,C Translation of $! 40-50 units/day
genetic code to $! pulsatile & rhythmic
ribosomes $! increases in 8-10 mins after a meal
Proinsulin A,B,C 2 inter Nucleus $! peaks within 30-45 mins
Insulin A,B 2 inter, Synthesized in $! circulates in unbound form
1 intra polyribosomes of $! degraded in liver, kidneys & tissues
RER $! Basal Insulin levels: 10-20 uU/mol
$! Plasma Half-life: 5-8minute
PHYSIOLOGY)[DKA)(201632017)]) 182)
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GLUT Transporters Stimulators
GLUT Dependency Affinity Sulfonylureas – oral treatment of Type II diabetes; Receptors
GLUT-1/3 Insulin Low affinity hexokinase with ATP-dependent K channels – block & so directly
GLUT-2 independent High affinity stimulates insulin secretion & promote insulin’s action in
peripheral tissues
GLUT-4 Insuline Muscles & Adipose Tissues
dependent Insulin Secretion
Stimulators Inhibitors
Mechanism & Regulation of Insulin Secretion Sulfonylureas Somatostatin
Pancreatic B-cell function – fuel sensor that responds to Incretin Effect Catecholamines
changes in plasma energy substrates, releasing insulin in Vagal Parasympathetic Sympathetic
response to integrated signals from nutrients, hormones, AAs & Long chain Free FAs Leptin
somatostatin & neurotransmitter
Incretin Effect – GI hormones such as GLP-1, GIP, Gastrin,
Glucose – primary stimulus for insulin secretion Secretin, CCK
$! Released after a meal – causing increase in B cells
Mechanism of Glucose-stimulated insulin secretion sensitivity to glucose
)! Glucose enter cell via GLUT-1 transporter $! Anticipatory increase – insulin secretion
)! Mediates facilitated diffusion of glucose into cell $! GIP & GLP-1 – act by increasing Ca influx through
)! Once inside, Glucose ! G-6-P by glucokinase (rate- voltage-gated Ca channels
limiting step & considered major mechanism for $! Do not increase insulin secretion in absence of glucose
glucose sensing & adjustment of amount of insulin
secreted) Long Chain Free FAs – act through GPCR40 on B cell
)! Glucose-6-Phosphate – oxidized to form ATP increasing ATP through oxidation
)! Increased ATP inhibits ATP-sensitive K+ channels
)! Inhibition of K+ channel – causes membrane Amino acids & Vagal parasympathetic innervations –
potential to become more positive (depolarization) stimulates insulin secretion by increasing Ca intracellularly
)! Depolarization ! Activates voltage-gated Ca
channel in plasma membrane Sulfonylureas ATP-dependent Insulin
)! Activation of Ca channel – promotes Ca influx & K channels secretion
increase Ca con’c Incretins (GLP-1; GIP; Insulin Ca influx
)! Elevated Ca con’c in cytosol ! exocytosis & release CCK; Secretin; Gastrin) secretion
to blood insulin Long chain Free FAs ATP Insulin
secretion
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PHYSIOLOGY)[DKA)(201632017)]) 183)
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Inhibitors: Insulin receptor
Somatostatin – potent inhibitor of both insulin & glucagon; ,! Heterotetramer
decreases utilization of absorbed nutrients to prevent rapid ,! Contains 2 extracellular alpha chains & 2 membrane-
exhaustion of food spanning beta chains
,! Once insulin reaches target tissue ! binds to alpha
Catecholamines (Epinephrine & Norepinephrine) – subunit of insulin receptor ! autophosphorylation of
released during sympathetic stimulation; stimulates alpha- beta-subunit receptor
2-adrenoreceptors; inhibits insulin secretion ,! Tyrosine kinase activity induced ! cascade of cell
phosphorylation ! increase/decrease activity of
Leptin (Adipocytokine) enzymes (including IRS)
.! Adipocyte-derived protein that signals infor to the ,! Substrates ! form complexes with docking proteins
hypothalamus about adiposity & nutrition (PIK3)
.! Controls eating & energy expenditure ,! Muscles & Adipose ! activation of insulin receptor !
