Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

PSL301H1S:
Human Physiology II

RESPIRATORY: OVERVIEW OF FUNCTION AND STURCTURE (LEC. 1)

Functions of the respiratory system
Structures of the respiratory system and their functions
How the respiratory system is protected from pathogens
How blood is transported to and from the lungs
How air gets into and out of the lungs
What happens during pneumothorax

Respiratory system works to transfer gases, regulate body pH, defend from airborne pathogens, and vocalizations
Airways
o Warms air to body temperature
o Humidifies air to 100%
o Filters air
Cilia:
Secretes watery saline
Beats in one direction to push out particles
Goblet cell:
Secretes mucus
Traps inhaled particles
Immune cells:
Secretes antibodies to disable pathogens: IgA (epithelial)
o Conducting system vs. Exchange surface

Alveoli
o One cell thick for epithelial and capillaries
Type I alveolar cell: epithelial cell
Type II alveolar cell: surfactant cell
o Macrophages in alveoli
o ECM = elastic fibers
o Gas exchange by passive diffusion down pressure gradients
Protection from pathogens and foreign particles
o Nose hairs filters
o Mucous and cilia
o Antibodies
o Macrophages in respiratory tract
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Blood transport to and from the lungs

Path of blood cell
o Right ventricle <3 pulmonary tract pulmonary arteries (going to both lungs) pulmonary arterioles
capillaries (being oxygenated) pulmonary veins left ventricle <3
Pulmonary vs. Systemic capillaries
o Pulmonary: carries O2 blood from lungs to heart
Overlapping branching = can compensate for blockage
o Systemic: carries O2 blood from LV to body
High risk of killing an area served by single branching of capillaries (i.e. not much overlap)

Air gets into and out of the lungs by pressure changes

Boyles Law: P1V1 = P2V2
o Inspiration: Patmos > Palv
o Expiration: Patmos < Palv
Inspiration muscles expand thoracic volume
o Diaphragm: main breathing muscle
Breathe in = contracts and moves down
Controlled by phrenic nerve from spinal C3/4/5
o External intercostals
o Sternocleidomastoids
o Scalenes
Expiration muscles only during active exhaling
o Internal intercostals
Forces rib cage inward
o Abdominal muscles
Forces rib cage inward, (-) abdominal volume

Pleura and pleural cavity important for lung inflation and movement without being fastened to thoracic wall
One pleural sac per lung
Fluid lubricates tissues as lungs expand
Intrapleural pressure: sub-atmospheric (3mmHg)
o Established in development
o Lung follows thoracic changes because of incompressible fluid in pleura, but needs low pressure
o Opposing elastic recoil pulls on chest wall and lung
Chest outward; lung inward elastic pull
o Decreasing during inspiration
3mmHg 6mmHg
Pneumothorax: lung collapse
o Injured lung = atmospheric pressure // Other lung = more negative intrapleural pressure to compensate
o Treat by manually inflating lungs and wet dressing only allow one-way airflow

PULMONARY VENTILATION (LEC. 2)

Properties of the lungs (compliance, resistance) affects ventilation
How lung function is measured (spirometry), definitions of lung volumes and capacities
Explain the changes in lung function seen in pulmonary disease

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Calculate total pulmonary and alveolar ventilation

Lungs properties that influence breathing

Compliance: ease of lung to change its volume because of intrapleural pressure
o Elastin fiber network
In the ECM between alveoli and endothelium
Elasticity decreases with age; inversely proportional to compliance (more elastic, less compliant)
Compliance = V/P
Low compliance = small volume, large pressure
Clinical conditions
Emphysema: high compliance // Pulmonary fibrosis = low compliance

o Alveolar surface tension
At the liquid-air interface
Overcome Palv to inflate the alveoli
Surface tension tends to shrink alveoli higher Palv
Surfactant: phospholipid disrupts H2O interaction
Made during fetal development, towards end of gestation; also by Type 2 alveolar cells
Prevents small alveoli from collapsing into large ones
o More surfactant in the smaller alveoli to equalize pressures
Resistance
o Type of flow
Laminar: resistance in inversely proportional to radius
Tubular: obstructions or change in diameter
Intermediate: mix of the two
o Airway diameter
Large diameter = more resistance
Trachea and bronchi (upper tract): large radii = more resistance
Bronchioles: large total cross-sectional SA = doesnt contribute to resistance
o Diameter can change; smooth muscle
Constriction= histamine, leukotrienes
Dilation= CO2, epinephrine, binding to 2 adrenergic receptors
More resistance = work muscle more to generate pressure change

Lung volumes and capacities

Volumes: unique
o Vt: normal breathing
o IRV: max. inhale volume change (after regular inhale)
o ERV: max. exhale volume change (after regular exhale)
o RV: trapped air, not exhaled
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Capacities: combinations of volumes

o Vital: max. inhale to max. exhale
o Inspiratory: regular exhale to max. inhale
o Functional residual: regular exhale to all of residual volume
Lung volume when intra-alveolar = atmospheric pressure
Buffers against changes in alveoli gas composition
Alveolar gas exchange volume > tidal volume
o Total lung: everything

FEV and FVC
o Forced expiratory volume: air volume forcefully exhaled in 1 second
o Force vital capacity: total air volume forcefully exhaled
o FEV/FVC = normally 80%
o Decrease by airway resistance (e.g. asthma)
o Changes due to disease
Restrictive lung disease: normal ratio, but smaller individual values (easy in, hard out)
Obstructive lung disease: low ratio

Calculating ventilation (pls know how to do this!!!!!!!!!!)

