PHYSIOLOGY

I. INTRODUCTION AND PRINCIPLES

A. Organization and Homeostasis

1. Cell is the basic living unit
2. About 100 trillion cells in an adult. RBCs comprise 25% of total.
3. Cells have fluid inside (ICF) and are surrounded by fluid (ECF)
4. Cells compose tissues, which compose organs, which compose systems, which compose the en-
tire human organism
5. There are differences among cells (e.g. contractility vs conductivity)
6. There are similarities among cells (e.g. CO2 production, conversion of nutrients to energy)
B. Body Fluid
1. 60% of adult human body
2. ICF (2/3)
a. High potassium, magnesium, phosphate content; CO2
b. Low glucose; oxygen; fatty acids; amino acids
3. ECF (1/3)
a. High sodium, chloride, bicarbonate, O2, amino acids, glucose
b. he internal environment is the focus of homeostasis
c. ECF = Plasma (1/4) + Interstitial fluid (3/4)
4. Homeostasis
a. Maintains the constancy of internal environment
b. Operates by means of negative feedback mechanism
c. System requirements:
1. Sensor (e.g. baroreceptor) + afferent nerve (detects and responds to change)
2. Control center (e.g. vasomotor center in medulla)
3. Effector (blood vessel + efferent nerve) (reverses change)
5. Normal values and Normal Range (upper and lower limits)
a. Maintained by negative feedback loops
b. Negative feedback characterized by a response that is opposite in direction to that of the
stimulus that initiated it. Thus a drop in blood pressure will provoke automatically responses
that tend to bring it back up to normal level.
c. Values made to oscillate from the mean but within tolerable limits
d. Compensatory capacity of homeostatic mechanisms has limits (sickness and death)
e.
f. Effectiveness of control system varies from one system to another (e.g. temperature control is
more effective than blood pressure control)
g. Very few physiological processes use positive feedback as controlling mechanism (e.g. parturi-
tion)
C. Typical Cell
1. Two major parts
a. Nucleus (surrounded by nuclear membrane)
b. Cytoplasm (surrounded by cell membrane)
2. Protoplasm substances that make up the cell
a. Water 70-85%
b. Electrolytes inorganic chemical for cellular reactions
c. Proteins 10-20%
1. Structural proteins e.g. microtubules
2. Globular proteins e.g. enzymes
d. Lipids
1. 2% (1) Phospholipids (2) Cholesterol (3) Triglycerides
2. Insoluble in water; form water barrier
e. CHO
1. For cell nutrition
2. Content varies in different cells (1% in typical cell; 3% in muscle cell; 6% in liver cell)
3. Cell membrane (Proteins 55%; Phospholipids 25%; Cholesterol 13%; other lipids 4%; CHO 3%)
a. Lipid bilayer interspersed with with globular proteins
1. Phosphate portion (hydrophilic) facing ICF and ECF)
2. Fatty acid portion (hydrophobic) facing the center of the membrane
b. Proteins
1. Integral proteins (span the entire bilayer) and act as:
a. Channels and pores
b. Carrier and enzymes
2. Peripheral proteins (attached to inner surface of membrane)
a. Attached to one end of integral protein
b. Acting as enzymes
c. Carbohydrates (in combination with proteins and lipids (glycoproteins or glycolipids)
1. Negatively charged
2. Connect cells
3. Hormone and transmitter receptors
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 4. Antibody receptors
4. Cytoplasm and organelles
a. Cytosol is the clear fluid part of cytoplasm in which particles are dispersed
b. Ribosomes are:
1. Sites of protein synthesis
2. Composed of RNA and proteins
c. Endoplasmic reticulum (ER) is a network of tubular and flat vesicular structures
1. ER space connected with space between the two layers of nuclear membrane
2. With many enzymes
3. Granular ER (with ribosomes) associated protein synthesis
4. Agranular ER (w/o ribosomes) associated with:
a. lipid and steroid synthesis
b. calcium storage in muscle
c. enzymes
d. ER vesicles pinch off from ER to fuse with Golgi apparatus (transfers content from ER to GA)
e. Golgi Apparatus are:
1. Stacked layers of flat vesicles
2. Prominent in secretory cells
3. For processing and compacting ER secretions
f. Lysosomes:
1. Are vesicular organelles formed by the GA
2. Are filled with hydrolytic enzymes (digest proteins, lipids, cho, and smaller substances)
3. Are digestive organelles of cell
4. Functions in atrophy of muscle (disuse); uterine size reduction after pregnancy; removal
of dead or damaged cells; autolysis; bactericidal
g. Peroxisomes
1. Formed either by self-replication or from Agranular ER
2. Contains oxidases (combine substances with oxygen) to form peroxide; peroxide also an
oxidizing substance with catalase oxidize toxic substances (e.g. alcohol by liver)
h. Secretory vesicles
1. Formed by GER system
2. Contain secretory products (e.g. tripsynogen of pancreatic cells)
i. Mitochondria
1. Has double membrane (inner membrane with shelves for enzymes)
2. Are selp-replicative (contains DNA)
3.
4. ATP is the energy currency of cell
j. Filaments and microtubules (microtubules serve as cytoskeleton of cells)
1. Fibrillar proteins that polymerize
2. e.g. actin, myosin, tubulin, microtubules found in cilia and flagella, centrioles, mitotic
spindle
k. Nucleus
1. Has double membrane
2. Contains DNA (genes) (In Chromatin form during interphase; in chromosome form during
mitosis)
l. Nucleolus
1. Has No membrane
2. Contains RNA and proteins
3. Becomes enlarged when cell is actively synthesizing proteins
5. Endocytosis
a. Pinocytosis is ingestion of extremely small vesicles containing ECF and proteins). Steps (need
ATP and ECF calcium):
1. Receptors in coated pits
2. Invagination of pit with aid of protein clathrin
3. Pinching off to form pinocytic vesicle
4. Fusion with lysosome to form digestive vesicle
5. Exocytosis of residual body
b. Phagocytosis is ingestion of large particles (bacteria; cells) e.g. macrophage and neutrophils
6. Ameboid locomotion and ciliary motion are seen in macrophages and epithelial linings.

II. TRANSPORT OF IONS AND MOLECULES THROUGH CELL MEMBRANE

A. Introduction
1. ICF differs from ECF because of the cell membrane
2. Cell membrane is lipid bilayer with integral proteins
3. Substances move through cell membrane by diffusion, osmosis, active transport, and vesicular
transport.

B. Diffusion
1. Movement of molecules from one location to another by random thermal motion.
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 2. Net flux between two compartments proceeds from higher to lower concentration of the diffusing
substance.
3. Diffusion equilibrium is reached when the concentrations in the two compartments become equal,
resulting in zero net flux.
4. Nonpolar molecules (e.g. O2, CO2, N2, alcohol) diffuse through the lipid portions of membranes
more rapidly than polar or ionized molecules because nonpolar molecules can dissolve in the
nonpolar lipids.
5. Mineral ions diffuse across the membranes by passing through ion channels formed by integral
membrane proteins
6. The net diffusion of ions across a membrane depends on the concentration (chemical) gradient
and the membrane potential (electrical) or electrochemical gradient.
7. The flux of ions across a membrane can be altered by opening or closing ion channels.
a. Channels are often selectively permeable
b. Opening and closing of gates are brought about by conformational change in the protein
channels
1. Voltage gating is opening and closing brought about by a change in the electrical poten-
tial across the membrane
2. Chemical gating is opening and closing brought about by ligand binding to ion channels
(e.g. acetylcholine)

8. Factors affecting net rate of diffusion.

a. Rate is directly proportional to membrane permeability
b. Permeability coefficient depends on the solute and the membrane through which diffusion is
taking place
1. Lipid-soluble particles diffuse through lipid bilayer; their permeability is proportional to
their lipid solubility
2. Water-soluble particles diffuse through the aqueous channels formed by integral pro-
teins; their permeability is proportional to their molecular size, shape, and charge.

c. Thickness of membrane or diffusion distance (inversely proportional)

d. Molecular weight (inversely proportional)
e. Temperature (directly proportional)
f. Number of channels opened or available (directly proportional)
g. Surface area for diffusion (directly proportional)
h. Concentration difference (directly proportional)
i. Pressure difference (directly proportional)
j. Electrical gradient (directly proportional); like charges repel, unlike charges attract.

C. Osmosis
1. It is the diffusion of water from a region of high water concentration to a region of low water
concentration when a barrier (semipermeable membrane) prevents the flow of solute.
a. The osmolarity (the total solute concentration in a solution) determines the water concentra-
tion.
b. The higher the osmolarity of a solution, the lower the water concentration.

2. Osmosis across a membrane that is permeable to water but impermeable to solute leads to:
a. An increase in the volume of the compartment on the initially high-osmolarity side and
b. A decrease in the volume on the initially low-osmolarity side.

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 3. Osmolarity is the total solute concentration of a solution.
a. One osmole is equal to 1 mol of solute particles.
b. Osmolarity is calculated by using the equation:

Osmolarity = g X C
Where: osmolarity = concentration of particles (osm/L)
g = number of particles in solution (osm/mol)
[e.g. g(NaCl) = 2; g(glucose) = 1]
C = concentration (mol/L)

Sample calculation: What is the osmolarity of a 1 M NaCl solution?

Osmolarity = g X C
= 2 osm/mol X 1 M
= 2 osm/L

c. Thus, a 1-M solution of glucose has a concentration of 1 Osm (1 osmole per liter), but a 1-M
solution of NaCl contains 2 osmoles of solute per liter of solution. A liter of solution contain-
ing 1 mol of glucose and 1 mol of sodium chloride has an osmolarity of 3 Osm.

d. A solution with an osmolarity of 3 Osm may contain 1 mol of glucose and 1 mol of NaCl, or 3
mol of glucose, or 1.5 mol of NaCl, or any other combination of solutes as long as the total
solute concentration is equal to 3 Osm.

4. Definition of terms.
a. Isosmotic. A solution having the same total solute concentration (osmolarity) as another so-
lution regardless of its composition of membrane-penetrating and nonpenetrating solutes.
1. Two solutions that have the same calculated osmolarity are isosmotic.
2. A solution with 150 mM of NaCl [2x150=300mOsm] is isoosmotic to a solution with 150
mM of glucose and 150 mM of urea [1x(150)+ 1x(150)=300mOsm]
b. Hyperosmotic. If two solutions have different calculated osmolarities, the solution with the
higher osmolarity is hyperosmotic.
A solution with 100 mM of glucose and 100 mM of CaCl2 [1x(100)+ 3x(100)= 400mOsm] is
hyperosmotic to a solution containing 150 mM of NaCl.
c. Hyposmotic. If two solutions have different calculated osmolarities, the solution with the low-
er osmolarity is hyposmotic. A solution with 50 mM of NaCl and 150 mM of urea
[2x(50)+1x(150)=250mOsm is hypoosmotic to a solution containing 150 mM of NaCl.

5. The osmotic pressure increases when the solute concentration increases. Thus a solution of 1 M
CaCl2 has a higher osmotic pressure than a solution of 1 M KCl because the concentration of par-
ticles is higher.

6. The osmotic pressure exerted by particles in a solution, whether they be molecules or ions, is de-
termined by the number of particles per unit volume of fluid and not the mass of the particles.

7. The higher the osmotic pressure of a solution, the greater the water flow into it.

8. Application of a pressure equal to the osmotic pressure of the solution will prevent the osmotic
flow of water into the solution from a compartment of pure water.

D. Water movement across cell membrane

1. The osmolarity of the extracellular fluid is about 300 mOsm. Since water is in diffusion equilibri-
um across cell membranes, the ICF also has an osmolarity of 300 mOsm.
2. Sodium and chloride ions are the major effectively nonpenetrating solutes in the ECF, while po-
tassium ions and the organic solutes are the major nonpenetrating solutes in the ICF.
3. Definition of terms:
a. Tonicity. A term used to describe the effect of a solution on the osmotic movement of water.
It is the effective osmotic pressure equivalent. For example, if an isosmotic glucose or saline
solution is separated from plasma by a membrane that is permeable to water but not to glu-
cose or NaCl, osmosis will not occur. In this case the solution is said to be isotonic to plasma.

b. Isotonic. Two solutions having the same effective osmotic pressure are isotonic because no
water flows across a semipermeable membrane separating them. A solution containing 300
mOsmol/L of nonpenetrating solutes, regardless of the concentration of membrane-
penetrating solutes that may be present is isotonic to plasma.

c. Hypertonic. If two solutions separated by a semipermeable membrane have different effec-

tive osmotic pressures, the solution with the higher effective osmotic pressure is hypertonic.
A solution containing greater than 300 mOsmol/L of nonpenetrating solutes, regardless of the
concentration of membrane-penetrating solutes that may be present is hypertonic to plasma.
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 d. Hypotonic. If two solutions separated by a semipermeable membrane have different effective
osmotic pressures, the solution with the lower effective osmotic pressure is hypotonic. A so-
lution containing less than 300 mOsmol/L of nonpenetrating solutes, regardless of the con-
centration of membrane-penetrating solutes that may be present.

4. Cells placed in hypotonic solutions swell, while cells placed in hypertonic solutions shrink.

E. Mediated-Transport System (Facilitated diffusion and Active transport)

1. The mediated transport of molecules across a membrane involves the binding of the transported
solute to a carrier protein in the membrane. Changes in the conformation of the carrier protein
move the binding site to the opposite side of the membrane, where the solute dissociates from
the carrier protein.

2. Carrier-mediated transport (i.e. facilitated diffusion and active transportt) is characterized by:
a. Specificity (e.g. calcium pump, glucose carrier, sodium pump)
b. Competitive inhibition (two substances competing for the same carrier)
c. Saturability which is expressed by Vmax of curve (plateau)

3. Facilitated Diffusion:
a. Is carrier-mediated
b. Moves
c. Does not require metabolic energy
d. Is exemplified by glucose and amino acid transport)

4. Active Transport:
a. Is carrier-mediated
b. Moves against an p
c. Requires input of metabolic energy
d. Types
1. In primary active transport the energy is derived directly from the breakdown of ATP or
some other high-energy phosphate compound.
a. Sodium-potassium pump in nerve cell membrane
b. Calcium pump in sarcoplasmic reticulum
c. Hydrogen pump (parietal cells of stomach; renal late distal tubular and cortical col-
lecting duct cells)

2. In secondary active transport the energy is derived secondarily from energy that has
been stored in the form of ionic concentration differences between the two sides of a
membrane, created in the first place by primary active transport.
a. Co-transport
1. The diffusion energy of sodium (established by a pump) is used to pull another
substance along with sodium through the cell membrane
2. Coupling mechanism is a carrier protein that has binding sites on the same side
for both sodium and the substance to be co-transported.
3. Example (sodium co-transport of glucose and amino acids in the renal tubules
and epithelial cells of the intestine)

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 b. Counter-transport
1. Similar to co-transport but the substance to be counter-transported binds to a
site which is located on the other end of the carrier protein opposite to that of
the sodium binding site.
2. The substance is transported in the opposite direction.
3. Example [sodium counter-transport of calcium (almost all cell membranes) and
hydrogen ions (renal proximal tubules)]

III. Membrane Potentials and Action Potentials

A. Introduction
1. All cells have membrane potentials
2. A membrane potential (Em) is the electrical energy difference between the inside and outside of
the cell. It is measured in millivolts (mV).