.! Directs storage of excess caloric intake into adipose activation of PI3K ! speeds translocation of GLUT-4
tissue instead of peripheral tissues ,! Increased GLUT 4 transporters ! Greater rate of
Glucose movement from ECF via Facilitated diffusion
Somatostatin Insulin & Glucagon
Insulin Receptor Substrates (IRS) – mediates effects of
Catecholamines Insulin secretion glucose on fat & protein metabolism
Leptin Insulin Output
Phosphoinositide-3-kinase (PI3K) – major pathway in
Insulin Leptin Output mediation of insulin-stimulated glucose transport &
metabolism
GLUT-4 transporters Glucose movement
Metabolic Effects of Insulin:
Insulin (Glycogenic)
+! Hormone of abundance Principal Actions of Insulin
+! Great abundance of energy giving foods on diet Type Rapid Intermediate Delayed
+! Important role in turning excess energy into stores of Time Seconds Minutes Hours
carbohydrate, protein, fat Protein & glycogen mRNAs
+! Orchestrates fuel metabolism during periods of feeding Effect synthesis for
& fasting Glucose; Protein degradation lipogenic
+! Diminishes mobilization of endogenous fuel stores amino & phosphorylation of
+! Stimulates carbohydrate, lipid & amino acid synthesis acids; K+ gluconeogenic
+! Antigluconeogenetic, antilipolytic & antiketotic to insulin
PHYSIOLOGY)[DKA)(201632017)]) 184)
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Glucagon Major Fuel source during exercise
$! Large peptide Fuel Period
$! Preproglucagon – proteolutically cleaved in alpha cell in Brief Exercise Muscle Glycogen
cell-specific manner to produce the 29-amino acid Plasma glucose (40%) Longer periods (1-2 hours)
peptide
Free FA (60%)
$! Circulates freely & has haf-life to about 5 minutes
FFA Very prolonged exercise
$! Liver – main site of action
$! Glycogenolytic; gluconeogenetic; lipolytic & ketogenic
Circulating catecholamines – stimulate the secretion of
$! Hormone of energy release
glucagon via Beta-2 adrenergic receptors; released in
$! Increase plasma concentration of glucose & ketones respone to chronic hypoglycemia to amplify effects of
glucagon; acts as primary counter regulatory hormones on
Glucagon Secretion skeletal muscles & adipose tissues
Stimulators Inhibitors
Hypoglycemia Hyperglycemia Pancreatic B cells – contain GABA; released coincidentally
Amino acids Fatty acids with insulin during hyperglycemia
Acetylcholine Ketones
Epinephrine Somatostatin GABA – acts on A cells to inhibit glucagon secretion by
Norepinephrine Insulin activating GABA receptors; Cl- channels & resulting Cl-
CCK, VIP, NPY GLP-1 & GIP influx hyperpolarizes A cells
Exercise
Decrease blood glucose – primary regulator of glucagon Blood glucose Glucagon
secretion; indirect effect of removal of insulin’s inhibitory
effect on glucagon Catecholamines Glucagon
CCK – released after ingestion of protein-rich food; increase CCK Gluconeogenesis Glucagon
glucagon by causing release of glucose from liver &
gluconeogenesis of amino acids Amino acids Glucagon Insulin
High Amino Acids – stimulate secretion of glucagon & GABA Insulin Glucagon
promotes rapid conversion of amino acids to glucose; also,
stimulates insulin secretion Glycogenolysis – exceeds glycogen synthesis & supports
hepatic glucose output for 12 hours; takes over after
Exercise – beneficial in preventing blood glucose by glycogenolysis
increasing glucose production
PHYSIOLOGY)[DKA)(201632017)]) 185)
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Ketogenesis – supplements blood glucose in that the brain Somatostatin – secreted by delta cells; manufactured by D
can use ketone bodies after several days of fast cells of GIT, hypothalamus & other CNS sites; play role in
regulation of islets cells’ secretion
Major effects of Glucagon in liver:
Stimulates Inhibits Regulation of Somatostatin:
Glycogenolysis Cholesterol synthesis Stimulated by Inhibited by
Gluconeogenesis Glycolysis Glucagon Insulin
Beta oxidation of FA Glycogenolysis Amino acids
Lipolysis Fatty acids
Ketogenesis GIT hormones
Production of VLDL Increase blood glucose
PHYSIOLOGY)[DKA)(201632017)]) 186)
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Fuel Homeostasis: Factors Insulin Glucagon