Total pulmonary ventilation = tidal volume x respiratory rate breaths/min
o Normally 6000mL/min
o AKA Minute ventilation
Alveolar ventilation = (tidal volume dead space volume) x respiration rate
o Volume of fresh air reaching exchange surface normal 4200mL/min
o Dead space ventilation
Conducting airways: trachea, bronchi, conducting bronchioles
First air exhaled is from the dead space
Dead space is not fully exhaled
First air inhaled is stale air from dead space (air exhaled into the dead space)
Dead space = 150mL
Ventilation can be improved by increasing depth and rate of breathing

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

GAS EXCHANGE AND GAS TRANSPORT (LEC. 3)

How much O2 and CO2 is in the air and alveoli
What determine how much gas dissolves into solution
How much O2 and CO2 is in the blood
How is O2 transported in the blood
How is CO2 transported in the blood

Daltons law of partial pressures

Total Patmos = Sum of partial pressures
o Partial pressure = fractional concentration x total pressure
o PB = PO2 + PCO2 + PN2 + PH2O
Fractional concentration: FO2 = 21%, FCO2 = 0.04%
PH2O = 47mmHg

Gas exchange of O2 and CO2 in the alveoli

Gas dissolution in solution depends on:
o Partial pressure
o Solubility of gas
o Temperature of solution
Partial pressure in alveoli
o PO2 = 100mHg // PCO2 = 40mmHg
Less than dry air so that gases move down pressure gradients
Passive diffusion for gas exchange
o Gas transfer = constant x partial pressure gradient x area/wall thickness
A/W thickness depends on alveoli exchange surface, distance between alveoli and capillary
CO2 more water soluble than O2
Conditions affecting gas exchange
o Emphysema
Higher compliance lowers PO2 in capillaries, sometimes alveoli
o Fibrotic lung disease
Different alveolar exchange surface = hard to get O2 into lungs
(-) PO2 in blood and alveoli
o Pulmonary edema
Fluids increase diffusion distance = low PO2 in capillaries
o Asthma
Bronchioles constrict
Low PO2 in alveoli = low Po2 in capillaries

Gases in the blood and their transfer

Oxygen and carbon dioxide amount in the blood
o Arterial blood: PO2 = 100, PCO2 = 40 (same as alveoli)
o Tissues: PO2 = 40, PCO2 = 46
o Venous blood: same as tissues
PO2 increases during blood oxygenation
Oxygen transport in blood
o Most O2 transported in RBCs, bound to hemoglobin
Hemoglobin: porphyrin ring, 4 Heme per hemoglobin
Reversible rxn of O2 + Hb Hb-O2
o Oxygen-Hemoglobin Dissociation Curve
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Right shift = more O2 unloading at the tissues
Exercise drops PO2 at tissues allow for more O2 unloading (45% more)
o Factors affecting affinity of Hb for O2
pH
Acidic = more unloading (right shift)
Less effect at high PO@ in the alveoli
Temperature
High temperature = more unloading (right shift)
PCO2 (Bohr Effect)
High PCO2 = more unloading (right shift)
2,3-DPG
Glycolysis intermediate, or made by RBCs in low oxygen (e.g. high altitude)
Inhibited by oxy-Hb
More O2 unloading (right shift)
o Oxygen transfer from mother to fetus
Fetal Hb has more affinity for O2
2,3-DPG in moms blood rising in first trimester = promote O2 transfer across membranes
Carbon dioxide transport in blood
o Different transport methods
Mainly as bicarbonate in plasma from RBCs
Carbonic anhydrase to convert
Hemoglobin buffers H+ product in RBC
Chloride shift: bicarbonate to plasma, Cl into blood cell
Carbamino-Hb
CO2 bound to protein portion
Dissolved in plasma (only 7%)
o CO2 transport from RBC to alveoli = reverse process of the chloride shift, carbonic anhydrase
o Haldane Effect
Higher PO2 = less CO2 carried in the blood
Increases CO2 unloading to the alveoli
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

PO2 inversely proportional to the

total blood CO2

CHEMICAL REGULATION OF BREATHING (LEC. 4)

Describe how CO2 and O2 are monitored
How chemoreceptors influence ventilation
How blood pH is regulated
Causes of acidosis and alkalosis

Breathing is regulated by a feedback system with ventilation, gas exchange, partial pressure of CO2 and O2, and
chemoreflexes
CO2 is most important as for regulating breathing
o Rising PCO2 increases the stimulus to breathe, increasing ventilation
Monitor CO2 and O2 by chemoreceptors
o Central chemoreceptors
Medulla oblongata
Detect [H+] in CSF
CO2 diffuses through BBB, produces H+ and
bicarbonate through buffering rxns
H+ closes K+ channels --> chemoreceptors
depolarize
Provides the most drive for breathing
Ventilation increases linearly with PCO2
Five minutes to respond fully to changes in
arterial PCO2
o Peripheral chemoreceptors
Carotid, aortic bodies
Detect [H+] in blood
Low O2 closes K+ channels in glomus cell (carotid body)
Depolarization --> open VG Ca2+
Ca2+ influx and H+ binding to receptor --> Dopamine released to sensory neuron
More sensitive if PO2 falls
Less O2 = greater change in ventilation over smaller changes in CO2
Chemoreceptors influence ventilation by sending signals up to the respiratory control centre
o Control centre = Medulla Oblongata and Pons
Central chemoreceptors send signals directly (very near the control centre)
Peripheral chemoreceptors send through afferent sensory neurons
o Somatic motor neurons innervate effector muscles
Inspiration and expiration muscles

Blood pH gives an indication of the CO2 levels.