B. Origin of membrane potential. The membrane potential is produced by the separation of charge.
Charge separation can occur under several conditions.

1. When a membrane separating two solutions is permeable to only one of the ions, there is the
tendency for the ions to diffuse to the area of least concentration, creating an imbalance of
charges.

a. If positively charged ions diffuse (due to force of concentration gradient) to the other side of
the membrane, the area where they came from would develop electronegativity. A mem-
brane potential is now produced (one side negative relative to the other side)
b. This membrane potential (the electronegativity) tends to attract the diffusing ions and inhibit
further movement. There is now an electrical force acting in opposite direction to the concen-
tration force.
c. The net movement of the ions will continue until the opposing electrical force of the increas-
ing membrane potential reaches a strength that is equal in magnitude to the concentration
force.

d. The membrane potential at which the electric force is equal in magnitude but opposite in di-
rection to the concentration force is called the equilibrium potential for that ion.

e. The membrane potential depends on the concentration gradient of the permeable ion.

f. The equilibrium potential is also called the diffusion potential or Nernst potential.

g. The Nernst potential can be calculated using the formula:

Cin
Eion 61 log , where
Cout

Eion = the electrical potential (mV)

Cin = the concentration of the ion inside the cell (mmol/L)
Cout = the concentration of the ion outside the cell (mmol/L)

h. Table below gives the Nernst potentials for selected important electrolytes.

Nernst Potential for Ions Commonly Found in Nerve and Muscle Cells

Ion Concentration (mmol/L) Nernst

Intracellular Extracellular Potential (mV)

Na+ 15 140 +58

K+ 135 4 -92
Ca++ 10-4 2 +129
H+ 10-4 40 X 10-6 -24
Cl- 4 120 -89
HCO3- 10 24 -23

2. The electrogenic nature (because it pumps 3 Na+ out of the cell for every 2 K+ pumped into the
cell) of the Na+-K+ pump also contributes directly to the production of the resting membrane po-
tential.

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 3. The Na+-K+ pump, by maintaining across the membrane the Na+ and K+ concentration gradients
that drive diffusion of ions, contribute indirectly to the resting membrane potential.

C. Resting Membrane Potentials of Nerves

1. The membrane potential of large nerves when they are not transmitting electrical signals is about
90 millivolts. The inside of the cell being negative relative to the outside.

2. A resting (steady-state) membrane potential is established in normal cells when the membrane is
permeable to several ions but the Na+ -K+ pump prevents ions from reaching equilibrium.

3. The cell membrane of a resting nerve is much more permeable to potassium than sodium and so
the membrane potential is close to the potassium equilibrium potential, that is, inside negative
relative to the outside. The diffusion of sodium and potassium contributes about 86 mV to the
membrane potential.

4. The sodium-potassium pump also contributes directly to the potential because they are
electrogenic to the tune of 4 mV to give a total of 90 mV.

D. Nerve Cell Action Potential

1. Nerve signals are transmitted by action potentials.

2. The action potential is a transient change in the membrane potential that conveys information
within the nervous system.

3. Electrically excitable cells (e.g., nerve and muscle cells) generate action potentials when they are
stimulated by a change in membrane potential (i.e., by the flow of current into and out of the
cell).

4. Changes in the membrane potential is caused by the flow of current through ion-specific chan-
nels that open or close in response to changes in membrane potential. The phases of the nerve
cell action potential are discussed here. Other cell types will be discussed when the organ-system
involved is taken up.

5. Excitable cells undergo rapid depolarization if the membrane potential is reduced to a critical level
(i.e., the threshold potential).
a. Once the threshold potential is reached, the remainder of the depolarization is spontaneous.
b. The action potential is an all-or-none response to a stimulus; that is, if the stimulus is strong
enough to reach threshold, the changes in membrane potential that characterize the action
potential are always the same.
c. The rapid depolarization of the membrane after threshold is reached is the depolarization
phase, or upstroke, of the action potential. The upstroke is produced by the flow of Na+ into
the cell.

6. The portion of the action potential during which the membrane is positive is the overshoot. The
peak of the action potential is the overshoot potential.

7. The rapid return of the membrane toward its resting potential is the repolarization phase, or
downstroke, of the action potential. The downstroke is produced by the flow of K+ out of the cell.

8. The membrane potential becomes more negative than its resting value at the end of the action
potential. This is the hyperpolarization phase, or undershoot, of the action potential.

E. Activation of the action potential

1. The all-or-none characteristic of the action potential is based on the behavior of the regulatory
gates that cover the ion-specific channels present in electrically excitable cells. In nerve cells,
there are two channels: one specific for Na+ ions and the other specific for K+ ions.

2. The Na+ channel has two gating particles (an m gate and an h gate).
a. The m gate covers the extracellular side of the Na+ channel, and the h gate covers the intra-
cellular side of the Na+ channel.
b. Both the m and the h gates must be open for Na+ to flow through the Na+ channel.
c. When the m gate is open, the channel is said to be activated.
d. When the h gate is closed, the channel is said to be inactivated.

3. The K+ channel has one gating particle, the n gate.

a. The n gate covers the extracellular side of the K+ channel.
b. The n gate must be open for K+ to flow through the K+ channel.
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 1. When the n gate is open, the K+ channel is activated.
2. The K+ channel does not have an inactivation gate

4. Changes in the membrane potential cause the opening and closing of the gates in a time-
dependent fashion.
a. The voltage- and time-dependent nature of the gating particles produces an action potential
when the nerve membrane is depolarized to threshold.
b. When the membrane is at rest (-70 to 90 mV), almost all of the channels are closed.
1. The Na+ channel is closed by the m gate. However, the h gate is in the open position. In
this condition, the Na+ channel is described as being closed but available for excitation.
2. The K+ channel is closed by the n gate.
3. Although almost all of the channels are closed, there are approximately 10 times as
many open K+ channels as open Na+ channels; therefore, the membrane potential is
close to EK.

5. When the membrane is depolarized to threshold (approximately 70 to 50 mV), a positive feed-

back (regenerative) process produces the all-or-none upstroke of the action potential. That is, the
response of the membrane to the stimulus (the opening of the m gates) causes an effect (mem-
brane depolarization) that produces an even greater response.

6. The downstroke follows the upstroke as part of the all-or-none response.

a. Depolarization of the membrane causes the inactivation of the Na+ channels, and the flow of
Na+ into the cell stops.
b. Depolarization of the membrane activates the K+ channels, and K+ flows out of the cell,
causing the membrane to repolarize.

7. also occurs as part of the all-or-none response.

a. The n gates close slowly as the membrane repolarizes; therefore, the K+ conductance (GK)
is higher at the end of the action potential than during the resting state.
b. The high GK causes the membrane to hyperpolarize (i.e., become more negative than the
resting membrane potential).
c. Eventually, the n gates close and the membrane potential returns to its resting level.

8. The time-dependent nature of the gating particles is essential for the production of the all-or-
none action potential.

a. If the h gates closed as rapidly as the m gates opened (i.e., if the Na+ channel was inacti-
vated and activated at the same time), Na+ could not flow into the cell.
b. Similarly, if the n gates opened as fast as the m gates opened (i.e., if Na+ and K+ activation
occurred at the same time), the upstroke could not occur.

9. Absolute refractory period. During this interval, another action potential cannot be elicited, re-
gardless of the strength of the stimulus.
The absolute refractory period begins at the start of the upstroke and extends into the down-
stroke.

10. Relative refractory period. During this interval, a second action potential can be elicited if the
stimulus is sufficient. The stimulus must be greater than normal because some Na + channels are
still inactivated and more K+ channels than normal are still open.
a. The relative refractory period begins when the absolute refractory period ends.
b. The action potential elicited during this interval has a lower upstroke velocity and a lower
overshoot potential than does the normal action potential.

F. Conduction of the action potential occurs along the axon.

1. The action potential generated at one location on the axon acts as a stimulus for the production
of an action potential on the adjacent region of the axon.
a. The magnitude of the action potential does not change as it is conducted along the axon be-
cause new action potentials are being generated constantly.
b. This is different from the spread of an electrotonic potential which diminishes in size along
the axon.

2. The speed of propagation depends on the type of fiber. Propagation is faster in myelinated fibers
than it is in unmyelinated fibers.
a. In myelinated fibers, the action potentials are generated only at the nodes of Ranvier, the
region of the axonal cell membrane exposed to the ECF.
1. The nodes occur every 100-500 µm. In general as the diameter of the axon increases,
the internodal distance increases. The membrane area between the nodes is covered by
an insulating sheath of myelin formed from the Schwann cell membranes.

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 2. Because the action potential appears to jump from node to node, this type of propaga-
tion is called saltatory propagation.

b. In unmyelinated fibers, new action potentials must be generated at each contiguous patch of
membrane.

3. The speed of propagation is proportional to the fiber diameter.

a. In myelinated fibers, the speed of propagation is approximately six times the fiber diameter.
The diameter of myelinated fibers ranges from 1-20 µm in diameter; therefore, propagation
velocities vary from 6-120 m/sec.
b. In unmyelinated fibers, the speed of propagation is proportional to the square root of the di-
ameter. The largest unmyelinated fibers are approximately 1 µm in diameter; their action po-
tentials propagate at a velocity of approximately 1 m/sec.

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 IV. SKELETAL MUSCLE CONTRACTION

A. Muscle fiber is cross striated by alternating light and dark bands.

1. A (dark) band: Thick filaments (myosin) surrounded by thin filaments (actin). H zone (myosin on-
ly) found in its center.
2. I (light) band: Thin filaments (actin) attached to Z lines only.
3. Two successive Z lines form the boundary of a sarcomere, the functional unit of the muscle.

B. Filaments.
1. Myosin: Thick filaments with cross bridges. Its heads have ATPase activity.
2. Actin: Thin filaments with 3 components:
a. Troponin, a calcium binding protein.
b. Tropomyosin, which covers the myosin binding site in actin.
c. G actin, in which myosin cross-bridge binding sites are found.

C. Contraction produces:
1. Narrowing of I band and H zone.
2. No change in the width of A band.
3. Movement of the Z lines toward the center (shortening).

D. Events in neuromuscular coupling and contraction-relaxation.

1. Action potential initiated and propagates in motor neuron axon.
2. Action potential triggers the release of acetylcholine (Ach) from axon terminals at neuromuscular
junction.
3. ACh diffuses from axon terminals to motor end plate in muscle fiber.
4. ACh binds to receptor sites on motor end plate, opening sodium and potassium ion channels.
5. More sodium ions move into the fiber at the motor end plate than potassium ions leaving, depo-
larizing the membrane, producing the end-plate potential(EPP).
6. Local currents depolarize the adjacent plasma membrane to its threshold potential, generating an
action potential that propagates over muscle fiber surface and into the fiber along the transverse
tubules.
7. Action potential in transverse tubules triggers release of calcium ions from lateral sacs of sarco-
plasmic reticulum.
8. Calcium ions bind to troponin on the thin filaments, causing tropomyosin to move away from its
blocking position and thus uncovering the cross-bridge binding sites on actin.
9. Energized myosin cross bridges on the thick filaments bind to actin.
10. Cross-bridge binding triggers release of energy stored in myosin, producing an angular move-
ment of each cross bridge.
11. ATP binds to myosin, breaking linkage between actin and myosin and thereby allowing cross
bridges to dissociate from actin.
12. ATP bound to myosin is split, transferring energy to myosin cross bridge.
13. Cross bridges repeat steps 9 to 12 producing movement of thin filaments past thick filaments.
14. Cycles of cross-bridge movement continue as long as calcium remains bound to troponin.
15. Cytosolic calcium decreases as calcium is actively transported into sarcoplasmic reticulum by Ca-
ATPase.
16. Removal of calcium from troponin restores blocking action of tropomyosin, the cross-bridge cycle
ceases, and the muscle fiber relaxes.

E. Types of contraction.
1. Isometric contraction.
a. Tension developed without shortening.
b. No work done (e.g. pushing against a wall).
2. Isotonic contraction.
a. Tension developed with muscle shortening.
b. Work is done (e.g. lifting a light weight).

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F. Types of skeletal muscle fibers (Slow VS Fast muscle)

Slow (red) Fast (white)

Speed of contraction - Slow Fast

Myosin-ATPase activity - Low High
ATP source - Oxidative Anaerobic
Glycolytic enzyme - Low High
Mitochondria - Many Few
Capillaries - Many Few
Myoglobin content - High (hence red) Low (hence white)
Glycogen content - Low High
Fiber diameter - Small Large
Fatigue onset - Fatigue resistant Relatively fatigable
Adapted for activity - Prolonged work Rapid but short work
(e.g. marathon) (e.g. sprint)

G. Factors determining muscle tension.

1. Number of muscle fibers contracting:
a. Recruitment of motor units
b. Number of muscle fibers per motor units
c. Asynchronous activity of motor units
2. Tension produced by each contracting muscle fiber:
a. Stimulation frequency (summation and tetanus)
b. Initial or resting length (at this length tension is maximal)
c. Duration of activity (fatigue)
d. Type of muscle

V. NEUROMUSCULAR TRANSMISSION

A. Neuromuscular Junction
1. The motor end plate is made up of branching nerve terminals invaginating into the muscle fiber
but lying outside the muscle membrane.
2. Invagination is called synaptic gutter. The space between nerve terminal nerve membrane and
the muscle membrane is the synaptic cleft. The subneural clefts are infoldings of muscle mem-
brane which increase the synaptic surface area.
3. Acetylcholine traverses the synaptic cleft to bind to nicotinic receptors on the muscle membrane.
4. About 125 vesicles or 1,250,000 acetylcholine molecules are released per depolarization of the
nerve terminal.
5. During rest, the nerve releases spontaneously 10,000 molecules to produce the miniature end-
plate potential (MEPP).
6. When discharging, the nerve releases 125 vesicles which produce the end plate potential (EPP).
7. The nicotinic receptor are made up of 5 subunit proteins (2 alpha, beta, gamma, and delta sub-
units) and form cationic channels in the membrane.
8. Acetylcholine binding opens channels allowing Na+ influx. Influx produces the local potential
change called end plate potential which in turn initiates action potential by positive feedback.
9. Successful production of action potential requires a large number of acetylcholine binding.
10. Curare and botulinum toxin produce weak or subthreshold EPP.

B. Neuromuscular Transmission Events

1. Nerve impulse reaches and depolarizes nerve terminal.
2. ECF calcium enters axon to combine with acetylcholine vesicles.
3. The combination causes rupture of vesicle and release of acetylcholine. This is inhibited by the
presence of high concentration of magnesium in the ECF.
4. Acetylcholine traverses synaptic cleft and binds to cholinergic receptors in the muscle membrane.
4. Ligand-gated channels open leading to membrane depolarization.
5. Action potential is propagated to the interior via T-tubules.
6. Acetylcholinesterase found on the muscle membrane adjacent to the receptor, hydrolyses the ace-
tylcholine and terminates its action.
7. Acetyl and choline are then taken up by the nerve terminal and recycled.