Regulatory & Counter regulatory Hormone Main effect Blood glucose; FFA; Blood glucose;
Different Hormones that fuel metabolism: Ketones; Amino acids FFA; Ketones
1.! Favoring either storage or dissipation of energy Glycogenesis
)! Insulin favors storage Cellular glucose
)! Glucagon, epinephrine, cortisol, GH & thyroid uptake Inhibits
hormone promotes dissipation of these fuels Lipogenesis Stimulates
Lipoprotein Lipase
2.! Feedback of plasma glucose concentration on K+ uptake into No Effect
secretion of hormones & their plasma glucose cell
)! Insulin – fall in blood glucose Protein Syntesis
)! Energy dissipating hormones – causes rise in Hormone-sensitive
blood glucose con’c
lipase
Glycogenolysis Inhibits Stimulates
3.! Blood glucose controller
Gluconeogenesis
)! Insulin – major regulatory hormone
Lipolysis
)! Glucagon, Catecholamines, Cortisol & GH
– counter regulatory hormones Ketogenesis
PHYSIOLOGY)[DKA)(201632017)]) 187)
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ADRENAL PHYSIOLOGY
Adrenal Zone Description Secretions Regulation Mnemonics
Glomerulosa Thin outermost Does not express Mineralocorticoids: Angiotensin II; G = SALT
layer (15%) CPY17 Aldosterone Potassium
Cortex Fasciculata Middle & widest Secretes small amounts Glucocorticoids: HPA axis via F=
zone (75%) of androgen & estrogen Cortisol ACTH SUGAR
Reticularis Inner zone of Secretes small amounts Androgen: Andorgen- R = SEX
cortex (10%) of estrogen & Sex hormones stimulating
glucocorticoids hormone; ACTH
Medulla Chromaffin cells – Neural crest-derived cells assoiciated (80%)Epinephrine;
with sympathetic ganglia (20%)Norepinephrine
Hormones secreted by adrenal cortex and its functions Synthesis & Kinetics of Adrenal Steroids
Hormones Functions Principal secretion
Mineralocorticoids Affect electrolytes Aldosterone Cholesterol – substrate for human steroids
(Sodium & Potassium) synthesis; provided by LDLs in circulating
Glucocorticoids Increase blood glucose Cortisol plasma
concentration; Add’l Acetate – synthesizes cholesterol in small
effect on both protein amounts de novo
& fat metabolism
Sex hormones Exhibits same effect on Androstenedione; )! Transport of cholesterol is regulated by
testosterone; Dehydroepiandrostene feedback mechanism that alters amount
available for cholesterol synthesis
)! Cholesterol enters cell and is delivered into
60% aldosterone – combines with plasma proteins
the mitochondria
Adrenal hormone Plasma concentration Secretory Rate
)! Cleavage by enzyme cholesterol desmolase
Aldosterone 6ng/100ml 0.15mg/day to form pregnenolone
Cortisol 12ng/100ml 15-20mg/day )! All steps in synthesis of aldosterone, cortisol
(Fluctuates throughout the day) & androgens occur in mitochondria &
endoplasmic reticulum
Cortisol bound Adrenal Medulla Secretion )! A change in one hormone can cause
Transcortin > Albumin Epinephrine > Norepinephrine different types of hormones
)! 90-95% cortisol binds to cortisol-binding
Half-life Circulating Norepinephrine
globulin/transcortin
Cortisol > Aldosterone Sympathetic > Adrenal
)! Degraded in the liver & conjugated to
(60-90min) (20min) NS (70%) Medulla (30%)
glucuronic acid, to lesser extent, to sulfate
PHYSIOLOGY)[DKA)(201632017)]) 188)
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Aldosterone escape – return to normal of Na+ & H2O excretion by 45minutes = required time before rate of Na+
kidney as result of pressure natriuresis & pressure diuresis; BP transport increases
remains ELEVATED as long as levels of aldosterone is HIGH Nongenomic action of cAMP formation
aldosterone
PHYSIOLOGY)[DKA)(201632017)]) 189)
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Aldosterone Effect on Potassium SGK1 ENaC K+ channels
Aldosterone Hypokalemia
SGK = Serum Glucocorticoid-stimulated Kinase
Aldosterone Hyperkalemia
CAP1 ENaC K+ channels
K+ secretion CAP1
K+ permeability
PHYSIOLOGY)[DKA)(201632017)]) 190)
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Functions of Glucocorticoids D.! Protein Metabolism
95% glucocorticoid activity = results from secretion of Cortisol Protein Catabolism
cortisol (Hydrocortisone) & small significant amount of
corticosterone Cortisol Protein Synthesis