PCO2 controlled by respiratory system
o Fast response (5-10min), eliminates a lot of carbonic acid per day (10,000mmol)
Bicarbonate (HCO3-) controlled by renal and other systems
o Less efficient than PCO2 control
8-12h, 100mmol eliminated fixed acids per day
Acidosis: pH < 7.35
o Less CO2 excretion; lung disease, sedative OD

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

o Gain of H+ or loss of bicarbonate HCO3; methanol poisoning, ketoacidosis, diarrhea

o Compensation: activate chemoreceptors
H+ secreted by the kidneys as NH4+ or complexed with buffers
Increased respiratory rate lowers PCO2 (hyperventilation)
Alkalosis: pH > 7.45
o Excess CO2 excretion; hyperventilation, aspirin poisoning
o Loss of H+ or gain of bicarbonate; vomiting
o Compensation: inactivate chemoreceptors
H+ reabsorbed by kidneys; bicarbonate secreted
Buffer systems release H+
Decreased respiratory rate increases PCO2 (hypoventilation)

NEURAL REGULATION OF BREATHING (LEC. 5)

Describe the factors that can affect breathing
Describe the final common pathway for control of respiratory muscles
Understand the regions involved in generating respiratory rhythm
Describe the types the airway and lung receptors and their functions

Spinal motor neurons are the final common pathway for controlling respiratory muscles
Phrenic motor neurons = Inspiration control
o Diaphragm
o C3.4.5 cervical cord segments
o Relationship between tidal volume and phrenic nerve activity
Periodic activity for diaphragm contraction; lowered activity during passive expiration
Intercostal motor neurons = Expiration control
o Intercostal muscles
o T1-12 thoracic spinal cord segments

Respiratory rhythm is generated by pre-motor neurons in the medulla

Ventral and Dorsal respiratory group (DRG and VRG)
o Receives input from:
Chemoreceptors (central and peripheral)
Higher brain centers
Goes to the PRG (pontin respiratory group) that receives input from the DRG
o Pattern generating neurons mainly in VRG control pattern of pre-motor neuron activation
o Pre-motor neurons in VRG and DRG activate the respiratory motor neurons in spinal cord (phrenic,
intercostal)
Pre-Botzinger complex in the VRG
o Rhythm generating region
Rhythm-generating neurons make respiratory rhythm by pacemaker activity
Pre-Botzinger rhythms of stimulation in medulla slice reflects the breathing rhythms found in vivo
o Connection in the neuron groups in Botzinger and pre-Botz regions influences pacemaker
Pontin Respiratory Group (PRG)
o Gets sensory info form DRG
o Influences initiation and termination of inspiration, but not the main driver of respiration
o Provides tonic input to medulla, coordinating a smooth rhythm

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Factors affecting the rhythmic breathing driven by medulla and

pons
Speech
Chemoreceptors
Reflexes (sneezing, coughing)
Posture affects the intercostals and abdominal
Startled = gasp
Emotion (fear, anxiety, sorrow)
Pain that increases breathing: shallow vs. rapid

Airway and lung receptors function to control breathing pattern

and initiate several reflexes
Stretch receptor
o Trachea to bronchioles: upper respiratory tract
o Sends info up by the vagus nerve
o Herin-Breuer reflex: protects the lungs from overstretching
Overstretch increases the duration of expiration
o Function: control breathing pattern --> tidal volume and frequency
Irritant receptors
o Throughout the airway
o Responds to irritating stimuli by triggering breathing and bronchoconstriction (prevent entrance)
o Initiate several following reflexes
Reflex Receptor Nerve
Sneeze Nasal Trigeminal Nerve (3)
Aspiration Epipharyngeal Glossopharyngeal
Cough Laryngeal, Tracheal Vagus (8)
Sighs J-receptors in Juxtapulmonary Vagus (8)
capillary

Congenital Central Hypoventilation alters respiratory control in patients

Mutation in PHOXb2
o Encodes for a transcription factor important for autonomic neuron development
o PHOXb2 expressed in pFRG and RTN
Site for central chemoreceptors and receiving info from peripheral chemoreceptors
pFRG/RTN sends info to pre-Botz complex, thus plays role in regulating rhythm
Symptoms:
o Alveolar hypoventilation during sleep
o Altered respiratory control: less of no ventilator responses to high CO2 hypercarbia or low O2 hypoxia
o ANS degeneration

HIGH ALTITUDE AND EXERCISE (LEC. 6)

Describe the physiological responses to high altitude
Describe the respiratory and cardiovascular changes that occur in exercise
Outline how ventilation is matched to O2 consumption and CO2 production
Define cardio-respiratory fitness
List the long-term benefits of exercise