11
C. Relevant drugs.
1. Nicotine mimics action of acetylcholine.
2. Curare blocks acetylcholine binding.
3. Neostigmine, physostigmine, malathion, and DFP prolong the activity of acetylcholine by inhibiting
acetylcholinesterase.

D. Clinical correlate.
1. Myasthenia gravis, an autoimmune disease is due to reduced cholinergic receptors in the skeletal
muscle membrane.
2. MG is characterized by muscle weakness (e.g. ptosis) and easy fatigability.
3. Neostigmine and physostigmine can ameliorate the symptoms of MG.

E. Smooth Muscle Characteristics

1. Types
a. Multiunit smooth muscles are discrete, independent and nerve-controlled fibers. Example:
iris, ciliary muscle and piloerector muscle.
b. Unitary smooth muscles are masses of many muscle fibers contracting as a single unit.
1. Fibers adherent to each other
2. Gap junctions join cell membranes (free ionic flow)
3. Behave as functional syncytium
4. Found in visceral organs and blood vessels
2. Unstriated, but myosin and actin present.
3. No Z lines but has dense bodies that are attached to membranes
4. No troponin but has calmodulin
5. Calmodulin binds calcium producing activation of myosin kinase. The activation phosphorylates
the myosin head with subsequent binding of head to actin. The cycle is then repeated.
6. When calcium decreases in concentration myosin phosphatase is activated causing the removal
of phosphate from myosin head. The cycle stops and relaxation ensues.

F. Compared with skeletal muscle:

1. Smaller and shorter fibers
2. Slower cycling of cross bridges
3. Slower onset of contraction and relaxation (longer total contraction time)
4. Lower energy consumption for contraction (economical)
5. Higher maximum force of contraction
6. Greater percentage of shortening
7. Ability to return to its original force of contraction after stretching or shortening. Maintains pres-
sure (tension) at different lengths (stress-relaxation and reverse stress-relaxation).

G. Control
1. Nervous by autonomic nervous system.
a. Acetlcholine and norepinephrine (parasympathetic and sympathetic)
b. Resting potential ranges from -50 to 60 mV
c. Spike potentials (similar to skeletal muscle)
d. Action potentials (similar to cardiac muscle)
e. Calcium primarily responsible for depolarization of membrane and flows through calcium
channels
f. Calcium from ECF also used for contraction (binding to calmodulin)
2. Hormones can stimulate muscles
3. Stretch can produce depolarization
4. Tissue factors can also stimulate muscles eg. Of blood vessels (low oxygen, high carbon dioxide
and hydrogen ions)

12
THE CARDIOVASCULAR SYSTEM

I. HEART MUSCLE; THE HEART AS A PUMP

Physiology of Cardiac Muscle

A. Functional Anatomy
1. The three types of cardiac muscle are atrial, ventricular, and specialized excitatory muscle fibers.
2. Cardiac muscle is striated; with organized actin and myosin.
3. The muscle is a functional syncytium (many individual fibers contracting as a single unit) and is
due to intercalated disks that act as gap junctions for rapid ionic flow from one cell to the next.
4. The atrial syncytium is separated from ventricular syncytium by fibrous tissue skeleton that pre-
vents direct transmission of action potentials from atria to ventricles. The AV bundle crosses this
fibrous tissue

B. Action Potentials
1. The TMP in cardiac muscle is from -85 to 90 mV; in pacemaker cells from -90 to 100 mV.
2. Action potential has a spike (like skeletal muscle) and a plateau (like smooth muscle) that pre-
cedes an abrupt repolarization.
3. The long action potential duration increases muscle contraction time.
4. In the action potential the fast sodium channels account for the steep upstroke; the slow calcium
channels (open more slowly and remain open longer) account for the plateau, and the delayed
but rapid efflux of potassium through channels account for the abrupt repolarization.
5. The velocity of conduction in atrial and ventricular muscles is slower than that seen in skeletal
muscles and nerves
6. The absolute refractory period (cannot be excited by an impulse coming from the normal pace-
maker) coincides with action potential and lasts for 0.3 second. The relative refractory period
(can be excited but with great difficulty) follows absolute refractory period with a duration of 0.05
second.
7. Premature contraction can occur during the relative refractory period but the force of contraction
is weaker than normal and so no wave summation occurs (unlike in skeletal muscle)

C. Excitation-Contraction Coupling
1. The action potential propagated to the T tubules leads to calcium release from sarcoplasmic re-
ticulum (like skeletal muscle)
2. Calcium ions from the ECF (through T tubules) enter the sarcoplasm to contribute significantly to
the force of contraction (unlike skeletal muscle, but similar to smooth muscle)

D. The Cardiac Cycle

1. Contraction and Relaxation
a. Systole is the period of contraction (expels blood from chamber)
b. Diastole is the period of relaxation (fills the chamber with blood)

2. Electrocardiogram (ECG)
a. The P wave is due to atrial depolarization and precedes atrial systole
b. The QRS wave is due to ventricular depolarization and precedes ventricular systole
c. The T wave is due to ventricular repolarization and precedes ventricular relaxation

E. Atrial Pumps
1. Venous blood flows continually into the right atrium (from the vena cava) and left atrium (from
the pulmonary veins).
2. 75% of ventricular filling occurs when atrium is relaxed the remaining 25% is due to atrial con-
traction
3. Atrial waves
a. a wave due to atrial contraction
b. c wave due to ventricular contraction
c. v wave due to slow flow of blood into atria while AV valves are closed

F. Ventricular Pumps
1. The left ventricle is thicker than right ventricle and the ventricles are separated from each other
by the interventricular septum.
2. Left ventricular contraction aids right ventricular contraction
3. Normally the left ventricular volume and output are equal to the right ventricular volume and
output.
4. The left ventricular systolic pressure is greater than the right ventricular systolic pressure
5. End-diastolic (EDV) volume is the volume of blood in the ventricle just before systole (or at the
end of diastole) and is about 120 ml.
6. End-systolic volume (ESV) is the volume of blood remaining in the ventricle after systole and is
normally about 50 ml.

13
 7. Stroke volume (SV) is the volume ejected from the ventricle during systole and is about 70 ml at
rest.
8. ESV = EDV SV.
9. Ejection fraction is percentage of EDV that is ejected (N = 60%).

G. Cardiac Valves and Papillary Muscles

1. A-V valves (tricuspid on the right, mitral on the left) prevent backflow of blood from the ventri-
cles to the atria during systole.
2. Semilunar valves (pulmonary on the right, aortic on the left) prevent backflow of blood from the
pulmonary artery and aorta into the ventricles during diastole.
3. Valves open and close when there is pressure difference across the valve.
4. Papillary muscles (attached to valves by chordae tendineae) contract to prevent backward bulg-
ing of A-V valves during systole.

H.
1. Systolic Interval (see Table for description)
a. Isovolumetric contraction
b. Rapid ejection
c. Reduced ejection
d. Protodiastole
2. Diastolic Interval
a. Isovolumetric relaxation
b. Rapid filling
c. Reduced filling
d. Atrial systole

I. Preload and Afterload

1. Preload is the degree of tension on the muscle at the start of contraction
a. Directly related to the end-diastolic pressure or end-diastolic volume
b. Increases when the venous return increases and vice versa
2. Afterload is the load against which the muscle exerts its contractile force
a. Is the pressure in the artery into which blood is ejected (resistance)
b. This corresponds to the systolic pressure

J. Regulation of Heart Pumping

1. Intrinsic regulation or Frank-Starling mechanism of the heart
a. Frank-Starling mechanism of the heart is the intrinsic ability of the heart to adapt to changing
volumes of inflowing blood
b. Within physiological limits, the heart pumps all the blood that comes to it without allowing
excessive damming of blood in the veins
c. The force of contraction and stroke volume increases in direct proportion to the increase in
venous return or end-diastolic volume
2. Autonomic nervous system
a. Sympathetic stimulation increases the contractility of the heart
1. Increases heart rate (positive chronotropic effect)
2. Increases force of contraction (positive inotropic effect)
b. Parasympathetic stimulation decreases heart rate
3. Other Factors
a. Too much plasma potassium decreases heart rate and contractility (flaccid) as well as
atrioventricular conduction
b. Too much plasma calcium causes spasm. Too little causes flaccidity.
c. High body temperature increases heart rate. Very low temperature decreases heart rate

14
Phase Time Events at Onset of Phase Main Events During Phase Events at Close of Phase

Isovolumetric 0.06 s Onset of contraction Closure of AV valves; SL valves close Opening of SL valves
Contraction Preceded by QRS wave First heart sound produced
No change in EDV (120 ml)
Rapid rise in ventricular pressure
RV: from 10 to 25 mm Hg
LV: from 10 to 80 mm Hg

Rapid Ejection 0.11 s Opening of SL valves Rapid outflow from ventricles Peak of ventricular pressure
Ventricles and arteries RV volume drops from 120 to 70 ml Pulmonary pressure = 25 mm Hg
now common chambers LV volume drops from 120 to 70 ml Aortic pressure = 120 mm Hg
Ventricular pressure rising
RV pressure: from 10 to 25 mm Hg c wave registered
LV pressure: from 80 to 120 mm Hg

Reduced 0.14 s Peak of intraventricular Declining outflow of blood Onset of ventricular relaxation
Ejection pressure RV ejects 20 ml more blood
T wave recorded LV ejects 20 ml more blood END of SYSTOLE

Protodiastole 0.03 s Onset of ventricular Rapid drop in intraventricular Closure of SL valves

relaxation pressure (due to retrograde flow of blood)

Isovolumetric 0.06 Closure of SL valves Continued ventricular relaxation Opening of AV valves

Relaxation No change in volume = 50 ml
Both AV and SL valves closed v wave registered
Rapid drop in ventricular pressure
RV pressure: from 10 to 4 mm Hg
LV pressure: from 100 to 10 mm Hg

Rapid 0.11 Opening of AV valves Rapid flow of blood into ventricle Slowing of inflow rate
Filling Atria and ventricles are Ventricular volume rises rapidly
from 50 to 90 ml in 0.11 secs
Third heart sound recorded

Reduced 0.20 Slowing of inflow from Continued slow flow from atria to Onset of atrial contraction
Filling atria to ventricles ventricles (volume rises to 100 ml Preceded by P wave

Atrial 0.11 Onset of atrial con- Additional flow from atria (20 ml) End of diastole

15
Systole traction a wave is recorded
Fourth heart sound recorded

16
 c. RHYTHMICAL EXCITATION OF THE HEART

1. Specialized Excitatory and Conductive System of the Heart

1. For generating rhythmical impulses that control beating of the heart
2. For conducting the pacemaking impulses rapidly throughout the heart
3. Conduction from sinus node internodal pathways (atria) A-V node A-V bundle bundle
branches (Purkinje fibers) ventricles

2. Sinus Node
1. The normal pacemaker of the heart
2. It is located in superior lateral wall of right atrium
3. It is self excitatory and exhibits spontaneous depolarization at phase 4
4. TMP = - 55 mV.
5. Action Potential Phases:
a. Phase 0: Due to sodium influx in fast fibers; due to calcium influx in slow fibers.
b. Phase 1: Due to sodium and rapid calcium and potassium fluxes in both fibers.
c. Phase 2: Due to calcium influx and shows a plateau in fast fibers (slow repolarization and prolonged
refractory period).
d. Phase 3: Rapid repolarization due to rapid potassium efflux.
e. Phase 4: Nonpacemaker cells show constant and stable potential but pacemaker cells show a slow
diastolic depolarization.
6. Autorhythmicity is due to leakiness of membranes to sodium ions that brings the potential to threshold
level spontaneously. Action potential is initiated by the opening of fast sodium channels that brings po-
tential to threshold (- 40 mV).
7. Threshold voltage when reached activate the slow calcium-sodium channels to complete the action po-
tential. The action potential is slower to develop and recovers also slowly (unlike ventricular muscles)
8. Repolarization is due to opening of potassium channels which causes hyperpolarization at the tailend of
the action potential.
9. The hyperpolarization is followed by spontaneous depolarization and cycle is repeated

3. Atrial conduction
1. Action potentials produced in the SAN conducted to atrial muscles.
2. Conduction is faster when conducted by specialized atrial muscles called the internodal pathways (ante-
rior, middle, and posterior).

4. Atrioventricular conduction
1. A-V node and A-V bundle are slow conducting fibers and are responsible for the delay of transmission of
impulse from the atria to the ventricles
2. The A-V nodal delay allows time for the atria to empty their contents into the ventricles before ventricu-
lar systole begins
3. The A-V bundle penetrates the fibrous barrier and thus transmits cardiac impulse from the atria to the
ventricles
4. Normally, the A-V bundle allows conduction of action potentials in only one direction

5. Ventricular conduction
1. The Purkinje fibers exiting from the A-V bundle divides into left and right bundle branches (at the top of
interventricular septum) which spread down subendocardially to the apex of the ventricle and then back
to the base of the heart
2. The Purkinje fibers conduct the impulse to the ventricular muscles at a very rapid rate and the two ven-
tricles can contract synchronously.

6. Control of Excitation and Conduction in the Heart

1. Intrinsic Control
a. SAN is the normal pacemaker of the heart and sets the cardiac rhythm, inspite of the fact that other
parts of the heart are capable of autorhythmicity.
b. The intrinsic discharge rate of the SAN is 70 to 80 per minute, the A-V node 40 to 60 per minute
and the Purkinje system in the ventricles, 15 to 40 per minute
c. SAN sets the pace because, by having the higher discharge rate, it depolarizes the other potential
pacemakers before they can discharge on their own
d. If any of the potential pacemakers discharge faster than the SAN, it becomes the pacemaker (an
ectopic pacemaker)
e. A pacemaker shift can also occur if the impulse from the sinus node is prevented from reaching the
ventricle as seen in A-V block.

2. Nervous Control
a. Parasympathetic (vagal) stimulation slows cardiac conduction and heart rate

17
 b. Acetylcholine is the neurotransmitter of the parasympathetic nerves supplying the heart. It hy-
perpolarizes the pacemaker cells.
c. Sympathetic nerves supplying the heart release norepinephrine which increases the permeability of
the cells to sodium and calcium.
d. Sympathetic stimulation increases heart rate, impulse conduction rate and force of contraction of
the heart

d. THE NORMAL ELECTROCARDIOGRAM

1. Heart rate range:

1. Normocardia: 60 to 100 beats per minute
2. Bradycardia: less than 60 beats per minute
3. Tachycardia: more than 100 beats per minute

2. ECG Configurations.
1. P wave represents atrial depolarization
2. QRS wave represents ventricular depolarization
3. T wave represents ventricular repolarization. The downslope of the T wave is the so-called vulnerable
period and a PVC during this period ("R on T") can lead to fibrillation.
4. P-R interval is a measure of the AV conduction.
5. Q-T interval is a measure of the duration of the electrical systole.
6. R-R interval is a measure of the duration of the cardiac cycle. 60 divided by the R-R interval in se-
conds is equal to the ventricular rate.
7. J point is the termination of the QRS complex, when the entire myocardium is depolarized.
8. S-T segment is normally isoelectric. Depression or elevation indicates myocardial strain or ischemia.
Displacement is due to current of injury.