Cortisol AA transport to extrahepatic
A.! Gluconeogenesis – best known effect tissue
Cortisol Enzymes required for Cortisol Formation to RNA
AA!Glucose conversion
Cortisol Mobilization of AA from Cortisol Liver Proteins & Plasma Proteins
extrahepatic tissue
Cortisol AAs availability in plasma Cortisol Conversion of amino acid to
glucose
Cortisol Gluconeogenesis
E.! Stress & Inflammation
Cortisol Insulin effect to inhibit Stress ACTH Secretion Cortisol
gluconeogenesis
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Cortisol causes resolution of Inflammation Effect of INCREASE Cortisol on Different Tissues & Organ System
<! Administration of Cortisol System Effect
+! Mobilization of AAs to repair damaged tissues Production of Vasodilator Prostaglandins
+! Increase glucogenesis & makes extra glucose Cardiovascular
Vasoconstriction
available in critical metabolic systems
+! Increased FAs for cellular energy Reproductive Reproductive behavior
+! Cortisol effect for inactivating/removing
inflammatory products Skeletal Muscle strength
PHYSIOLOGY)[DKA)(201632017)]) 193)
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REPRODUCTIVE PHYSIOLOGY
Similarities & Differences Y chromosome – single most important
Gender Male Female gene determinant for maleness
5th week of Gestation Indifferent Gonads 1! Contains SRY gene (Sex-determining
Reproductive cell origin Primordial Germ Cell region of Y) – located on distal arm of Y
Coelomic Epithelium Sertoli cells Granulosa cells chromosome
Mesenchymal/ Leydig cells Theca cells 1! Contains H-Y gene- next to SRY gene
Interstitial cell line
Mitosis Before puberty Before birth X-chromosome – only important in female
in the absence of Y-chromosome; Single
Continuous source of Stops during latter
chromosome is sufficient to cause
new germ cells part of fetal life
development of female genital ducts &
Meiosis After puberty After fertilization
genitalia
Reproductive cell Spermatogonia Oogonia
46 chromosomes Primary Spermatocyte Primary Oocyte 2nd X chromosome – inactive in other
23 chromosomes Secondary Spermatocyte Secodary Oocyte tissues
23 chromosomes Spermatids Mature Ovum
23 chromosomes Mature Sperm Basic Component of Reproductive System
) Component Function
Gender Male Female Gonads Endocrine function for
Cells Sertoli Leydig Granulosa Theca hormonal regulation;
Expresses FSH receptor Yes Yes Exocrine function for
Expresses LH receptor Yes Yes Yes gametogenesis
HDL & LDL receptor Yes Yes Reproductive Gamete development,
Tract function & transport;
Androgen receptor Yes
Fertilization,
Steroidogenic Yes Yes Yes
implantation & gestation
CYP11A1 Yes Yes for women
CYP17 (17-hydroxylase Yes Yes
& 17,20-lyase activity)
CYP19 Yes Yes
Produces Estradiol 17" Yes Yes
17"-HSD Activity Yes Yes Yes Little
3"-HSD Activity Yes Yes
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Male Reproductive System Spermatogenesis
$! Continuous, Life-long gametogenesis )! Spermatogonia – derived from primordial germ cells
$! High density of sperm that migrate into testis during embryo formation &
$! Roles of Gonadal Hormones become immature germ cells
.! Support of gametogenesis )! Spermatocytogenesis – divides mitotically to generate
.! Maintenance of male reproductive tract & sperm daughter spermatogonia
production )! Majority of daughter cells enter meiotic division
.! Maintenance of secondary sex characteristics & libido )! Result into haploid spermatozoa
)! Incomplete cytogenesis ! Daughter cells remain
Testes interconnected by cytoplasmic bridge contributing the
•! Reside outside the abdominal cavity in scrotum to synchrony of development of clonal population
maintain temperature at least 2 degrees less than )! Spermiogenesis (Streamline spermatozoa)
body temp. Part Organelle Component/Function
•! Divided into 300 lobules ! Divided into 2-4 loops of Head Condensed Acrosome; Anterior 2/3; contains
seminiferous tubules nucleus enzymes like hyaluronidase &
•! Each loop ! empties to Rete testis ! Continuous proteolytic enzymes
with Efferent Ductules ! Head of Epididymis Body Mitochondria Generates motile energy