High altitude presents the main problem of hypoxia

High altitude >1500m

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Physiological responses to hypoxia work to increase ventilation and O2 unloading at tissues

o Peripheral chemoreflex leads to hyperventilation
Increased sensitivity due to low PO2 at high altitude
Hyperventilation effects
Decreased PCO2
Less unloading of O2 (left shift of curve to higher pH)
o 2,3-DPG made by RBCs
Intermediate of glycolysis
Increases O2 unloading (right shift of the curve)
Degrades when blood is stored
Conditions related to high altitude
o Mountain sickness
Increased blood flow to the brain = headache, irritated, insomnia, nausea
o High altitude cerebral edema
Ataxia (abnormal gait), disorientation, coma/ death from capillary leaking, brain swelling
o High altitude pulmonary edema
Lung swelling, shortness of breath
Local control of blood flow in lungs produces cough
Ventilation-perfusion occurs in high altitude when there is not enough oxygenation of lungs
o Mismatch = ventilation decreases in a group of alveoli
PCO2 increases, PO2 decreases
o Local control mechanisms to re-match ventilation and perfusion
Vasoconstriction to under-ventilated alveoli and perfusion
Blood flowing from the alveoli group is more oxygenated than during mismatch
Pulmonary edema
Treatment
o Acetazolamide: diuretic, inhibits carbonic anhydrase (converts CO2 and water to bicarbonate and H+)
o Glucocorticoids to treat inflammation in cerebral edema
o Nifedipine: lowers pulmonary artery pressure

Exercise
Oxygen consumption increases, requiring cardiovascular and breathing regulation
o Changes in cardiovascular physiology
Blood diverted to exercising muscles by local control vasodilation
Increase in H+, CO2, temperature
Less O2
CV control center in medulla receives feedforward control
Rapid: muscle mechanoreceptors and proprioceptors
o Detects active and passive muscle movement
o Can be activated by central command (descending motor commands)
Slower: Peripheral chemoreceptors, muscle blood vessel receptors
Decrease PNS, increase SNS = increase cardiac output CO
Blood pressure MAP increases
More cardiac output but less peripheral resistance
Baroreceptor response adjusted to allow for increased MAP
o Changes in respiratory physiology

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Deeper breathing: pressure changes in the thorax

Exercise starts --> rapid increase in ventilation -->
steady state --> decrease after exercise ends
Local control of blood gases and pH until anaerobic
exercise
Aerobic exercise
o Constant arterial PO2
Ventilation delivers O2 to
body
o Constant arterial PCO2
o Constant arterial pH
o Decreasing venous PO2
o Increasing ventilation
Anaerobic exercise
o Constant arterial PO2
o Decrease PCO2
o Arterial pH drops
Lactic acid for ATP raises
pH
Cardio-respiratory fitness
o Ability to transport and use O2
o VO2max = maximum oxygen used during intense body exercise; maximum aerobic exercise
L/min or mL/kg/min
20-30 year olds
Males: 33.5 L/min
Females: 22.5 L/min
Normalised by weight
Males 4550 mL/kg/min
Females 3545 mL/kg/min
Benefits of aerobic exercise
o Improves glucose tolerance and insulin secretion
More GLUT4-Rs to muscles
More Insulin receptors
o Make more mitochondria for skeletal muscle oxidative capacity
o Increase VO2max
o Decrease resting heart rate and blood pressure
o Increase CO, max heart rate, and blood volume

RENAL: COMPARTMENTS (LEC. 1)

TBW = 5060% body weight: 2/3 ICF, 1/3ECF
Sodium stays in the ECF
Water crosses cell membranes (osmolality)
Plasma vs. interstitial volume depends on the balance between oncotic pressure and hydrostatic pressure

Fluid compartments
Body water percentage of weight depends on fat-muscle ratio (i.e. water weight is a function of muscle mass)
o Muscle has the most water in the body
o Higher fat-muscle ratio in women, older, and chronic illness
o Water percentage decreases with age
o 42L
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

ICF: intracellular (40%) --> 28L

o Higher concentration of K+ ions, and proteins
ECF: extracellular (20%) --> 14L total
o Interstitial fluid and Plasma
Interstitial: 80% of ECF = 12L (2/3)
Plasma: 20% of ECF = 3L (1/3)
o Higher concentration of Na+, Cl-, and bicarbonate

Solutes
Osmolality: the concentration of solutes in water creates an osmotic force
o Osmotic force is water moving across semi-permeable membrane in response to osmotic gradient
Gradient established by difference in osmolality in compartments (function of particles amount)
Equalize the concentration by moving water to higher solute
o Osmolality is the same in each compartment
Cell membrane cant tolerate osmotic gradients
ECF vs. ICF volume
o Na+ with an anion (salt) stays in the ECF as the main osmole
o Equalize osmolality by water moving across cell membrane
Na-K ATPase maintains solute gradients; ubiquitously expressed in cells

Movement of water between compartments

Between the ICF and ECF: osmolality drives water movement
o Adding water
Goes into ECF --> dilutes ECF Na+ --> water moves to ICF
Both ECF and ICF volumes rise, cells swell
o Adding salt
More concentrated ECF Na+ --> increase ECF osmolality --> water moves from ICF to ECF to
equalize osmotic gradients
Cells shrink
Between interstitial and plasma compartments: leaky capillary and opposing forces
o Leaky exchange capillary epithelium

o Starling forces: Hydrostatic pressure vs. Oncotic pressure
Oncotic pressure: made by charged proteins, larger
Albumin is highly concentrated in plasma
Limited permeability = albumin mainly stays in plasma
Drives water to move within plasma
Hydrostatic pressure: made in capillaries by heart pumping
Drives water to move into interstitial space
Fluid flux = permeability x (Hydrostatic Oncotic)