3. Mean Electrical Axis.

1. Normal axis range: -15 to +90o.
o
2. Left axis deviation (LAD): -15o to -90o (e.g. LVH or LBB)
3. Right axis deviation (RAD): +90o to +180o (e.g. RVH or RBB)

4. ECG Leads.
1. Bipolar leads:

a. Lead I is the potential difference between the left arm (LA) and right arm (RA)
or LA-RA. Positive electrode on the LA.
b. Lead II is the difference between the left leg (LL) and the right arm (RA) or LL-RA. Positive elec-
trode on the LL.
c. Lead III is the difference between the left leg (LL) and the left arm (LA) or LL-LA. Positive electrode
on the LL.

3. Augmented Unipolar Leads.

a. aVR is the difference between RA and the sum of LA and LL.
b. aVL is the difference between LA and the sum of RA and LL.
c. aVF is the difference between LL and the sum of RA and LA.

4. Precordial Unipolar Leads.

a. V1: exploring (+) electrode on 4th ICS at right parasternal line.
b. V2: electrode on 4th ICS at left parasternal line.
c. V3: electrode placed halfway between V2 and V4.
d. V4: electrode on 5th ICS at left MCL.
e. V5: electrode on left anterior axillary line at V4 level.
f. V6: electrode on midaxillary line at V4 level.

V1 and V2 usually show large S waves while V5 and V6 show large R waves. In V3 and V4 the R and S
waves are approximately equal in amplitude (transition points.

18
 Medical Physics of Pressure, Flow, and Resistance

A. Overview of the Circulation

1. Arteries. The arteries function as low-resistance conduits and as pressure reservoirs for maintain-
ing blood flow to the tissues during ventricular relaxation.
2. Arterioles. Arterioles, the major site of resistance to flow in the vascular system, play a major role
in determining both mean arterial pressure and the distribution of flows to the various organs
and tissues.
3. Capillaries.
a. Capillaries are the site of exchange of nutients and waste products between blood and tis-
sues.
b. Capillary blood flow is determined by the resistance of the arterioles supplying the capillaries
and by the number of open precapillary sphincters.
c. Blood flows through the capillaries more slowly than in any other part of the vascular system
because of the huge cross-sectional area of the capillaries.
4. Veins.
a. Veins serve as low-resistance conduits for venous return.
b. Veins are very compliant and contain most of the blood in the vascular system.

B. Hemodynamics. Physical principles involved in circulation.

1. Pressure-flow relationship:
Q = P/R where P is pressure difference and R is resistance.
Significance: Flow between two points in the cardiovascular system is directly propor-
tional to the pressure difference between the points and inversely proportional to the re-
sistance.

2. Poiseuille's equation:
Q (flow in ml/min) = ____P. r4 ________
8.viscosity.length
Significance: Vessel diameter exerts the greatest effect on flow, the radius being raised
to the 4th power.

3. Continuity equation which states that the velocity of flow times the cross-sectional area of a ves-
sel is at all points constant.

v1 x A1 = v2 x A2 where v is velocity at one point and A is cross-sectional area at

one point
Significance: As the X-sectional area of the vessel increases the velocity must decrease
since the mass of blood moving in the body is constant. Thus velocity of blood flow in the
capillaries is very slow because the capillary segment has the greatest total cross-
sectional area.

4. Laplace equation
T = P.r2 where T is the total force across the X-sectional area of the tube (ten-
sion) and r is radius of the tube

Significances: This equation tells us why:

a. Aneurysms tend to rupture.
b. Capillaries can withstand relatively high pressure.
c. There is a critical closing pressure for vessels.
d. Dilated hearts consume more O (produces more tension) to do the same amount of work that
2
a normal heart does.
e. Surfactant is needed to prevent alveolar collapse.

5. Compliance = Increase in volume/Increase in pressure

Significance: Veins being compliant can store more blood (higher capacitance) than ar-
teries of the same length and size. Veins can be filled with blood with a relatively small
rise in pressure.

6. Fahreaus-Lindqvist phenomenon. This refers to the apparent decrease in blood viscosity as blood
flows through smaller vessels. This is related to plasma skimming.

7. Reynold's number. This expresses the probability of turbulence to occur.

Re = (fluid density) (tube diameter) (velocity of flow)
viscosity of fluid

19
 Significance: Turbulent flow occurs when blood is moving very fast or when it suddenly
enters a dilated segment of a vessel. Turbulence tends to occur when the hematocrit is
decreased.

Vascular Distensibility, Functions of Arterial and Venous Systems

A. Vascular Distensibiltiy.
1. All blood vessels are distensible but the veins are the most distensible of all. Veins are 8 times
more distensible than arteries.
2. Veins are 24 times more compliant than arteries.
3. Stress-relaxation is exhibited by veins (as well as arteries to a slight degree) and is referred to as
delayed compliance. This allows veins to return to its original pressure after blood is removed
from or added to it.
B. Arterial Pressure Pulsations
1. Arterial distensibility allows for the sudden surge of blood into the aorta to be dampened and, with
the contribution of arterial resistance, cause the disappearance of pulsation by the time blood
reaches the capillaries.
2. Distensibility also contributes to the continuity of blood flow during the entire cardiac cycle be-
cause it allows arteries to recoil elastically during diastole and provide the force to push blood
even when the ventricle is relaxing.
3. Pulse pressure is the difference between the systolic pressure and diastolic pressure. It is affected
by stroke volume and compliance.
4. The greater the stroke volume the greater the pulse pressure. The less compliant the higher the
pulse pressure.
5. The pulse pressure is elevated in aortic regurgitation, patent ductus arteriosus, and arteriosclero-
sis. It is low in aortic stenosis.

C. Clinical Arterial BP Measurement.

1. The palpatory method measures only the systolic pressure.
2. The auscultatory method measures both the systolic and diastolic pressure.
a. Based on turbulent flow of blood as it jets through a partially occluded vessel (e.g. brachial ar-
tery).
b. The sound produced called the Korotkoff sounds are used to determine systolic and diastolic
pressure
c. First tapping sound indicates systolic pressure.
d. Muffled sound indicates diastolic pressure.

D. Veins and Their Functions

1. Blood from the systemic veins flows into the right atrium. The pressure in the right atrium is thus
called the central venous pressure.
2. Right atrial pressure is regulated by a balance between the ability of the heart to pump blood out
of it and the tendency for blood to flow into it. Output should equal venous return to avoid
changing the atrial pressure.
3. Normal right atrial pressure is about 0 mm Hg.
4. When atrial pressure rises (above 6 mm Hg) then the peripheral venous pressure rises.
5. When man is standing, the veins contain a column of blood which produces a hydrostatic pres-
sure. Thus the venous pressure near the ground is higher than the venous pressure at a higher
level.
6. In a man who is standing absolutely still, the venous pressure in the feet is about 90 mm Hg. At
the heart level it is 0 mm Hg and at the neck level because of the collapsibility of the neck veins
the pressure is also 0. In the skull because the veins do not collapse, the saggital sinus has a
pressure of 10 mm Hg.
7. The venous valves in the legs prevent the pressure from rising to a very high level when man is
standing. The contraction of the leg muscle compresses the vein pushing blood upwards and the
valves prevent the return of the blood downward.
8. Thus during walking the venous pressure at the foot level is 25 mm Hg.
9. Incompetence of valve (e.g. varicose veins, pregnancy) causes abnormally high venous pressure
and edema.
10. Veins function also as blood reservoir and can restore blood pressure by shifting their content
during venoconstriction.

20
MICROCIRCULATION AND LYMPHATIC SYSTEM

A. Microcirculation
1. Arteriole. Plays the major role in controlling blood flow to tissues being highly muscular
2. Metarteriole. Controls blood flow into capillaries with its precapillary sphincters. Sphincters are re-
laxed by:
a. Low oxygen tension in the tissue area
b. High concentration of waste product of metabolism
3. Capillaries. Single layered-vessel where fluid exchange between blood and interstitial space takes
place.
a. About 10 billion in the entire body with a total surface area of 600 square meters.
b. Pores allow easy diffusion of water and solutes, but not proteins
c. Oxygen and carbon dioxide pass through the endothelial wall

B. Factors affecting rate of diffusion across capillary wall

1. Size of pores which vary from organ to organ
2. Molecular size of substance
3. Concentration difference across the capillary wall

C.
1. Capillary hydrostatic pressure
2. Interstitial hydrostatic pressure
3. Plasma colloid osmotic pressure due to plasma proteins
4. Interstitial fluid colloid osmotic pressure due to fluid proteins

D. Capillary-interstitial fluid exchange

1. At the arteriolar end of the capillary there is net filtration of fluid
2. At the venular end there is net reabsorption of fluid
3. The amount reabsorbed is slightly less than the amount filtered
4. The lymphatic system returns the remaining fluid back to the circulation

E. Lymphatic system.
1. Carries fluid and protein (lymph) from the interstitial spaces
2. Also a major route for absorption of nutrients from the gastrointestinal tract
3. The lymphatic channels pass through lymph nodes that filter bacteria and debris
4. The thoracic duct receives the lymph from the lower part of the body and the left side of the
head, left arm and chest. The thoracic duct empties into the venous system at the juncture of the
left interior jugular vein and subclavian vein. Lymph from right side of the trunk enter the right
lymph duct which then empties into the venous system at the junction of the right subclavian
vein and internal jugular vein.
5. Valves in the system insure forward flow of lymph
6. Rate of flow influenced by:
a. Interstitial hydrostatic pressure
b. Contraction of lymphatic vessels
c. Compression by surrounding tissues i.e. muscles, massage, elastic stockings

F. Edema. Accumulation of fluid in the interstitial space.

G. Factors that promote edema:
1. Decreased plasma colloid osmotic pressure (e.g. kwashiorkor, nephrosis)
2. Increased capillary hydrostatic pressure (e.g. prolonged standing)
3. Increased capillary permeability (e.g. allergy, burns)
4. Lymphatic blockade (e.g. tumor, post-radical mastectomy, filariasis)

LOCAL CONTROL OF BLOOD FLOW

A. Tissues in general have the ability to control blood flow in their area so that the flow is proportional
to their metabolic rate. Notable deviations include
1. Cutaneous blood flow is regulated by thermoregulatory mechanism
2. Renal blood flow is regulated by the need of the body to maintain blood pressure and excrete
metabolic waste.

21
B. Mechanisms of Local Blood Flow Control
1. Acute control
a. Occurs within seconds or minutes
b. Effected by dilating or constricting the arterioles, metarterioles and pre-capillary sphincters
c. Increased blood flow brought about by vasodilation occurs in:
1) Increased tissue metabolism (e.g. active hyperemia, exercise)
2) Increased demand for oxygen (e.g. exercise, fever, hyperthyroidism)
3) Decreased oxygen availability (e.g. reactive hyperemia, high altitude, pneumonia, cya-
nide poisoning)

4) Accumulation of vasodilator substances (e.g. nitric oxide, adenosine, ADP, CO2, lactic ac-
id, potassium ions and hydrogen ions)
5) Lack of ATP (e.g. beriberi)

2. Long-term control
a. Occurs later than acute control and lasts for days or weeks.
b. Characterized by altering tissue vascularity in response to changes in tissue oxygenation.
c. Angiogenesis or growth of new blood vessels occurs in:
1) Tissue ischemia (e.g. coronary artery disease)
2) Tissue overgrowth (e.g. tumor)
3) Tissue hypermetabolism (e.g. hyperthyroidism)

C. Humoral Regulation of the Circulation

a. Hormones
1) Vasoconstrictors
a) Norepinephrine, epinephrine
b) Angiotensin II
c) ADH or vasopressin
d) Endothelin
e) Prostacyclin, prostaglandin E

2) Vasodilators
a) Thromboxane A2, prostaglandin F
b) Bradykinin
c) Histamine
b. Ions and other chemicals
1) Vasoconstrictors (e.g. Calcium ions)
2) Vasodilators
a) Potassium ions
b) Magnesium ions
c) Sodium ions
d) Plasma osmolarity
e) Hydrogen ions
f) Carbon dioxide

22
 e. NERVOUS REGULATION OF ARTERIAL PRESSURE

Figure 1. Basic pathways involved in the medullary control of blood pressure. The putative
neurotransmitters
are in parenthesis. GABA, gamma aminobutyric acid; E, epinephrine; Glu, glutamine; Ach,
acetylcholine;
NE, norepinephrine; IML, intermediolateral gray column; NTS, nucleus tractus solitarius.

A. Vasomotor centers (VMC). See Figure 1.

1. Group of neurons located in medulla that control blood pressure.
2. Project excitatory signals to sympathetic preganglionic neurons in the intermediolateral gray col-
umn of the spinal cord.
3. C-1 (vasoconstrictor area) is at anterolateral part of upper medulla
4. A-1 (vasodilator area) is at anterolateral part of lower medulla
5. A-2 (sensory area) receives signals from CN IX and X
6. Normally exerts vasomotor tone (sympathetic)
7. Heart is also controlled by the VMC (CEC lateral part; CIC medial)
8. Norepinephrine acts on alpha receptors to cause vasoconstriction
9. Acetylcholine on muscarinic receptor to decrease heart rate

B. Factors affecting the activity of the VMC

1. Direct stimulation
a. CO2
b. Hypoxia
2. Excitatory inputs
a. From cortex via hypothalamus
b. From pain pathways and muscles
c. From carotid and aortic chemoreceptors
3. Inhibitory inputs
a. From cortex via hypothalamus
b. From lungs
c. From carotid, aortic, and cardiopulmonary baroreceptors

C. Baroreceptor reflex (see Figure 2)

1. Baroreceptors are in carotid sinus and aortic arch wall

23
 2. High pressure stimulate receptors increased discharge to medulla inhibition of C-1 and exci-
tation of vagal center vasodilation and low heart rate
3. Low pressure decreases receptor discharge vasoconstriction and tachycardia
4. Adaptability (resetting) makes it unimportant in long-term control

D. Chemoreceptor reflex
1. Carotid and aortic bodies
2. Stimulated by low O2, high CO2, and high hydrogen ions
3. Acts only when pressure drops below 80 mm Hg
E. Atrial reflex to kidneys (Volume reflex)
1. Stretching of atria dilation of afferent arterioles in kidneys more urine
2. Stretch of atria decreased ADH secretion more urine
F. Atrial reflex to heart (Bainbridge reflex)
1. Stretch atria vagus n. medulla sympathetic n. increased heart rate
2. Prevents damming of blood in veins, atria, and pulmonary circulation
G. CNS ischemic response
1. Ischemia of brain increased sympathetic activity vasoconstriction
2. Acts only when BP below 60 mm Hg
3. Cushing reaction (similar to CNS ischemic but stimulated by increased intracranial pressure
H. Abdominal compression reflex
1. Occurs with baroreceptor, chemoreceptor reflexes when BP drops
2. Abdominal muscles contract to compress veins in abdomen
3. Causes translocation of blood increased venous return

f. RENAL-BODY FLUID SYSTEM CONTROL OF ARTERIAL PRESSURE

1. Principle: Kidneys play the pivotal role in the long term control of arterial
pressure
2. Process: ECF AP DIURESIS & NATRIURESIS ECF
AP
1. Diuresis - water loss in urine
2. Natriuresis - salt loss in urine
3. Increased fluid volume increases AP by: see diagram on renal-body fluid
system
1. Cardiac output
2. Total peripheral resistance (TPR) secondary to AUTOREGULATION secondary to increased
CO
4. Components of long term BP control (see Figure 3)
1. Kidneys
2. Renin enzyme from JG cells; splits angiotensin I from angiotensinogen
3. Angiotensin II from angiotensin I; vasoconstrictor; stimulates aldosterone secretion; increases
salt and water retention by kidneys
4. Aldosterone hormone from adrenal cortex; increases sodium renal reabsorption
5. ADH hormone from hypothalamus via posterior pituitary; increases water reabsorption in kid-
neys
6. Thirst center in hypothalamus

5. Hypertension (HPN)
1. Defined as (for adults aged 18 years and older):
a. Systolic P > 140 mm Hg
b. Diastolic P > 90 mm Hg
2. Lethal effects:
a. workload on heart heart failure; coronary heart disease
b. arterial pressure rupture of blood vessel (CVA or stroke)
c. multiple hemorrhages in kidneys renal failure; uremia

6. Causes of HPN
1. Volume loading HPN ( ECF volume due to salt retention)
a. HPN initially due to rise in cardiac output (CO)
b. CO returns to normal because of autoregulation
c. Autoregulation increases TPR with AP at higher level
d. Seen in:
1. Anephric patients (dialysis)
2. Primary aldosteronsm
2. Angiotensin II-associated HPN
a. Renin-secreting tumor (JG cell tumor)
b. Goldblatt HPN (renal artery constriction)
24
 c. Ischemic kidneys
3. Coarctation of aorta BP upper part of body greater than lower part.