•! Viable Sperm – stored in tail of Epididymis & Vas Tail Flagella Axoneme – central skeleton
Deferens for several months Collection of mitochondria
surrounding the axoneme
Compartments within each lobule:
Compartment Composition Leydig Cells
Intratubular Seminiferous Epithelium, Sperm cells, 1! Steroidogenic stromal cells
Sertoli cells 1! Synthesizes cholesterol de novo through LDL receptors &
Peritubular Neurovascular elements, CT cells, HDL receptors
Immune cells & Interstitial cells of Leydig 1! Stores cholesterol as cholesterol esters
0! Free cholesterol ! Cholesterol ester hydroxylase
Spermatogonia ! Primary Spermatocytes ! Secondary 0! Cholesterol ! Pregnenolone (CYP11A1)
Spermatocytes ! Spermatid ! Mature Sperm 0! Pregnenolone ! Progesterone (17-Hydroxyprohesterone)
0! Pregnenolone ! Androstenedione (CYP17 & 3"-HSD/
Sperm motility is also regulated by cAMP & Calcium 3"-hydroxysteroid dehydrogenase)
PHYSIOLOGY)[DKA)(201632017)]) 195)
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Sertoli cells Maturation of Sperm in the Epididymis
$! Surround sperm cells & provide structural support within $! From Seminiferous Tubules, sperm travels 6m long
epithelium tubule of epididymis for several days
Junctions Function $! Sperm = non-motile & cannot fertilize ovum
Sertoli-sperm cell Adhering & gap junction; $! After 18-24hours in Epididymis, develops capability
junctions Guide sperm toward the lumen of motility is developed
Sertoli-Sertoli cell Blood-Testis Barrier; Tight junctions $! After ejaculation, final motility is achieved
occluding junctions in Basal & Adluminal compartments $! 2 testes = 120 million sperm each day
$! Storage may be up to months or no longer than few
Functions days if high level of ejaculation & sexual activity
9! Sperm cell viability & development
9! Express androgen receptors & FSH receptors to support Sertoli cells & Epithelium of Epididymis = secrete
spermatogenesis special nutrient fluid that is ejaculated along with sperm
9! Express enzyme CYP19 (Aromatase) – converts Leydig containing testosterone, estrogen, enzymes, special
cell-derived testosterone to potent estrogen estradiol-17" nutrients that is essential for sperm maturation
9! Production of Androgen-binding protein (ABP) –
maintains high androgen level within adluminal Stored Sperm
compartment, lumen of seminiferous tubules Vas Deferens Epididymis
9! Provides appropriate bathing medium for sperm
>
9! Assists in mobilization of immotile sperm
9! Phagocytic function by engulfing residual bodies Normal motile, fertile sperm = capable of flagellated
9! Produces anti-mullerian hormone – induces regression of movement at velocitits of 1-4mm/min
the embryonic mullerian duct that is programmed to give
rise to female reproductive tract Medium pH Sperm motility
9! Produces Inhibin Neutral/Alkalinity
Acidity
Hormonal Factors that Stimulate Spermatogenesis
Testosterone Growth & division of testicular
germinal cells Temperature Sperm activity Lifespan
Luteinizing Stimulates Leydig cells ! testosterone
hormone secretion
Life expectancy of sperm in the female genital tract = 1-
Follicle-Stimulating Stimulates Sertoli cells ! Conversion 2days
Hormone of spermatids to sperm
Estrogen Essential for spermatogenesis
Growth Hormone Controls metabolic functions of testis
PHYSIOLOGY)[DKA)(201632017)]) 196)
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Prostaglandins aid fertilization via: Capacitation of spermatozoa
+! Reacting female cervical mucus to make it more receptive $! Required for fertilization of ovum
to sperm movement $! 1-10 hours= Time required to activate sperm for
+! Causes backward/reverse peristaltic contractions in uterus final processes of fertilization
& oviduct to move ejaculated sperm toward the ovaries (! Uterus & Fallopian Tube = wash away inhibitory
factors suppressing sperm activity in male genital
Organ Seminal Vesicle Prostate Gland ducts
Secretion Mucoid material Thin, milky fluid (! After ejaculation, sperm in vagina swim away from
Contents Fructose, Citric acid, Citrate ion, Phosphate cholesterol vesicles upward into uterine cavity !
Prostaglandins, ion, Clotting enzyme, losing excess cholesterol over next few hours !