Clinical aspects
Lab test to determine ICF volume
o Na+ concentration inversely proportional to ICF volume
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Clinical exam to determine ECF volume

o Plasma volume: jugular venous pressure, blood pressure
o Interstitial: edema

GLOMERULUS (LEC. 2)
Renal blood flow is 2025% of cardiac output
GFR is dependent on blood flow and Starling forces, autoregulated by afferent arteriolar tone
Prostaglandins and ANGII are important when blood pressure is low
GFR is the best index of overall kidney health
Serum creatinine to estimate GFR in humans

Anatomy and Main Function

Structures of the kidney
o Cortex: has Bowmans capsule, proximal and distal tubules, afferent
arterioles, and glomeruli
o Medulla: has the loops and collecting ducts
o Movement of fluid to the bladder is not gravity-dependent
Path of blood in the kidney
o Arcuate artery --> afferent arteriole --> glomerulus --> efferent
arteriole --> peritubular capillaries --> arcuate vein
o Afferent arterioles have vascular smooth muscle
Glomerulus anatomy
o Capillaries wrapped in podocytes
Fenestrated endothelium for filtration
Filtration slits between foot processes of podocytes
Foot process sits on the basal lamina, and faces the lumen of Bowmans capsule
o Mesangial cells between capillaries contract: changes blood flow
o Very leaky to water
Function: filtration
o Filters solutes and water from glomerular capillary to Bowmans space
o 25% of cardiac output

Ultrafiltration of the glomerulus

Uses Starling forces
o Glomerular capillary pressure (Pgc)
Moves water out of the capillaries into Bowmans
Filtration only starts when Pgc overcome hydrostatic
pressure
o Tubular hydrostatic pressure (Pt)
Moves water into the capillaries
Constant pressure
o Oncotic pressure ()
Albumin presence draws water into the capillaries
Increases towards the efferent arteriole
Higher concentration as water is filtered earlier in glomerulus
If this increases, less filtration
Ultrafiltration coefficient (Kf)
o Increase Kf = more water filtered to Bowmans
o Encompasses both water permeability and surface area
Filtration of small solutes
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

o Convection: solutes dragged along with water due to hydrostatic pressure

Freely filtered: Na+, K+, Cl-, glucose, bicarbonate, urea, creatinine
Contraction/dilation of afferent and efferent arterioles regulates GFR, affecting ultrafiltration
o Dilated afferent or constricted efferent = keep blood in glomerulus = higher GFR
o Plasma flow
Directly proportional to the GFR (higher flow, more filtration until physical limitations)
Renal blood flow (plasma flow) is the most important determinant of GFR
o Arterial blood pressure and renal vascular resistance
o Myogenic reflex in afferent arteriole
High BP = dilate afferent
Low BP = constrict afferent
+ ANGII: constrict efferent
+ Prostaglandins: dilate afferent
o MAP afferent resistance
Increase MAP in response to excess solute flow to macula densa (before distal tubule)
Tubuloglomerular feedback = GFR autoregulation
o High GFR --> flow past macula densa increases --> paracrine from macula to afferent arteriole -->
vasoconstriction --> decrease hydrostatic pressure in glomerulus --> GFR decreases

Permselectivity of the glomerulus

Uses size, charge, and shape
o Size selectivity
Less than 15kD is freely filtered; progressive restriction until 60kD
Albumin is 68kD, restricted permeability by size and charge
Cubulin and Megalin protein-protein structure binds albumin
o Prevents escape of albumin into lumen
o Brush Border membrane
Luminal albumin is reabsorbed as amino acids after broken down by lysosomes
720mg albumin enters Bowmans capsule, then reabsorbed by receptors in proximal tube
o Charge selectivity
Less permeable to negative solutes
o Shape selectivity
Globular vs. linear solutes

Measurements in humans
GFR: Measure of kidney function, less than 90mL/day or 125L/day
Measuring GFR with inulin or creatinine
o Determine the clearance of solute from circulation, where reabsorbed = secreted
Inulin: exogenous large carbohydrate
Creatinine: endogenous filtration marker
Made by muscles
Freely filtered with limited secreted (<10%)
GFR = Flow rate x (urine creatinine / plasma creatinine)
o GFR inversely proportional to Pcreatinine
Women have a slightly higher albumin-creatinine ratio

Diabetes mellitus affects the glomerulus

Permselectivity: less restrictive to albumin damaged glomerulus
Ultrafiltration: declines due to decreased oncotic pressure gradient (leaky albumin)

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

TUBULES (LEC. 3)
Reabsorption and secretion of most solutes are linked to Na+ and Na/K ATPase
Na+ crosses the luminal membrane down its electrochemical gradient
Luminal Na+ transport includes: co-transporters, anti-porters, and channels
Proximal tubule and loop for bulk reabsorption (Na+, water, Cl-, bicarbonate)
P.T. is leaky with no large gradients, and organic solute transporters
Collecting duct for regulation (Na+, water, Cl-, bicarbonate, K+)
C.D. has tight junction and possible large gradients

Background information
Tubules work to maintain water and solute balance by reabsorbing solute/water, secreting solute
o More than 99% of filtered water and sodium are reabsorbed
100mL fluid/min filtered, 1mL/min urine
Normal urine volume is 0.52L per day
21,000 mmol Na+ filtered, 150 mmol Na+ excreted