4. Toxemia of pregnancy - glomerular filtration rate (aggravated by salt)

5. Neurogenic HPN transient
6. Essential HPN most common; Rx: Vasodilator drugs and Diuretics

HEMORRHAGE

ARTERIAL PRESSURE
Angiotensin II &
FIRING BY ARTERIAL BARORECEPTORS
Vasopressin (ADH)

VMC ACTIVATION (+)

(+)

PARASYMPATHETIC SYMPATHETIC SYMPATHETIC SYMPATHETIC

DISCHARGE TO HEART DISCHARGE TO HEART DISCHARGE TO VEINS
DISCHARGE TO ARTERIOLES

HEART RATE CONSTRICTION

CONSTRICTION

VENOUS PRESSURE

VENOUS RETURN

END-DIASTOLIC
VOLUME

STROKE VOLUME

CARDIAC OUTPUT TOTAL PERIPHERAL RESISTANCE

ARTERIAL PRESSURE
(RESTORATION TOWARD NORMAL)

Figure 2. Arterial baroreceptor reflex compensation for hemorrhage. The compensatory mechanisms do
not restore arterial pressure completely to normal. All arrows signifying increases or decreases are rela-
tive to the state immediately following the hemorrhage. Plasma angiotensin II and vasopressin are also
reflexly increased and help constrict arterioles.

ARTERIAL PRESSURE

RENIN RELEASE (JG cells)

ANGIOTENSINOGEN (Plasma) ANGIOTENSIN I

ANGIOTENSIN CONVERTING ENZYME: ACE (Lung)

ANGIOTENSIN II

DIRECT VASOCON- STIMULATION OF

STRICTOR ACTION ADRENAL CORTEX

OTHER BLOOD RENAL BLOOD ALDOSTERONE

25
VESSELS VESSELS SECRETION

RENAL BLOOD NACL REABSORPTION

FLOW

RETENTION OF ECF OSMOLALITY

SALT & WATER

BLOOD VOLUME ADH SECRETION (Pituitary)

THIRST DRINKING

VENOUS RETURN

CARDIAC OUTPUT

TPR AUTOREGULATION

ARTERIAL PRESSURE

Figure 3. Activity of the Renal-Body Fluid-Angiotensin-Aldosterone-ADH System in response to lowered

arterial pressure.

26
 g. CARDIAC OUTPUT; VENOUS RETURN; REGULATION

1. Cardiac output. The quantity of blood pumped into aorta each minute.
Mean CO in adults = 5 L/min
1. Mean CO in males = 5.6 L/min
2. Mean CO in females = 4.5/min (or 10 to 20% less than the males)
2. Venous return is quantity of blood flowing from veins into the atrium
each minute.
1. To avoid damming of blood somewhere in the circulatory system, cardiac output (CO) must in
the long run equal venous return (VR).
2. CO controlled by VR
a. The heart itself is not the primary controller of CO.
b. The factors that affect blood flow into the heart from the veins
are the primary controllers.
3. Frank Starling law of the heart and the F-S curve.
a. States that ventricular performance is proportional to the initial fiber length of the contracting
muscle.
b. This means that within physiological limits, the greater the heart muscle is stretched during
filling, the greater will be the force of contraction and the greater will be the quantity of
blood pumped into the aorta.
c. The relationship is generally presented in the form of a diagram relating end-diastolic vol-
ume, pressure or atrial pressure (preload) to systolic pressure or stroke volume, the curve
being called the Frank-Starling curve.
3. Cardiac output is directly proportional to the arterial pressure and in-
versely proportional to the total peripheral resistance. This can be expressed in the following forms:

AP = CO x TPR; CO = AP/TPR; TPR = AP/CO

4. Factors that improve cardiac output

1. F-S mechanism allows an increase in CO up to 13 L/min.
2. Sympathetic stimulation allows an increase of up to 25 L/min (hypereffective heart).
3. Hypertrophy allows an increase of up to 40 L/min (hypereffective heart)

5. Causes of Hypoeffective Heart

1. Inhibition of sympathetic; activation of parasympathetic
2. Abnormal rate and rhythm of heart
3. Valvular heart disease
4. Hypertension
5. Congenital heart disease
6. Myocarditis
7. Coronary heart disease

6. High Cardiac Output Conditions (due to TPR) VR CO

1. Beriberi thiamine deficiency; vasodilation
2. Arteriovenous fistula (shunt) abnormal connection between artery and vein
3. Hyperthyroidism generalized in tissue metabolism; O2 consumption
4. Anemia generalized vasodilation and decreased viscosity

7. Low Cardiac Output Conditions

1. Cardiac diseases
2. Decreased blood volume
3. Acute venous obstruction
4. Obstruction of large veins

8. The Venous Return or vascular function curve.

1. This relates the venous return to right atrial pressure.
2. An increase in mean systemic pressure is reflected in a shift of the venous return curve to the
right.
3. The slope of the venous return curve is determined by the resistance of the arterioles.
a. A clockwise rotation of the curve indicates a decrease in total peripheral resistance. When
TPR decreases, the venous return increases.
b. A counterclockwise rotation indicates an increase in TPR.

27
9.
1. CO (L/min) =
_______O2 consumption (ml/min)____________
[O2]pulmonary vein [O2]pulmonary artery

2. The equation is solved as follows:

a. O2 consumption for the whole body is measured.
b. Pulmonary vein [O2] is measured in a peripheral artery.
c. Pulmonary artery [O2] is measured in systemic mixed venous blood.

h. HEART SOUNDS; VALVULAR & CONGENITAL HEART DEFECTS

1. Normal Heart Sounds

1. First HS -V valves; systolic timing; heard with stethoscope.
2. Second HS tethoscope.
3. Third HS weak rumbling sound; occurs middle third of diastole; inrushing blood from atria; rec-
orded by phonocardiogram; heard in heart failure.
4. Fourth HS low frequency; due to atrial contraction; flow into ventricle; normally phonocardio-
gram only; heard in heart failure

2. Clinical Valve Areas

1. Aortic valve at second right ICS along right parasternal line.
2. Pulmonic valve at second left ICS along left parasternal line.
3. Mitral valve at fifth left ICS along midclavicular line.
4. Tricuspid valve at left side of xiphisternal junction.

3. Valvular Lesions in Rheumatic Heart Disease

1. Rheumatic fever is due to streptococcal infection followed by an autoimmune response.
2. Valves are scarred producing:
a. Stenosis or narrowing (e.g. mitral stenosis)
b. Regurgitation or incompetence (e.g. mitral regurgitation).
3. Flow of blood thru damage valve produces murmurs
a. Systolic murmurs in:
1. Tricuspid and mitral regurgitation
2. Pulmonic and aortic stenosis
b. Diastolic murmurs in:
1. Tricuspid and mitral stenosis
2. Pulmonic and aortic regurgitation
4. Abnormal Circulatory Dynamics in Valvular Heart Diseases
a. Aortic stenosis (narrowed aortic opening)
1. Compensated stage
a. Decreased stroke volume and cardiac output
b. Left ventricular hypertrophy
c. Elevated left ventricular pressure
d. Lowered aortic pressure
e. Elevated left atrial pressure
f. Increased blood volume
g. Polycythemia and increased hematocrit
2. Decompensated stage (in failure)
a. Marked increase in severity of abovementioned features
b. Dilatation of left ventricle and atrium
c. Pulmonary edema
d. Ischemia of left ventricle
b. Aortic regurgitation
a. Leaky aortic valve.
b. Volume and pressure changes similar to aortic stenosis
c. Mitral stenosis (impeded blood flow through mitral valve)
1. Compensated stage
a. Low arterial pressure
b. Reduced left ventricular stroke volume and output
c. Increased left atrial volume and pressure
d. Increased right ventricular pressure
e. Left atrial and right ventricular hypertrophy
f. Small left ventricle
2. Decompensated stage
a. Reduced mean arterial pressure.
b. Increased severity of the features of compensated stage
28
 c. Pulmonary edema
d. Left atrial dilatation with atrial fibrillation and tachycardia
e. Ischemia of right ventricle
d. Mitral regurgitation
1. Reflux of blood into left atrium during systole.
2. Changes similar to mitral stenosis with one except ion; the left ventricle is enlarged

5. Congenital Heart Diseases

a. Patent ductus arteriosus (left to right shunt; acyanotic)

1. The ductus areriosus that connects the aorta to the pulmonary artery during fetal life
fails to close after birth. So aortic blood flows back to the pulmonary artery, then to the
lungs, then to the pulmonary veins, then to the left heart, then to the aorta and back to
the pulmonary artery again.
2. Characteristics:
a. Elevated left ventricular output
b. Low cardiac reserve and respiratory reserves
c. Left ventricular hypertrophy due to overloading
d. Right ventricular hypertrophy due to pulmonary hypertension
e. Machinery-like murmur
f. If uncorrected, death occurs usually between 20 to 40 years due to cardiopulmonary
failure
b. Interventricular septal defect (left to right shunt; acyanotic)
1. A hole in the interventricular septum
2. Characteristics:
a. Right ventricular hypertrophy
b. Elevated right ventricular systolic pressure
c. Presence of oxygenated blood in the right ventricle
d. Systolic murmur
c. Interatrial septal defect (left to right shunt; acyanotic)
1. Large patent foramen ovale
2. Characteristics:
a. Elevated right ventricular volume and output
b. Elevated right ventricular pressure
c. Right ventricular hypertrophy
d. Pulmonary congestion
e. Right ventricular failure
f. Oxygenated blood in the right atrium and right ventricle
d. Tetralogy of Fallot (right to left shunt; cyanotic)
1. Components:
a. Overriding aorta
b. Pulmonary stenosis
c. Interventricular septal defect
d. Right ventricular hypertrophy
2. Characteristics:
a.
b. Elevated right ventricular pressure
c. Low oxygen level in arterial blood
d. Fatal if uncorrected

i. SHOCK, HEART FAILURE, and EDEMA

SHOCK

1. Shock is generalized inadequacy of blood flow throughout the body.

2. Stages
1. Nonprogressive (compensated) stage compensatory reflexes adequate for recovery & include:
a. Baroreceptor reflexes and CNS ischemic response
b. Angiotensin formation and Vasopressin (ADH) formation
c. Body fluid conservation and translocation of fluid reserves
d. Thirst and Drinking
2. Progressive stage compensation inadequate; needs outside intervention; may die due to vicious
cycle of cardiovascular deterioration
a. Cardiac depression decreased coronary flow
b. Vasomotor failure occurs late and due to brain hypoxia
c. Toxin release by ischemic tissues (histamine; serotonin; enzymes; etc); endotoxin from
gram-negative bacteria
d. Generalized cellular deterioration (active transport loss; lysosomal breakdown)
29
 3. Irreversible stage death imminent; cannot be saved

3. Decreased CO as cause.
1. Cardiac diseases
2. Infarction
3. Fibrillation
4. Cardiac arrest
4. Decreased VR as cause.
1. blood volume
2. vasomotor tone (venodilation; neurogenic shock)
3. Venous obstruction
5. Hypovolemia as cause.
1. Hemorrhage
a. Loss up to 10% of blood volume nonprogressive
b. Sympathetic reflexes
1. arteriolar tone - TPR
2. venous tone - VR and CO
3. cardiac activity
c. Reflexes prioritize blood pressure over cardiac output
d. Reflexes prioritize brain and heart over other organs
e. Autoregulation in brain and heart maintains flow even with low
BP
2. Plasma loss
a. Intestinal obstruction
b. Severe burns
3. Dehydration
a. Diarrhea
b. Excessive sweating
6. Sepsis as cause.
1. Dessiminated infection; bacteremia; septicemia
2. Special features
a. High fever
b. Marked vasodilation
c. High cardiac output
d. Disseminated intravascular coagulation
7. Effects of shock
1. Cellular level
a. ATP production
b. sodium-potassium pump
c. nutrient utilization
d. rupture of lyzozymes
2. Generalized effects
a. Muscle weakness
b. Hypothermia (except in septic shock)
c. Mental changes (stupor, coma)
d. Renal ischemia and failure oliguria and anuria
8. Therapy
1. Whole blood for blood loss
2. Plasma and dextran for plasma loss (e.g. burns)
3. Intravenous fluids and ORS for dehydration (e.g. diarrhea, vomiting)
4. Vasoconstrictors for neurogenic shock
5. Glucocorticosteroids and antibiotics for septic shock

HEART FAILURE

A. Heart failure is a decreased cardiac contractility such that cardiac output is inadequate.
B. Sympathetic effects and fluid retention by the kidneys produce its signs and symptoms.
C. Heart failure may involved only the left or right side of the heart or it may involve both ventricles.
D. Common signs include tachycardia, cardiomegaly, easy fatigabi-lity, pulsus deficit, pulsus alternans
and gallop rhythm.
E. Right-sided failure characteristics:
1. Elevated venous pressure
2. Dependent edema of the pitting type
3. Distended jugular veins with venous waves prominent
4. Hepatomegaly and ascites
5. Right ventricular enlargement
F. Left-sided failure characteristics:
1. Exertional dyspnea
2. Orthopnea and paroxysmal nocturnal dyspnea
30
 3. Pulmonary edema (rales and wheezing)
4. Left ventricular enlargement
G. Treatment would include:
1. Diuretics in order to relieve the edema.
2. Digitalis a cardiotonic drug that increases the con-tractility of the heart.
3. Dietary restriction of salt.
4. Dilators (e.g. ace-inhibitors and nitrates)

EDEMA

A. Some fluid are filtered at the arterial end of the capillary into the interstitial space. Most of this is re-
absorbed at the venous end of the capillary back to the blood.
B. The small amount that remains is returned to the veins via the lymphatics. Accumulation of fluid in
this space is called edema.
C. Forces that influence the movement of fluid across the capillary wall, also called the Starling's forces
are:
1. The capillary hydrostatic pressure that tends to push fluid out of the capillary and the interstitial
colloid osmotic pressure that tends to draw fluid into the interstitial space.
2. The capillary colloid osmotic pressure (due to plasma proteins) which tends to draw fluid back in-
to the capillary and the interstitial hydrostatic pressure that tends to push fluid back to the capil-
lary.
D. Edema tends to develop when the:
1. Plasma colloid osmotic pressure is decreased such as that seen in protein malnutrition, burns and
protein-losing nephropathy).
2. Capillary hydrostatic pressure is increased such as that seen in heart failure, renal failure, and
excessive vasodilation.
3. Capillary permeability is increased such as that seen in allergy, burns, vitamin C deficiency and
prolonged ischemia.
4. Lymph flow is blocked such as that seen in compression by tumors, lymph nodal infiltration (eg.
filariasis) and surgical removal of the lymphatics and nodes (eg. mastectomy).