Fibrinogen Profibrinolysin acrosome much weaker
During Empties contents into Slightly alkaline (! While in male genital ducts
emission & ejaculatory duct characteristics of Continuous exposure to many floating vesicles
ejaculation shortly after vas prostatic fluid maybe from seminiferous tubules (large amounts of
deferens empties quite important for cholesterol) ! toughening acrosome & preventing
sperm successful fertilization release of enzymes
of ovum (! Membrane of Sperm = more permeable to calcium
ions ! enters sperm in abundance giving flagellum
Semen = ejaculated during male sexual act its whiplash motion
Distribution Fluid from
Acrosome enzymes & Acrosome Reaction
60% Seminal vesicles
Enzymes Function
30% Prostate glands Hyaluronidase Depolymerizes the hyaluronic acid
10% Vas deferens polymers in intercellular cement
Small amounts Bulbourethral gland that holds ovarian granulosa cells
together
pH 6.0-6.5 = optimal pH for sperm to be motile Proteolytic Digest proteins in structural
enzymes elements of tissue cells that
Average pH of semen = 7.5 adhere to the ovum
Stored enzymes Begin to be released ! opening
Ca2+ ions = causes changes in cellular membrane that cover pathways between granulosa cells
leading edge of acrosome ! release enzymes rapidly as sperm so that sperm can reach the ovum
penetrates granulosa cell mass & zona pellucida of ovum
PHYSIOLOGY)[DKA)(201632017)]) 197)
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Fate and Actions of Androgens Peripheral Testosterone Actions
Intratesticular Androgen +! Regulates Sertoli cell function
"! Concentrated within adluminal compartment +! Increases RBC production
"! CYP19 (Aromatase) = converts small amount of +! Bone growth
testosterone to estradiol-17" +! Erectile function & libido
"! Levels greater than 100x more concentrated than +! Protein anabolic effect on muscle
circulating testosterone levels for normal +! Development of male genitary tract
spermatogenesis
Mechanism of Androgen Action
Peripheral Conversion to Estrogen Testosterone & DHT
;! Adipose tissue, Testosterone ! Estrogen •! Act through same androgen receptor (AR)
;! Bone maturation •! AR resides in cytoplasm ! chaperone protein (in
;! Insulin sensitivity absence of ligand)
;! Improves lipoprotein profiles •! Chaperone protein dissociation
•! Nuclear translocation of Androgen-AR complex
Peripheral Conversion of Testosterone •! Recruitment of Coactivator protein & general
-! Can be converted into potent non-aromatizable androgen transcription factors
5!-dihydrotestosterone by enzyme 5!-reductase
Transport & Metabolism of Androgens
Isoforms of 5!-reductase Testosterone bind to serum protein
5!-reductase 1 5!-reductase 2 Distribution Bound
'! Contributes to sebaceous '! Masculinization of 60% Sex hormone-binding globulin (SHBG)
gland & acne associated genitalia
38% Albumin
w/ puberty '! Growth & activity of
2% Free hormone
'! Selective 5!-reductase 2 penis & prostate gland
inhibitors '! Darkening & folding of
scrotum Testosterone excreted in urine
'! Treatment of prostatic
'! Growth of pubic, facial, Distribution
hypertrophy & prostatic
cancer body & axillary hair 50% Urinary 17-ketosteroids (conjugated
'! Strong growth-promoting '! Increased muscle mass androgens, -diol/-triol derivatives)
effects 30% Ketosteroids from testis
PHYSIOLOGY)[DKA)(201632017)]) 198)
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Hypothalamus-Pituitary Axis Prolactin
! Testis is regulated by parvicelular hypothalamic $! Mediated by Dopamine – a Prolactin-inhibiting factor
gonadotrophin-releasing hormone (GnRH) neurons $! Large amounts may cause impotency
-! Produces Luteinizing hormone (LH) & Follicle-stimulating
hormones (FSH) Inhibin
'! Induced by FSH
Cell Regulated Sertoli Cell Leydig Cell '! Feeds back on gonadotrope to selectively inhibit FSH
Stimulators LH FSH & Testosterone production
Negative feedback Stimulates synthesis '! 2 types are formed from 3 polypeptide subunits (!,
via: Testosterone, in “nurse cell” aspect "A & "B)
Other effects DHT, Estradiol-17" of Sertoli cell '! Activin – formed when sub-units "A & "B combine
Inhibiting Stimulation of as heterodimers "A"A, "B"B & "A"B ! Stimulates
expression of LH-" synthesis of dimeric FSH secretion
& GnRH receptor protein inhibin
Andropause
Male Reproductive Tract ;! Male climacterium
,! Sperm maturation - decapacitation ;! Principle: Spermatogenesis & testosterone production
,! Sperm storage & Emission do not suddenly decline at certain point in life of male
,! Production & Mixing of sperm w/ seminal contents unless pathologic process intervenes