Anatomy of the nephron

Proximal tubule, Loop of Henle, Distal tubule, Collecting duct
Tubular capillary network: transfer between the capillary and tubule
o On the basolateral membrane of nephron cells
Brush border microvilli on luminal membrane
o Increases SA for more absorption

Concepts of tubule physiology

Four general ways of solute-tubule interaction
o Full secretion (inulin)
o Full reabsorption (glucose)
o Net reabsorption (urea)
o Net secretion (penicillin)
Transporting epithelial cells
o Polarization localizes transporters to luminal membrane vs
basolateral membrane
Active transport for Na+
Electrochemical gradient moves anions with Na+
Osmosis for water, following solute reabsorption
Paracellular pathway or membrane transporters for
permeable solutes

Sodium and glucose

Na+ reabsorption to capillary
o Na+ moves down concentration gradient into the epithelial cell
Co-transporters: Na+/glucose and Na+/phosphate (both move into the epithelial cell)
Antiporter: Na+/H+ (H+ moves out into the lumen)
o Na+/K+ ATPase active transport on basolateral membrane moves Na+ from epithelial to capillary
Keeps ICF Na+ concentration low
Glucose full reabsorption to capillary
o 750mmol glucose filtered through Bowmans per day
o Two transporters

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

SGLUT2: mopping up glucose

Proximal, low affinity, high capacity
SGLUT1: paper towels to clean up
More distal part of proximal, high
affinity, low capacity
o Filtration
Linear relationship to plasma concentration,
no saturation
o Reabsorption
Linear to plasma concentration until transport
maximum (Tm = 375mg/min)
o Excretion
Zero excretion until Tm is reached; linear
relationship
E.g.: diabetes

Tubular segments
Proximal tubule
o Bulk reabsorption of solutes and water
Leaky isotonic reabsorption Na+
Reabsorbs all of the glucose
o NHE3: Na+/H+ exchanger
o Mechanism for bicarbonate reabsorption
o Only location of glucose, phosphate, and amino acid co-transporter
o Transcellular movement of organic ions from blood to lumen
E.g.: Sulfate
Thick ascending limb
o Reabsorbs 20-30% Na+
o NKCC2: luminal transporter for Na-K-2Cl
Inhibited by furosemide (diuretic)
o K+ channels in luminal membrane excrete K+ into lumen
o Impermeable to water
o Fluid is hypotonic to the plasma
Dilute lumen fluid, concentrated interstitial fluid
Distal convoluted tubule
o Reabsorb 5-10% Na+ and water
o NCC: Na+/Cl- co-transporter on the luminal membrane
Inhibited by thiazides (diuretics) less potent than furosemides
o Important in diluting urine
Collecting duct
o Least reabsorption of filtered Na+
Aldosterone receptors: can increase Na+ reabsorption
o ENaC: epithelial Na+ channel on luminal membrane
o Less permeable to Cl-
o Low capacity by can make large concentration gradients

SODIUM BALANCE (LEC. 4)

Cardiovascular receptors signal to kidney for Na+ excretion regulation
Dietary Na+ has major impact on ECF volume

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Na+ depletion/excess
ANGII directly stimulated Na+ reabsorption
Aldosterone stimulates Na+ reabsorption at collecting duct
ANP inhibits Na+ reabsorption from MCD

Gaining and losing Na+

Lose Na+ in the ECF
o Sweating, diarrhea, vomiting, osmotic diuresis (hyperglycemia), diuretics, blood loss, and decreased intake
o Nephron response: excrete 0.05% of filtered Na+
Gain Na+ primarily from diet
o Nephron response: excrete 1.5% of filtered Na+

Sensing ECF volume

Arterial baroreceptors
o Carotid body and aortic arch
o Senses arterial volume and pressure through the wall tension
o SNS activation and RAS
In response to decreased ECF (less baroreceptor activity)
SNS activated --> make renin --> ANGI --> ANGII --> AT1 receptor on kidney to adjust Na+
reabsorption
Opposite for increased ECF
Afferent arteriole
o Juxtaglomerular apparatus in the kidney
o Renin in the afferent arteriole wall sense pressures and flow
Less pressure = make renin
Regulation of renin secretion
Arterial blood pressure
SNS activity
Dietary sodium
Atrial stretch receptors
o Atrial myocytes secrete ANP in response to atrial stretch
More stretch = more ANP release
Goes to the brain, blood vessels, and ANP receptor in kidney
Stretch from vasodilation (thus shut down SNS)

ANGII in the RAS pathway increases Na+ reabsorption

Increases proximal tubule reabsorption
o Enhances Starling forces in the peritubular capillaries
More oncotic pressure = hydrostatic pressure is not powerful enough to bring solute back
o More plasma is diverted into Bowmans capsule
o Increase efferent arteriole resistance
Increases Na+ movement through transporters (works with norepinephrine)
o NHE3 on the proximal tubule Na+/H+ antiporter
o NCC on the distal tubule Na+/Cl- co-transporter
Releases aldosterone from the adrenal cortex
o Aldosterone receptors in the collecting duct = fine tuning of Na+ channels for reabsorption
Basolateral membrane
Hormone-receptor complex is a transCR factor for luminal channels and pumps --> Na+
absorption and K+ secretion (e.g.: ENaC)
Also modulates existing channels and pumps

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Excess Na+ in the body results in mechanisms to excrete more Na+