THE RESPIRATORY SYSTEM

I. GENERAL FUNCTIONS AND ORGANIZATION

A. Functions of the Respiratory System.

1. Provides oxygen
2. Eliminates carbon dioxide
3. Regulates the blood's hydrogen-ion concentration (pH)
4. Forms speech sounds (phonation)
5. Defends against microbes
6. Traps and dissolves blood clots
7. Influences blood concentrations of chemical messengers

B. Organization of the Respiratory System.

1. The respiratory system comprises the lungs, the airways leading to them, and the chest struc-
tures responsible for movement of air into and out of them.
a. The conducting zone of the airways consists of the trachea bron-
chi, and terminal bronchioles. Its functions include:
1. Phonates (vocal cords).
2. Warms and moistens the air.
3. Defends against microbes and other toxic chemicals and foreign matter; cilia, mucus, and
phagocytes perform this function.
4. Provides a low-resistance pathway for airflow; resistance is physiologically regulated by
changes in contraction of airway smooth muscle and by physical forces acting upon the
airways.
b. The respiratory zone of the airways consists of the respiratory
brochioles, alveolar ducts and sacs (alveoli) which are the sites of gas exchange.

2. The lungs and the interior of the thorax are covered by pleura between the surfaces of which is
an extremely thin layer of intrapleural fluid.

3. The volume of air in the lungs at the end of a quiet (unforced) expiration is the functional residu-
al capacity (FRC). At this volume, only passive forces of the lungs and chest wall are acting.

31
 5. At FRC, the lungs are stretched and are attempting to recoil, whereas the
chest wall is compressed and attempting to move outward. This creates a subatmospheric
intrapleural pressure.

6. The difference between the intrapleural pressure and the alveolar pressure is
the transpulmonary pressure, which is the force acting to hold the lungs open.

Figure 4. Summary of alveolar, intrapleural, and transpulmonary pressure changes and air flow
during inspiration
and expiration of 500 ml of air. On the respiratory pressure scale, the normal atmospheric
pressure (760 mmHg)
has a value of zero. Note that the transpulmonary pressure exactly opposes the elastic re-
coil of the lungs at the
end of both inspiration and expiration.

C. Ventilation and Lung Mechanics.

1. Bulk flow of air between the atmosphere and alveoli is proportional to the difference between the
atmospheric and alveolar pressures and inversely proportional to the airway resistance: F =
(Patm - Palv)/R.
2. During quiet inspiration, the contractions of the diaphragm and external intercostal muscles in-
crease the volume of the thoracic cage. The diaphragmatic contraction increases the vertical di-
ameter of the thoracic cage whereas the intercostals increase the anteroposterior and horizontal
diameters of the chest.
a. This makes intrapleural pressure more subatmospheric, increases transpulmonary pressure,
and causes the lungs to expand.
b. This expansion initially makes alveolar pressure subatmospheric, which creates the pressure
difference between atmosphere and alveoli to drive air flow into the lungs.
c. During quiet respiration most of the tidal volume is due to diaphragmatic contraction.
d. In forced inspirations other inspiratory muscles contract to increase the depth of breathing.
These are the sternocleidomastoid muscles, anterior serrati, and the scaleni.

3. During quiet expiration, the diaphragm and external intercostal muscles cease contracting, allow-
ing the elastic lungs and chest wall to recoil passively toward their original size.

a. This initially compresses the alveolar air, raising alveolar pressure and driving air out of the
lungs.
b. In quiet breathing, expiration is passive and does not require contraction of the expiratory
muscles.
c. In forced expirations, the contraction of the internal intercostal muscles and the abdominal
muscles (rectus abdominis) are needed. The intercostal moves the anterior chest wall down-
ward and toward the spine, whereas the abdominal muscles push the abdominal contents
upward thereby compressing the lungs.

4. Lung compliance is determined by the stretchability of the lung elastic connective tissues and the
surface tension of the fluid lining the alveoli. The latter is greatly reduced, and compliance in-
creased, (lungs are easier to expand) by surfactant, produced by the type II cells of the alveoli.

32
 5. Surfactant also increases alveolar radius, reduce capillary filtration and stabilize the alveoli.

6. Airway resistance determines how much air flows into the lungs at any given pressure difference
between atmosphere and alveoli.
a. Airways are constricted by histamine, parasympathetic nerves, decreased carbon dioxide, irri-
tants and some eicosanoids. Mucus can occlude bronchioles and forced expiration may cause
bronchio-lar collapse.
b. Airways are dilated by epinephrine, sympathetic stimulation, increased carbon dioxide, and
some eicosanoids. During inspiration the airways open by lateral traction.

7. Work of inspiration can be divided into three fractions:

a. That required to expand the lungs against its elastic forces, called compliance or elastic work.
Most of the work of breathing is directed toward overcoming elasticity. Restrictive lung dis-
ease decreases compliance whereas emphysema increases compliance.
b. That required to overcome the viscosity of the lung and chest wall structures, called tissue
resistance work.
c. That required to overcome airway resistance during the movement of air into the lungs,
called the airway resistance work. Bronchospasm increases airway resistance.

Figure 5. Lung volumes and capacities recorded on a spirometer. The capacities are the
sums of
two or more lung volumes. Note that residual volume, functional residual capacity and
total lung
capacity cannot be measured with a spirometer.

8. Pulmonary ventilation events are divided into volumes and capacities.

a. The tidal volume (TV) is the volume of air inspired or expired with each normal breath. Its
normal value is 500 ml.
b. The inspiratory reserve volume (IRV) is the extra volume of air that can be inspired over and
beyond the normal tidal volume. It is about 3000 ml.
c. The expiratory reserve volume (ERV) is the extra amount of air that can be expired maximal-
ly by forceful expiration after the end of a normal tidal expiration. It is about 1100 ml.
d. The residual volume (RV) is the volume of air still remaining in the lungs after the most
forceful expiration.
e. The inspiratory capacity (IC) equals the tidal volume plus the inspiratory reserve volume.
This is the amount of air (about 3500 ml) that a person can breathe beginning at the normal
expiratory level and distending the lungs to the maximum amount.
f. The functional residual capacity (FRC) equals the expiratory reserve volume plus the residual
volume. This is the amount of air remaining in the lungs at the end of normal expiration
(about 2300 ml).
g. The vital capacity (VC) equals the inspiratory reserve volume plus the tidal volume plus the
expiratory volume. This is the maximum amount of air that a person can expel from the
lungs after a maximal inspiration (about 4600 ml).
h. The total lung capacity (TLC) is equal to the vital capacity plus the residual volume (about
5800 ml).
i. The values given above are for adult males. The normal values in women are about 25%
lower.
j. The interrelationships between these volumes and capacities can be expressed as follows:
33
 IC = TV + IRV FRC = ERV + RV
VC = IC + ERV TLC = VC + RV
VC = IRV + TV + ERV TLC = IC + FRC

9. The volume expired during the first second of a forced vital capacity (FVC) measurement is the
FEV1 and normally averages 80% of FVC. Below this value indicates increased airway resistance
to expiration (eg. asthma).

10. Minute ventilation is the total amount of new air moved into the respiratory passages each mi-
nute and is equal to the product of tidal volume and respiratory rate. Alveolar ventilation is the
total amount of air that reaches the the alveoli each minute and is equal to the product of (tidal
volume minus dead space volume) and respiratory rate.

Figure 6. Partial pressures of carbon

dioxide
and oxygen in inspired air and vari-
ous places
in the body. Note that the PO2 in the systemic
arteries is shown as identical to that in the pul-
monary veins; actually the arterial value should be slightly less because of venous ad-mixture as
the blood passes through the left
ventricle.

D. Exchange of Gases in Alveoli and Tissues

1. General information about some gases.

a. The total atmospheric pressure at sea level is 760 mm Hg.
b. Dry air is 79% nitrogen and 20% oxygen. At higher altitudes the barometric pressure de-
creases with distance from sea level but the percentage of oxygen and nitrogen remains es-
sentially constant.
c. The percentage of a gas in a mixture of gasses determines its partial pressure and is repre-
sented as P. The PO2 (oxygen partial pressure) of air at sea level is therefore (760 x 20%)
152 mm Hg.
d. Partial pressure of the gas, it's solubility coefficient, and temperature determines the amount
of gas that is dissolved in liquid.
e. CO2 is 24 times more soluble than O2 in plasma. CO2 is 20 times more diffusible than O2
through the cell membrane.
f. CO has an affinity for hemoglobin which is 200 times more than O2.
g. Alveolar air differs from atmospheric air because water vapor (humidification) and CO2 are
added to it while O2 is extracted from it. Their total pressures are however equal (both =
760 mm Hg).

2. In the steady state, the net volumes of oxygen and carbon dioxide exchanged in the lungs per
unit time are equal to the net volumes exchanged in the tissues.
a. Typical volumes per minute are 250 ml for oxygen consumption and 200 ml for carbon diox-
ide production. The respiratory quotient in this case is (200/250) 0.8.
b. Exchange of these gases in lungs and tissues is by diffusion, due to differences in partial
pressures.

3. Normal alveolar pressure for oxygen is 105 mm Hg and for carbon dioxide, 40 mm Hg.
34
 a. At any given inspired PO2, the ratio of oxygen consumption to alveolar ventilation determines
alveolar PO2 -- the higher the ratio, the lower the alveolar PO2.
b. The higher the ratio of carbon dioxide production to alveolar ventilation, the higher the alveo-
lar PCO2.

4. Average value at rest for systemic venous PO2 is 40 mm Hg and for PCO2, 46 mm Hg.

5. As systemic venous blood flows through the pulmonary capillaries, there is net diffusion of oxy-
gen from alveoli to blood and carbon dioxide from blood to alveoli.
a. By the end of the pulmonary capillaries, the blood gas pressures have become equal to those
in the alveoli.
b. Therefore, the PO2 and PCO2 in the systemic arterial blood are virtually identical to those in
the alveoli.

6. Inadequate gas exchange between alveoli and pulmonary capillaries may occur when capillary
surface area is decreased, when the alveolar walls thicken, and when there are ventilation-
perfusion inequalities.
a. The latter are minimized by local intrapulmonary homeostatic responses in which the low
PO2 constricts the pulmonary blood vessels and the high PCO2 dilates the airways.
b. The major consequence of significant uncompensated mismatching is that the systemic arte-
rial PO2 is considerably lower than the alveolar PO2.
c. Ventilation-perfusion ratio or VA/Q refers to the ratio between alveolar ventilation (gas avail-
able for exchange per minute) and the pulmonary blood flow (blood available for exchange
per minute).
1. At rest the VA is about 4200 ml/minute and the Q is about 5000 ml/minute. Thus, for
the entire lungs the VA/Q is 0.84.
2. Due to gravity, the VA/Q in the apical portion of the lung is higher than the lower areas
and is lowest in the basal regions in an upright lung.
3. Below normal VA/Q means either:
a. Underventilation which causes hypoxia.
b. Overperfusion which is a form of physiologic shunt.
c. Zero ventilation in which pulmonary blood is unable to exchange gases with the al-
veoli. This is a true shunt. The static alveolar air is eventually absorbed and the alve-
oli collapse (atelectasis).
4. Above normal VA/Q means either:
a. Overventilation in which the total dead space rises.
b. Underperfusion in which there is decreased blood flow and is seen in pulmonary em-
bolism and emphysema.
c. In both instances there is waste of ventilation.

7. In the tissues, net diffusion of oxygen occurs from blood to cells, and net diffusion of carbon di-
oxide from cells to blood.

E. Transport of Oxygen in the Blood

1. Each liter of systemic arterial blood normally contains 200 ml of oxygen, more than 98 percent of
which is bound to hemoglobin, and the rest of which is dissolved.
2. Hemoglobin increases the oxygen binding capacity of blood and its oxygen content. Whole blood
can bind oxygen 60 times more than plasma.
3. One gram of hemoglobin can combine with 1.34 ml of oxygen. Thus blood with 15 gm% of he-
moglobin has a combining capacity of 20 ml/100 ml.

35
 Figure 7. Oxygen-hemoglobin dissociation
curve,
at pH 7.40 and temperature at 37O C.

4. The major determinant of the degree to

which hemoglobin is saturated with oxy-
gen is blood PO2.
a. Hemoglobin is almost 100% saturat-
ed at the normal systemic arterial
PO2 of 105 mm Hg. The fact that
saturation is already more than 90%
at a PO2 of 60 mm Hg permits rela-
tively normal uptake of oxygen by
the blood even when alveolar PO2 is
moderately reduced.
b. Arterial blood is only 97% saturated because of the admixture of venous blood and some
physiologic shuntings (low VA/Q). It therefore has a PO2 of 95 to 100 mm Hg, which is less
than the alveolar PO2 of 105 mm Hg.
c. Hemoglobin is 75% saturated at the normal systemic venous PO2 of 40 mm Hg. Thus, only
25% of the oxygen has dissociated from hemoglobin and entered the tissues.

Figure 8. Effects of 2,3-DPG concentration, temperature, and acidi-

ty on the relationship between PO2 and hemoglobin saturation.

5. The affinity of hemoglobin for oxygen is decreased (also

known as a shift of the oxy-hemoglobin dissociation curve
to the right) by an increase in PCO2, hydrogen-ion concen-
tration (low pH), and temperature. All these conditions ex-
ist in the tissues and facilitate the release of oxygen from
hemoglobin. Bohr effect is the name given to the decrease
of hemoglobin's affinity for oxygen when the carbon diox-
ide tension in blood is high.

6. The affinity of hemoglobin for oxygen is also decreased by

erythrocyte DPG, which increases in situations associated
with hypoxia (e.g. high altitude and chronic lung disease)
and helps maintain oxygen delivery to the tissues.

F. Transport of Carbon Dioxide by Blood

1. Each liter of systemic arterial blood contains approximately 550 ml of "total" carbon dioxide, 90%
of which is bicarbonate.