,! Erection & Ejaculation ;! Sperm production declines after 50y/o
;! Can still maintain reproductive function throughout life
Male Sexual Process ;! Serum LH & FSH rises
Process Description Phases ;! Androgen production drops
Erection Result from afferent -! Flaccid phase Symptoms:
impulses from the -! Filling phase
:! Hot flushes
brain/penis via -! Tumescent phase :! Decrease libido & sexual potency
pudendal nerve -! Full erection phase :! Irritability
Ejaculation Spinal reflex w/ -! Emission :! Inability to concentrate
afferent pathways -! Ejactulation Proper :! Episodes of depression
similar to erection
PHYSIOLOGY)[DKA)(201632017)]) 199)
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Female Reproductive Tract Mural Granulosa Cells
Ovarian Follicle "! High numbers of FSH receptors
,! Functional unit of ovary "! Up-regulates CYP19 (Aromatase) – gene expression
,! Performs both gametogenic & endocrine function
,! Divides into stages: CYP19 ! androstenedione ! weak estrogen estrone
•! Resting Primordial follicle CYP19 ! Testosterone ! potent estrogen estradiol 17-"
•! Growing preantral follicle
•! Growing antral follicle FSH ! Expression of Inhibin B (Follicular phase)
•! Dominant Graafian follicle FSH ! LH receptors granulosa cells (Follicular phase)
•! Corpus luteum
Periovulatory period – time from LH surge to expulsion of
•! Atretic follicles
cumulus-oocyte complex out of the ovary (Ovulation)
Count Stage
7 million Starting number of primordial follicle Human Corpus Luteum
<300,000 Reproductive maturity 0! 14 days, +/- 2 days (Corpus luteum of menstruation)
450 Between Menarche & Menopausse 0! Regresses and becomes Corpus albicans
<1000 left At menopause 0! Involves release of Prostaglandins from both
granulosa lutein cells & uterus
Dominant Follicle Hormone Effect
.! Previous menstrual cycle Progesterone During LH surge; Peaks during
.! Antral follicles – recruited to begin rapid, midluteal phase
gonadotropin-dependent development FSH & LH Negative feedback from progesterone &
Prolifera quota estrogen
.! Decrease FSH levels ! Atresia ! Until one is left Inhibin A Secreted by granulosa lutein cell &
.! Largest follicle with most FSH receptor becomes selectively represses FSH secretion
dominant follicle Luteinization
.! Steroidogenic gland -! Change in steroidogenic function of theca & granulosa
-! Formation of corpus luteum capable of producing
Theca Cells high amounts of progesterone
'! LH receptors & produces androgens
'! Stimulates expression of steroidogenic enzymes Follicular atresia
'! Expression of CYP11A1, 3"-HSD & CYP17 with both %! Granulosa cells & oocytes undergo apoptosis
17-hydroxylase & 17,20-lyase %! Theca cells ! persist & repopulate cellular stroma of
'! Androgens – released from theca mural granulosa ovary to retain LH activity & ability to produce
cells androgens
PHYSIOLOGY)[DKA)(201632017)]) 200)
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Menstrual Cycle Menstrual Cycle
-! Length is averaged out to 28 days )! Corpus luteum dies; E & P levels fall
-! Range between 24-32 days )! Pituitary responds to falling E & P by increasing
-! 2 cycles with 2 phases per cycle: Ovarian & Uterine Cycle FSH secretion
)! FSH recruits large antral follicles ! Rapid growth
Ovarian Cycle – involves the maturation of ovarian follicle from phase ! secretes E & Inhibin
many primordial follicle found at birth )! E & Inhibin negatively feedback FSH
OVARIAN CYCLE )! FSH falls ! proliferative atresia to all but 1
Phases Follicular Luteal )! Dominant follicle produces high levels of E
Menstrual cycle 1st half 2nd half )! High E ! Positive feedback ! LH surge
Selection to become dominant Hormonal )! LH surge ! Meiotic maturation, ovulation &
follicle & ovulation secretions luteinization
Changes Recruitment & Growth of 15-20 of the )! Corpus luteum ! High P, along with E & inhibin
antral follicles corpus )! High P, E, Inhibin ! negative feedback on LH &
More follicular development occurs luteum FSH ! return to basal levels
independently than monthly )! Corpus luteum becomes less sensitive to LH !
menstrual cycle dies if LH level does not increase
PHYSIOLOGY)[DKA)(201632017)]) 201)
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Differences between enzymes Pregnancy
Hormone Estrogen Progesterone Human Placental Lactogen (hPL)
Forms Estradiol (most potent) Pregnenadiol '! Human chorionic somatomammotropin (hCS)
Estriol (Pregnant) Pregnenolone '! Structurally similar to prolactin & GH
Estrone (non-pregnant) '! Antagonistic action to insulin !