Increase baroreceptor activation = less SNS activity, shut down RAS pathway
ANP released from the atrium
o Excess Na+ increases vascular volume --> atrial myocytes stretch --> release ANP
o ANP inhibits aldosterone and renin = reduces Na+ reabsorption in collecting duct
o ANP increases GFR
o Works in the medullary collecting duct cells
Binds to luminal ANP receptors
Releases cGMP into the cell
Inhibits Na+ transporters (ENaC, ATPase, etc.)
Note! More Na+ intake results in ECF volume increase first before Na+ secretion increases
o Takes a few days for a new steady state at the expanded ECF volume

WATER BALANCE (LEC. 5)

Sensing osmolality in body fluid compartments
ADH is central and affects water permeability in the collecting duct
Loop of Henle establishes a concentration gradient
Aquaporin-2 channels allow for water reabsorption
Water excess --> supress ADH, low urine osmolality
Water depletion --> high ADH, high urine osmolality

Balance between water intake and output, 2.5L/day

Intake in diet and metabolic production
Water loss by skin and lungs (insensible loss), urine, and feces
o In order of most water loss: urine > insensible > feces

Water permeability along the nephron depends on tight junctions and aquaporin channels
Thick ascending limb = tight junctions, NO aquaporin channels
Collecting duct = tight junctions, can insert aquaporin channels into apical membrane (lumen-facing)

Sense volume in fluid compartments using osmoreceptors

Osmoreceptors: found in hypothalamus and pituitary gland
o Senses changes in ICF volume
Hypothalamic osmoreceptors (OVLT): stretch-inhibited cation channels
Cell shrinks --> channels open --> cation influx and cell depolarization --> AP leads to
more AVP secretion by the posterior pituitary (i.e. shrinking = ADH)
o OVLT nuclei: controls thirst
o SON: control vasopressin/ADH release

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Kidney handles water by making a gradient and regulating water permeability

Establish interstitial gradient for water
o Cortex: isosmotic to plasma // Medulla: progressively more
concentrated towards renal pelvis
o Loop of Henle
Countercurrent exchange in vasa recta
Water in the descending limb reabsorbed
into casa recta
Ascending limb ions (Na+, K+, Cl-, filtrate) are reabsorbed into vasa recta
o Descending limb has rising osmolality; only water reabsorbed
o Ascending limb makes less osmolality; only ions/solutes reabsorbed

Regulate water permeability in collecting duct

o ADH inserts aquaporin channels into apical lumen membrane
ADH receptor on basolateral membrane = GPCR --> cAMP
cAMP important for vesicle insertion with aquaporin channels into apical membrane
No ADH = aquaporin stays in the intracellular vesicles
Also activates PKA for expression of more aquaporin channels
Making concentrated urine
o Countercurrent prevents solute removal --> Na+ added from ascending limb stays in the medulla
o ADH inserts aquaporin channels
Water moves lumen --> hypertonic interstitium
Excreting dilute urine
o No ADH --> water stays dilute
Fluid from ascending limb is always dilute
o Minimum urine osmolality = 50mosmol/kg

Diabetes insipidus involves ADH deficiency

Caused by trauma
Thirst is still intact because ADH and thirst are handled by different brain regions
Cant sleep without ADH

POTASSIUM BALANCE (LEC. 6)

Normally K+ intake = K+ excretion
Serum [K] signals kidney to change K+ excretion
Majority (90%) of filtered K is reabsorbed in the proximal tubule and Loop of Henle
Collecting duct regulates K+ excretion
Aldosterone
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Potassium distribution in the fluid compartments

ICF: 98%, 4200mmol, 140mol/L (K+ mainly within cells)
ECF: 2%, 56mmol, 4mmol/L
Distribution is important for resting membrane potential
o Cellular K+ intake by 2-adrenergic and insulin-mediated regulatory pathways
2 activated by adrenaline (e.g. exercise)
Leads to cAMP --> PKA --> ATP for Na+/K+ ATPase
Insulin receptor (e.g. during meals)
PI3-K pathway --> aPKC --> activate Na+/K+ ATPase
o Metabolic acidosis and K+ balance
Reduces cell uptake of K+
Less NHE1 (Na+/H+) activity = less ATPase activity
o Hypokalemia
Hard to contract muscles
Promotes cardia arrhythmias
o Hyperkalemia
Muscle stiffness and weakness
Abnormal ECG
Cardiac arrhythmias

Effect of eating and exercise on K+ uptake

Eating glucose --> insulin secretion --> K+ uptake into ICF
o Insulin stimulates myocytes to take in K+: prevent hyperkalemia
Exercise = muscles release K+
o Local control for re-establishing K+ balance
Arterioles local dilating --> increase muscle blood flow
o Adrenaline: redistributes excess K+ into resting tissue