2. When carbon dioxide diffuse from the tissues into the blood, 10% remains dissolved in plasma
and erythrocytes, 30% combines with deoxyhemoglobin to form carbamino compounds, and
60% combines in the erythrocytes with water to form carbonic acid, which then dissociates
to yield bicarbonate and hydrogen ions. Most of the bicarbonate then diffuses out of the erythro-
cytes into the plasma in exchange for chloride ions (the chloride shift)(Figure 9).

3. The rapid conversion of carbon dioxide to bicarbonate is promoted by carbonic anhydrase which
are abundant inside the red cells.

36
 Figure 9. Summary
of CO2 movement.
Note that most of the
CO2 entering the
blood in the tissues
is converted to
HCO3- . This occurs
almost entirely in the
red cells because the
carbonic anhydrase
is located there, but
most of the HCO3-
then moves out of
the red cells into the
plasma in exchange
for chloride ions.

4. As venous blood flows through lung capillaries, PCO2 decreases because of diffusion of carbon
dioxide out of the blood into the alveoli, and all these reactions are reversed.

5. The binding of oxygen with hemoglobin in the lungs capillaries tends to displace carbon dioxide
from the blood promoting carbon dioxide release. In the tissue capillaries the release of oxygen
from hemoglobin increases its affinity for carbon dioxide and thus promoting carbon dioxide
transport. This effect of the oxygen-hemoglobin reaction on carbon dioxide transport is called the
Haldane effect.

G. Transport of Hydrogen Ions between Tissues and Lungs.

1. Most of the hydrogen ions generated in the erythrocytes from carbonic acid during blood passage
through tissue capillaries bind to deoxyhemoglobin because deoxyhemoglobin (formed as oxygen
unloads from oxyhemoglobin) has a high affinity for hydrogen ions.

2. The binding of hydrogen ions to deoxyhemoglobin is reversed as the blood flows through the
lung capillaries and the ions combine with bicarbonate to yield carbon dioxide and water.

H. Control of Respiration

1. The neural control of breathing involves the corticospinal tract for voluntary control and the
bulbospinal tract for automatic control.

2. Control centers are found in the medulla and pons. In the medulla are found the inspiratory neu-
rons which control the rhythmic activity of breathing.

3. Breathing depends upon cyclical inspiratory muscle excitation by the nerves to the diaphragm
(phrenic) and intercostal muscles (intercostal nerves). This neural activity is triggered by the me-
dullary inspiratory neurons.

4. The most important inputs to the medullary inspiratory neurons for the involuntary control of mi-
nute ventilation are from the peripheral chemoreceptors -- the carotid and aortic bodies -- and
the central chemoreceptors.

37
 5. Ventilation is reflexly stimulated, via the peripheral chemoreceptors, by a decrease in arterial
PO2, but only when the decrease is large.

Figure 10. Summary of chemical inputs

that stimulate ventilation. When arterial
PO2 decreases or when PCO2 or hydrogen-
ion concentration increases, ventilation is
reflexly increased.

6. Ventilation is reflexly stimulated, via both the peripheral and central chemoreceptors, when the
arterial PCO2 goes up even a slight amount. The stimulus for this reflex is not the increased
PCO2 itself but the concomitant increased hydrogen-ion concentration in arterial blood and brain
extracellular fluid.

7. Ventilation is also stimulated, mainly via the peripheral chemoreceptors, by an increase in arterial
hydrogen-ion concentration resulting from causes other than an increase in PCO2. The result of
this reflex is to restore hydrogen-ion concentration toward normal by lowering PCO2.

8. Ventilation is reflexly inhibited by an increase in arterial PO2 and by a decrease in arterial PCO2
or hydrogen-ion concentration.

9. During moderate exercise, ventilation increases in exact proportion to metabolism, but the sig-
nals causing this are not known. During very strenuous exercise, ventilation increases more than
metabolism.
a. The proportional increases in ventilation and metabolism during moderate exercise cause the
arterial PO2, PCO2, and hydrogen-ion concentration to remain unchanged.

b. Arterial hydrogen-ion concentration increases during very strenuous exercise because of in-
creased lactic acid production. This increase accounts for some of the hyperventilation seen
in that situation.

10. Ventilation is also controlled by reflexes originating in airway receptors, by painful and emotional
stimuli, and by conscious intent.

38
 11. There are centers in the pons which also influence breathing. One is the pneumotaxic center
which when stimulated limits the duration of the inspiratory phase of breathing and thus increas-
ing the respiratory rate. A lesion in this area results in inspiratory breathholding (apneusis).

12. Another center is the so called apneustic center whose activity is observed only when it is re-
leased from the control of the pneumotaxic center and the vagus nerves to the medulla have
been sectioned. When active it prevents the automatic switch off of the inspiratory ramp signal
and causes apneusis, wherein the lungs become almost completely filled with air, and only occa-
sional short expiratory gasps occur.

13. The Hering-Breuer reflex is mediated by stretch receptors in the lungs. A tidal volume of 1.5 liters
activates it which leads to the inhibition of medullary and pontine centers to stop inspiration. Ap-
parently this serves to protect the lungs from overinflation but has no role in normal breathing.

I. Causes of Hypoxia

1. Hypoventilation may be caused by:

a. A defect anywhere along the respiratory control pathway, from the medulla through the res-
piratory muscles.
b. Severe thoracic cage abnormalities.
c. Major obstruction of the upper airway. The hypoxemia of hypoventilation is always accompa-
nied by an increased arterial PCO2.

2. Diffusion impairment results from thickening of the alveolar membranes (eg. pulmonary edema)
or a decrease in their surface area (eg. emphysema). In turn, it causes failure of equilibration of
blood PO2 with alveolar PO2. Often it is apparent only during exercise. Arterial PCO2 is either
normal, since carbon dioxide diffuses more readily than oxygen, or reduced, if the hypoxemia
reflexly stimulates ventilation.

3. Shunt results from blood bypassing ventilated alveoli in passing from the right heart to the left
heart. The most common causes are cardiac defects that permit blood to flow directly from the
right heart to the left heart (eg. interventricular septal defect with pulmonic stenosis). Arterial
PCO2 generally does not rise since, the effect of the shunt on it is counterbalanced by the in-
creased ventilation reflexly stimulated by the hypoxemia.

4. Ventilation-perfusion inequality is by far the most common cause of hypoxemia. It occurs in

chronic obstructive lung diseases and many other lung diseases. Arterial PCO2, may be normal or
increased, depending upon how much ventilation is reflexly stimulated.

5. Stasis of blood flow (eg. heart failure and shock) results in stagnant hypoxia.

6. Histotoxic hypoxia refers to the condition in which cells are unable to extract oxygen from the
blood inspite of adequate blood PO2 (eg. cyanide poisoning).

J. Acclimatization to the Hypoxia of High Altitude

1. The peripheral chemoreceptors stimulate ventilation.

2. Erythropoietin, secreted by the kidneys, stimulates erythrocyte synthesis, resulting in increased

erythrocyte and hemoglobin content of blood.

3. Red cell DPG increases and shifts the hemoglobin dissociation curve to the right, facilitating oxy-
gen unloading in the tissues.

4. Increases in capillary density, mitochondria, and muscle myoglobin occur, all of which increase
oxygen transfer.

39
RENAL PHYSIOLOGY AND REGULATION OF WATER AND ELECTROLYTES

9. FUNCTIONAL ANATOMY AND BASIC PROCESSES

A. Functions and Structure of the Kidneys

1. The kidneys regulate the water and the ionic composition of the body, excrete wastes product
and foreign chemicals, and secrete three hormones -- renin, 1,25-dihydroxyvitamin D3, and
erythropoietin. The first two functions are accomplished by continuous processing of the plasma.

Figure 11. Each nephron consists of a renal

corpuscle, a proximal tubule, a loop of Henle,
and a distal convoluted tubule. The distal
convoluted tubules join the collecting duct,
which extends to the tip of the renal pyramid.
The renal corpuscle, the proximal tubule and
the distal tubule are in the cortex of the kid-
ney. The loops of Henle and the collecting
ducts extend into the medulla of the kidney.
An afferent arteriole carries blood to the
glomerulus. An efferent arteriole carries blood
from the glomerulus and gives rise to
peritubular capillaries, which surround the
nephron.

2. Each nephron in the kidneys consists of a glomerulus and a tubule.

a. Each glomerulus comprises a capillary tuft, which is supplied by
an afferent arteriole, and a Bowman's capsule, into which the tuft protrudes.

b. The tubule extends out from the Bowman's capsule and is sub-
divided into four segments: proximal tubule, loop of Henle, distal tubule, and collecting duct.
Distal tubules from different nephrons merge to form collecting ducts, and the latter empty
into the renal pelvis, from which urine flows through ureters to the bladder.

c. An efferent arteriole leaves the glomerular capillary tuft and

branches into peritubular capillaries, which supply the tubule.

B. Basic Renal Processes

1. The three basic renal processes are glomerular filtration, tubular reabsorption, and tubular secre-
tion. In addition the kidneys synthesize and/or catabolize certain substances.

2. Urine formation begins with glomerular filtration -- approximately 180 L/day -- of essentialy pro-
tein-free plasma into Bowman's capsule.
a. Glomerular filtrate contains all the plasma substances, other than protein and substances
bound to protein, in virtually the same concentrations as in plasma.

b. Glomerular filtration is driven by the hydrostatic pressure in the glomerular capillaries and is
opposed by both the hydrostatic pressure in Bowman's capsule and the osmotic force due to
the proteins in the glomerular capillary plasma.

c. The capillary hydrostatic pressure is decreased by constriction of the afferent arteriole and
increased by the constriction of the efferent arteriole.

3. As the filtrate moves through the tubules, certain substances are reabsorbed into the peritubular
capillaries.
40
 a. Tubular reabsorption rates are generally very high for nutrients, ions and water, are lower for
waste products.
b. Reabsorption may occur by carrier-mediated mechanisms or by diffusion.

c. Many of the carrier-mediated systems manifest transport maximums, so that when the fil-
tered load of a substance to be transported becomes very high, large amounts of the sub-
stance will escape reabsorption and appear in the urine.

d. Diffusion occurs for some substances to which the tubular epithelium is permeable, because
water reabsorption creates tubule-interstitium diffusion gradients for them.

4. Tubular secretion, movement from the peritubular capillaries into the tubules, is a pathway in
addition to glomerular filtration for a substance to gain entry to the tubule.

Substance Amount filtered per Amount excreted per Percent reabsorbed

day day
Water, L 180 1.8 99.0
Sodium, g 630 3.2 99.5
Glucose, g 180 0 100
Urea, g 54 30 44

Table 1. AVERAGE VALUES FOR SEVERAL COMPONENTS THAT UNDERGO FILTRATION AND
REABSORPTION

5. Clearance determination helps quantify renal function. The renal clearance of any substance is
the volume of plasma
per unit time. The formula for clearance is

Cs = Us.V
Ps

where
Cs = clearance of S
Us = urine concentration of S
V = urine volume per unit time
Ps = plasma concentration of S

6. Any substance (e.g. inulin) that is filtered, but not reabsorbed, secreted, or metabolized would
equal the GFR (i.e. its clearance must equal the volume of plasma originally filtered). The normal
GFR is 125 ml/min or 7.5 L/h or 180 L/d.
a. When the clearance of a substance is greater than the GFR, as measured by the inulin clear-
ance, that substance must undergo tubular secretion.

b. When the clearance of a filterable substance is less than the GFR, as measured by the inulin
clearance, that substance must undergo reabsorption.

7. Glomerular filtration rate (GFR) can be measured by means of inulin clearance (inulin being fil-
tered but neither reabsorbed nor secreted, that is Cinulin is equal to GFR)) and estimated by
means of the creatinine clearance. Renal plasma flow is measured using PAH (PAH being filtered
and secreted but not reabsorbed).

C. Micturition

1. Micturition occurs when bladder distention stimulates stretch receptors that trigger spinal reflexes
leading to parasympathetically mediated contraction of the bladder smooth muscle.

2. Voluntary control is exerted chiefly by stimulating or inhibiting the nerves to the pelvic dia-
phragm.

41
 II. RENAL CONTROL OF BODY WATER AND MINERAL COMPOSITION

A. Total-Body Balance and Internal Distribution of Sodium and Water

1. The body gains sodium and chloride by ingestion and loses them via the skin (in sweat), gastro-
intestinal tract, and urine.
2. The body gains water via ingestion and internal production, and it loses water via urine, the gas-
trointestinal tract, and evaporation from the skin and respiratory tract, and (as insensible loss
and sweat).
3. For both water and sodium, the major homeostatic control point for maintaining stable balance is
renal excretion.

B. Basic Renal Processes for Sodium and Water

1. Sodium is freely filterable at the glomerulus, and its reabsorption is a primary active process de-
pendent upon Na,K-ATPase pumps in the basolateral membranes of the tubular epithelium. Sodi-
um is not secreted.

2. Sodium entry into the cell from the tubular lumen is always passive. Depending on the tubular
segment it is either through channels or by cotransport or countertransport with other substanc-
es.

3. Sodium transport also drives, by cotransport, the secondary active reabsorption of glucose, ami-
no acids, and chloride and, by countertransport, the secretion of hydrogen ions.

4. Sodium reabsorption creates an osmotic gradient across the tubule, which drives water reabsorp-
tion.

5. Water reabsorption is independent of the action of ADH in all parts of the nephron except the
collecting ducts.

6. Water reabsorption from the collecting ducts depends on the presence of the posterior pituitary
antidiuretic hormone (ADH), which increases the permeability of these segments to water. A
large volume of dilute urine is produced when plasma ADH concentration and, therefore, water
reabsorption is low.

C. The Countercurrent Mechanism (see Figure 12)

1. The countercurrent mechanism is made up of the countercurrent multipliers (the loop of Henle
and the collecting duct) and the countercurrent exchangers (the vasa recta).
a. In the multiplying events:
(1) Tubular fluid progressively becomes hypertonic as it goes down the descending loop of
Henle due to the removal of water.
(2) Fluid osmolality decreases progressively as it flows up the ascending loop of Henle due
to the removal of NaCl while water remains.
(3) The hypotonic fluid entering the distal tubule is modified by ADH. In the presence of
ADH it becomes isoosmotic. In its absence it remains hypotonic.
(4) The fluid entering the collecting duct is modified again by ADH as it flows down the
duct. In the presence of ADH a concentrated urine is formed. In its absence a dilute
urine is formed.

b. In the exchanging events:

(1) NaCl and urea are passively reabsorbed from the ascending loop of Henle, diffuse
across the medullary interstitium into the descending limb of the vasa recta, and are
returned to the interstitium by the ascending limb of the vasa recta. These solutes re-
circulate in the vasa recta capillary loops and increase the medullary osmolality.

(2) Water diffuses from the descending limb of the vasa recta across the interstitial fluid and
into the ascending limb of the vasa recta.

2. Urea is recycled in the medullary area, accumulates there and acts to osmotically abstract water
from the descending loop of Henle.