Rise in con’c Before LH surge After LH surge Diabetogenicity during pregnancy
Conjugated to sulfuric/ Preferred substrate
glucoronic acids for 5!-reductase Human Chorionic Gonadotropic (hCG)
Effects (! Produced in syncytiotrophoblasts
Uterus Growth & Proliferation of Anti-estrogenic effect (! Structurally related to LH, FSH, TSH
spiral arteries on myometrium (! !-glycoprotein subunit (GSU) & hormone-
Endometrium Proliferative Secretory specific "-subunit
Oviduct Growth & Activity to tubal Cyclic activity of tubal (! stimulation of steroidogenesis prolonging life
musculature musculature of corpus luteum
Cervix Mucous secretion Scanty secretion (! help maintain placental steroidogenesis
Breasts Extension of mammary Acinar & lobular progesterone
ducts; lobule & alveolar development during (! Double every 2 days; peaks at 10 weeks
growth luteal phase (! Responsible for nausea/morning sickness
Vagina Thickening of epith (! Stimulates fetal Leydig cell to produce
Others Linear growth of bones Increase body temp. testosterone
Predecidual cells
:! develops after differentiation of stromal cells via progesterone Hormonal changes:
:! must be prepared to form the decidua of pregnancy to Hormone Estrogen Progesterone
orchestrate menstruation in absence of pregnancy Production Syncytiotrophoblast Placenta
Dependent on Maintain
Relaxin other cell to quiscent
3! Polypeptide hormone secreted by corpus luteum & prostate provide 19C- myometrium &
3! Maintains sperm motility in men & help sperm penetrate the ovum Effect androgens for pregnant
3! During pregnancy, relaxes symphysis pubis & dilates uterine aromatization uterus
cervix Resides in fetal Induces breast
adrenal cortex growth &
CYP19 (Aromatase) – basis for the use of aromatase inhibitors in Lacks CYP17 differentiation
treatment of estrogen-dependent breast cancer in postmenopausal
women
PHYSIOLOGY)[DKA)(201632017)]) 202)
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Luteal-placental shift – switch from corpus-luteum derived Prostaglandins & Other cytokines – increases uterine
progesterone to placental-derived progesterone at about 8th motility thereby facilitating delivery
week of pregnancy
Lactation
Fate of Dehydroepiandrosterone sulfate (DHEAS) in fetal During Pregnancy
zone throughout most of gestation "! Suppression of Prolactin-inhibiting factors (PIF)
1! First fate "! Inhibition of prolactin secretion by estrogen
DHEAS ! Syncytiotrophoblast ! Desulfation by placental After Parturition
steroid sulfatase ! 19C substrate ! Synthesis of "! Loss of prolactin inhibition by estrogen ! Milk
Estradiol 17B & Estriol secretion
"! Onset of lactation throughout the:
1! Second fate $! Let-down process = process of suckling & oxytocin
DHEAS ! 16-hydroxylation in liver by CYP3A7 ! $! Milk secretion – continued prolactin; suppressed PIF
Converted by syncytiotrophoblast ! Estrogen (Estriol)
Return of Menstruation after Delivery
Parturition Who do not nurse within 6 weeks
Hormonal Mechanical Who do nurse Low estrogen & progesterone output;
Estrogen Stretch of Cervix Ovulation is inhibited; Inhibition of LRH
Uterine PGs Stretch of Uterine musculature
Menopause
Progesterone Reflexes from birth canal 9! Ovaries become unresponsive to gonadotropins
9! Estrogen & Progesterone level drops
9! Loss of negative-feedback inhibition
Corticotropin-releasing hormone (CRH)
9! Rise in serum LH & FSH
$! Increase rapidly during late pregnancy & labor
9! Loss of ovarian inhibin
$! Promotes myometrial contractions
Menopause SHBG bound
Oxytocin
,! Secreted by pars nervosa & plays important role in FSH level > LH level Testosterone
= Estrogen
parturition (M) (F)
,! Stimulates most powerful uterine contractions Free form
Albumin bound
Estrogen Oxytocin Testosterone Estrogen
Testosterone
> Estrogen
(M)
< (F)
Progesterone Oxytocin (M) (F)
PHYSIOLOGY)[DKA)(201632017)]) 203)
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