K+ handling by the kidney

Proximal Tubule
o Bulk reabsorption of K+
o Paracellular diffusion (mainly) for K+ reabsorption
Also the presence of K+ channels for K+ excretion or absorption
Thick Ascending Limb
o Takes care of the rest of K+
o NKCC2: Na-K-2Cl transporter
On apical lumen membrane
Some recycling of K+ by ROMK (pumping back out into the lumen)
Some paracellular diffusion
Collecting Duct
o Principal in initial collecting duct responsible for K+ secretion
ROMK and Maxi-K+ channels in apical membrane
Na+ influx from ENaC enable K+ efflux by K/Cl- co-transporter
Collecting duct is less permeable to Cl- because of negative lumen
o Aldosterone receptors
Aldosterone secreted by adrenal cortex (zona glomerulosa)
Blood K+ levels aldosterone levels
Hyperkalemia = stimulate aldosterone secretion
Increases expression of Na+ channels
More channels, higher activation state (open probability)
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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Na+ reabsorption --> lumen negativity --> K+ secreted due to charge attraction
ALDOSTERONE = ENHANCE Na+ REABSORPTION, K+ SECRETION
Regulation of K+ secretion
o Na+ delivery
o Tubule flow rates
Low flow --> higher gradient --> more K+ secretion
o Lumen negativity
Made by Na+ reabsorption
o Aldosterone
Increases Na+ delivery

Aldosterone regulates both Na+ and K+ The Aldosterone Paradox

Low ECF volume = Na+ retention with normal K+ excretion
o Stimulate RAS pathway
o Less GFR --> less flow to collecting duct
o Normal K+ excretion: high aldosterone vs. less collecting duct flow
High ECF volume = K+ excretion without Na+ retention
o Inhibit RAS and aldosterone
No Na+ retention because inhibited ANGII
o More GFR --> inhibit proximal reabsorption --> more flow to collecting duct
o Normal K+ excreted: low aldosterone vs. increased collecting duct flow

Potassium meals and K+ regulation

K+ intake during meals: meal-driven K+ excretion
o Sequestered in liver and skeletal muscle
o Excreted
Activate splanchnic sensors = feed-forward regulation
Brain kaliuretic factors from Vagus nerve and gut signals
Gut kaliuretic factors from gut signals
Negative feedback regulation from kidney based on plasma K+ levels
Aldosterone and collecting duct
In between meals: K+ excretion
o K+ efflux from liver and skeletal muscle b/c less insulin
o Plasma K+ goes to kidney --> excreted

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

ACID-BASE (LEC. 7)
H+ secretion = Bicarbonate restoration into blood (1:1)
Ammonium in urine = New bicarbonate (1:1)
Ammonia is more important urinary buffer than HPO4
Phosphate amount is limited and cant be adjusted
Kidneys can increase ammonia availability by 5-10X
Changes in ammonium excretion affects variations in acid excretion

H+ in the body
Blood pH = 7.40 /// Urine can be acidic (5.0) or alkaline (8.0)
H+ from diet and metabolism
o Diet: fatty acids, amino acids
Sulfur amino acids (Cys, Met) metabolized to sulphuric acid (H2SO4)
o Metabolism: CO2, lactic acid, ketoacids
Buffers to keep neutral plasma pH
o Bicarbonate in ECF
o Proteins, hemoglobin, intracellular phosphates HPO4
o Phosphates, ammonia in urine

Bicarbonate buffer system

H+ + HCO3 H2CO3 CO2 + H2O
o Both sides can be independently regulated
CO2 by alveolar ventilation
Bicarbonate by kidney
Compensate metabolic with respiratory action, and vice versa
Primary changes Compensation
Metabolic Acidosis bicarbonate Less CO2
Alkalosi + bicarbonate More CO2
s
Respirator Acidosis + CO2 More bicarbonate
y Alkalosi CO2 Less bicarbonate
s
Ventilation or renal action to control acid-base balance
o Renal: reabsorb filtered bicarbonate, and make new bicarbonate
Bicarbonate reabsorbed mainly in proximal tubule
NHE secretes H+ to lumen --> With filtered bicarbonate, makes CO2 --> CO2 diffuses
into cell --> Carbonic Anhydrase (CAII) makes H+ and bicarbonate
o H+ regulated back to the NHE
o Bicarbonate reabsorbed into blood with Na+ (NBCe1a sodium-bicarbonate
transporter)
Regenerate bicarbonate in the proximal tubule [Ammoniagenesis]
Metabolize amino acid in mitochondria
o Amino acid enters by both apical and basal membrane transporters
o Glutamine makes NH4+ (ammonium) and bicarbonate
NH4+ excreted by NHE3 (NH4+ out, Na+ in)
Bicarbonate reabsorbed by NBCe1-a
Bicarbonate made by KG enzyme in mitochondria

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

Excreting ammonia/ammonium
Ammonium (NH4+): cant readily cross cell membranes
o Ammoniagenesis = more acidic environment
Ammonia: freely diffuses across membranes
Movement of ammonium (NH4+) through the nephron
o Ascending limb pushes NH4 out of the nephron because of Na+
reabsorption
Separates into NH3 and H+ so it can diffuse through the
membrane
H+ excretion through ammonium
NH4 is trapped in the lumen of the ascending
limb
o Ammonia shortcuts from loop/ascending limb to collecting duct
Combines with H+ to make ammonium --> excreted
100%
Secretion of H+ ions
o Type A intercalated cells in collecting duct deal with acidosis (high [H+])
Tight junctions
H+ enters by CO2 (reacts with bicarbonate)
Converted back to H+ by CAII anhydrase
Bicarbonate back to interstitium by Bicarbonate/Cl- antiporter
o Buffers to lower [H+]
H+ excreted by H+ ATPase
H+ to lumen, filtered K+ into cell
o K+ moves down gradient to be reabsorbed
Combines with NH3 and excreted

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 Midterm II is on Wednesday March 22, 2017 from 2:10PM3:00PM

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