42
 Figure 12. Generation of an interstitial fluid
osmolarity gradient by the renal counter-
current multiplier system and its role in the
formation of hyperosmotic urine. The thick-
ened line denotes the fact that the ascend-
u-
bule are always relatively impermeable to
water. The essential event in the counter-
current multiplier system is the active
transport of sodium and chloride out of the
ascending limb of the loop of Henle.

3. A small volume of concentrated urine is produced by the renal countercurrent multiplier system
when plasma ADH concentration is high.
a. The active transport of sodium chloride by the ascending loop of Henle causes a progressive
concentration of the interstitial fluid of the renal medulla but a dilution of luminal fluid.

b. ADH increases the permeability of the cortical collecting ducts to water, and so water is reab-
sorbed by this segment until the luminal fluid is isoosmotic to cortical interstitial fluid.

c. The luminal fluid then enters and flows through the medullary collecting ducts, and the con-
centrated medullary interstitium causes water to move out of these ducts, made highly per-
meable to water by ADH. The result is concentration of the collecting duct fluid and the
urine.

D. Renal Sodium Regulation

1. Sodium excretion is the difference between the amount of sodium filtered and the amount reab-
sorbed.

2. Glomerular filtration rate (GFR), and therefore filtered load of sodium are controlled by barore-
ceptor reflexes. Decreased vascular pressures cause decreased baroreceptor firing and increased
sympathetic outflow to the renal arterioles, resulting in vasoconstriction and decreased GFR.

3. The major control of tubular sodium reabsorption is the adrenal cortical hormone aldosterone
which stimulates sodium reabsorption in the late distal tubules and collecting ducts.

4. The renin-angiotensin system is one of the major controllers of aldosterone secretion.

a. Renin, the rate-limiting variable in the renin-angiotensin system, is secreted by the granular
cells of the kidney juxtaglomerular apparatus and catalyzes, in the blood, the formation of
angiotensin I from circulating angiotensinogen produced by the liver. Angiotensin I is then
cleaved to yield angiotensin II, which acts on the adrenal cortex to stimulate aldosterone se-
cretion.

b. When extracellular fluid volume decreases, renin secretion is stimulated by:

(1) Stimulation of the renal sympathetic nerves to the granular cells by baroreceptor reflex-
es.
(2) Pressure decreases sensed by the granular cells, themselves.
(3) A signal generated by low sodium or chloride concentration in the lumen of the macula
densa.

43
 5. Atrial natriuretic factor, secreted by cells in the atria in response to atrial distention, inhibits sodi-
um reabsorption.

6. Of the total sodium reabsorption:

a. Seventy five percent of tubular reabsorption of sodium occurs in the proximal tubule and is
an active transport process.

b. About twenty two percent occurs in the ascending limb of the loop of Henle and the
transport mechanism is passive.

c. In the distal tubule and the collecting duct sodium is also reabsorbed by a cation exchange
process in which potassium ion or hydrogen ion is secreted as sodium is reabsorbed. The cat-
ion exchange process is promoted by aldosterone.
(1) In hypoaldosteronism, hyperkalemia and acidosis is produced.
(2) In hyperaldosteronism, hypokalemia and alkalosis is produced.

E. Renal Water Regulation

1. Water excretion is the difference between the amount of water filtered and the amount reab-
sorbed.

2. In the proximal tubule about 80% of the filtered water is reabsorbed isoosmotically, that is it fol-
lows the absorption of a solute. Fluid entering the descending limb of the loop of Henle is always
isoosmotic to plasma.

3. In the loop of Henle, more solute is reabsorbed than water, thus making the fluid entering the
distal tubule always hypotonic to plasma.

4. GFR regulation via the baroreceptor reflexes plays some role in regulating water excretion, but
the major control is via ADH-control of water reabsorption.

5. ADH secretion by the posterior pituitary is controlled by the baroreceptors, particularly those in
the left atrium, and by osmoreceptors in the hypothalamus.
a. Via the baroreceptor reflexes, a low extracellular volume stimulates ADH secretion, and a
high extracellular volume inhibits it.

b. Via the osmoreceptors, a high body-fluid osmolarity stimulates ADH secretion and a low
osmolarity inhibits it.

6. ADH acts by increasing the permeability of the distal tubule and the collecting duct to water. This
is called free-water clearance.

7. With maximal ADH effect, 99% of the filtered water is reabsorbed; in the absence of ADH, only
88% is reabsorbed by the renal tubules.

F. Potassium Regulation
1. A person remains in potassium balance by excreting an amount of potassium in the urine equal
to the amount ingested minus the amounts lost in the feces and sweat.

2. Potassium is freely filterable at the glomerulus and undergoes both reabsorption and secretion,
the latter being the major controlled variable.

3. When body potassium is increased, aldosterone secretion is stimulated by an increased plasma

concentration of potassium, and the increased aldosterone then stimulates potassium secretion.

4. A person on a normal diet actively reabsorbs all filtered potassium in the proximal tubule. If po-
tassium intake is excessive then secretion occurs in the proximal tubule and reabsorption also
occurs in the distal tubule and collecting duct.

5. Potassium secretion in the distal tubule is coupled with sodium reabsorption.

44
G. Calcium Regulation
1. Plasma calcium concentration is maintained by control of urinary excretion, gastrointestinal ab-
sorption, and movement into and out of bone.

2. Parathyroid hormone increases plasma calcium concentration by influencing these processes.

a. It stimulates tubular reabsorption of calcium, movement of calcium out of bone, and for-
mation of the hormone 1,25-dihydroxyvitamin D3, which stimulates calcium absorption by
the intestine.
b. It also inhibits the tubular reabsorption of phosphate, and the lowered plasma phosphate
facilitates calcium movement out of bone.

3. Vitamin D3 is formed in the skin or ingested and then is metabolized, under stimulation by para-
thyroid hormone, to the active form, 1,25-dihydroxyvitamin D3 in the kidneys.

H. Hydrogen-Ion Regulation
1. Total-body balance of hydrogen ions is the result of both metabolic production of these ions and
net gains or losses via the gastrointestinal tract and urine. A stable balance is achieved by regu-
lation of urinary losses.

2. Buffering is a means of minimizing changes in hydrogen-ion concentration by combining these

ions reversibly with anions such as bicarbonate and intracellular proteins.

3. The kidneys not only excrete hydrogen ions but reabsorb bicarbonate.
a. Both processes require tubular hydrogen-ion secretion in a process catalyzed by carbonic
anhydrase.
b. These occur all throughout the nephron except in the descending loop of Henle.
c. Bicarbonate reabsorption occurs when secreted hydrogen ions combine with tubular bicar-
bonate to form carbonic acid which then dissociates to form water and carbon dioxide. Car-
bon dioxide diffuses into the tubular cells, combines with water and forms bicarbonate and
hydrogen ion. The bicarbonate is then taken up by the blood while the hydrogen is secreted
into the tubular fluid.
d. For each hydrogen ion secreted one sodium ion and one bicarbonate ion enter the blood-
stream.
e. Hydrogen secretion in the urine continues until the tubular fluid pH reaches 4.5. Once at-
tained, the secretion stops (the limiting pH).
f. This pH is not reached however because buffering occurs in the tubules to let the secretion
process continue. Three buffering reactions take place and these are the reactions of hydro-
gen ions with: (1) bicarbonates; (2) phosphates, to be excreted as titrable acid, and (3)
ammonia, to be excreted as ammonium salt.
g. The main precursor of ammonia in the tubules is glutamine.

4. Acid-base disorders are categorized as respiratory or metabolic.

a. Respiratory acidosis is due to retention of carbon dioxide, and respiratory alkalosis to exces-
sive elimination of carbon dioxide.
b. All other causes of acidosis or alkalosis are termed metabolic and reflect gain or loss, re-
spectively, of hydrogen ions from a source other than carbon dioxide.

I. Diuretics

1. Diuretics are agents that increase the production of urine.

2. Their mechanisms of action may be categorized into:
a. Sodium active transport inhibition (eg. chlorothiazide)
b. Chloride active transport inhibition (eg. furosemide)
c. Carbonic anhydrase inhibition (eg. acetazolamide)
d. Aldosterone antagonism (eg. spironolactone)
e. Osmotic diuresis (eg. mannitol)
f. ADH secretion inhibition (eg. alcohol)
g. GFR promotion (eg. caffeine)

45
THE PHYSIOLOGY OF THE GASTROINTESTINAL TRACT

I. FUNCTIONS OF THE GASTROINTESTINAL ORGANS

A. Overview

1. The gastrointestinal system transfers organic nutrients, minerals, and water from the external
environment to the internal environment. The four processes used to accomplish this function are
(1) digestion, (2) secretion, (3) absorption, and (4) motility.
a. The system is designed to maximize the absorption of most nutrients, not to regulate the
amount absorbed.
b. It does not play a major role in the removal of waste products from the internal environment.

2. The names and functions of the gastrointestinal organs are summarized in the table below.

Table 1. Functions of Gastrointestinal Organs.

ORGAN EXOCRINE FUNCTIONS

SECRETIONS
Mouth and pharynx Chewing (mechanical digestions); initiation of
swallowing reflex

Salivary glands Salt and water Moisten food

Mucus Lubrication
Amylase Polysaccharide-digesting enzyme
Esophagus Move food to the stomach by peris-taltic
waves
Mucus Lubrication
Stomach Store, mix, and dissolve food; regulate emp-
tying of dissolved food into small intestine
Solubilization of food particles; kill microbes
HCL Protein-digesting enzyme
Lubricate and protect epithelial cells
Pepsin
Mucus
Pancreas Secretion of enzymes and bicarbonate; also
has nondigestive endocrine functions
Digest carbohydrates, fats, proteins, and nu-
Enzymes cleic acids
Neutralize HCl entering the small intestine
Bicarbonate from the stomach
Liver Secretion of bile; many other nondigestive
functions
Bile salts Solubilize water-insoluble fats
Bicarbonate Neutralize HCl entering intestine from stom-
ach
Organic waste prod- Elimination in feces
ucts
Gallbladder Store and concentrate bile between meals

Small intestine Digestion and absorption of most substances;

mixing and propulsion of contents
Food digestion
Enzyme Maintain fluidity of luminal contents
Salt and water Lubrication
Mucus
Large intestine Storage and concentration of undiges-ted
(colon) matter; mixing and propulsion of contents
Lubrication
Mucus
Rectum Defecation

3. Each day the gastrointestinal tract secretes about 3.5 times more fluid into the lumen than is in-
gested. Only about 1 percent of the luminal contents are excreted in the feces.

46
B. Structure of the Gastrointestinal Tract

1. The wall of the intestine consists of four layers, i.e. from inside out, mucosa, submucosa,
muscularis externa, and serosa.

2. The epithelial cells, the endocrine and exocrine cells are located in the mucosa. The Meissner's
plexus (a network of nerve cells) and larger blood vessels and lymphatics are found in the
submucosa layer.

3. The muscularis externa has two layers, the circular muscle layer and the longitudinal muscle lay-
er. Between these layers is found a second network of nerve cells known as the myenteric plexus
(Auerbach's plexus), which together with the submucosal plexus is responsible for peristalsis.

4. The area available for absorption in the small intestine is greatly increased by the folding of the
intestinal wall, the presence of villi, and the microvilli on the surface of the epithelial cells.

5. The epithelial cells lining the intestinal tract are continuously replaced by new cells arising from
cell division at the base of the villi.

6. The venous blood from the small intestine, containing absorbed nutrients other than fat, passes
to the liver via the hepatic portal vein before returning to the heart. Fat is absorbed into the
lymphatic vessels (lacteals) in each villus.

C. Digestion and Absorption

1. Starch is digested by amylases secreted by the salivary glands and pancreas, and the resulting
disaccharides (sucrose, lactose, and maltose), as well as ingested disaccharides, are digested to
monosaccharides (glucose, fructose, galactose) by enzymes in the luminal membranes of the ep-
ithelial cells in the small intestine.
a. The monosaccharides are absorbed by secondary active transport.
b. Some polysaccharides, such as cellulose, cannot be digested and pass to the large intestine,
where they are metabolized by bacteria.

2. Proteins are broken down into small peptides and amino acids, which are absorbed by secondary
active transport in the small intestine.
a. The breakdown step to peptides is catalyzed by pepsin in the stomach and by the pancreatic
enzymes trypsin and chymotrypsin in the small intestine.
b. In the small intestine, peptides are broken down into amino acids by reactions catalyzed by
pancreatic carboxypeptidase and intestinal aminopeptidase.

3. The digestion and absorption of fat by the small intestine requires mechanisms that solubilize the
fat and its digestion products.
a. Large fat globules leaving the stomach are emulsified in the small intestine by bile salts and
phospholipids secreted by the liver.
b. Lipase from the pancreas digests fat at the surface of the emulsion droplets forming fatty
acids and monoglycerides.
c. These water-insoluble products of lipase action, when combined with bile salts, form mi-
celles that are in equilibrium with the free molecules.
d. Free fatty acids and monoglycerides diffuse across the luminal membranes of epithelial cells,
within which they are enzymatically recombined to form triacylglycerol, which is released as
chylomicrons from the blood side of the cell by exocytosis.
e. The released chylomicrons enter lacteals in the intestinal villi and pass, by way of the lym-
phatic system, to the circulation.

4. Fat-soluble vitamins are absorbed by the same pathway used for fat absorption. Most water-
soluble vitamins are absorbed in the small intestine by diffusion or carrier-mediated transport.
Vitamin B12 is absorbed in the ileum after combining with intrinsic factor secreted into the lumen
by parietal cells in the stomach.

5. Water is absorbed from the small intestine by osmosis following the active absorption of solutes,
primarily sodium chloride.

47
 II. GIT REGULATION

A. Regulation of Gastrointestinal Processes

1. Most gastrointestinal reflexes are initiated by luminal stimuli:

(a) distension, (b) osmolarity, (c) acidity, and (d) digestion products.
a. Neural reflexes are mediated by short reflexes in the enteric nervous system and by long re-
flexes involving afferent and efferent neurons to and from the CNS.

b. Gastrin, secretin, CCK, and GIP are secreted by endocrine cells scattered throughout the epi-
thelium of the stomach (gastrin) and small intestine (secretin, CCK, and GIP). Their proper-
ties are summarized in the table below.

Table 2. Properties of Gastrointestinal Hormones.

Hormones Gastrin CCK Secretin GIP

Structure Peptide Peptide Peptide Peptide

Endocrine cell Antrum of stom- Small intestine Small intestine Small intestine
location ach

Stimuli for Amino acids, pep- Amino acids, Acid in small Glucose, fat in
hormone release tides in stomach; fatty acids in intestine small intestine
Para-sympathetic small intestine
nerves

Stimuli inhibiting Acid in stomach

hormone release lumen

Target-Cell Responses
Stomach
Acid
secretion Stimulates Inhibits Inhibits
Antrum
contraction Stimulates Inhibits
Pancreas
Bicarbonate Potentiates Stimulates
secretion secretin's ac-
tions
Enzyme secre- Stimulates
tion
Insulin Stimulates
secretion
Growth Stimulates Stimulates Stimulates
Liver
Bicarbonate Potentiates se- Stimulates
secretion cretin's actions
Gallbladder
contraction Stimulates
Sphincter of Oddi
Relaxes
Small intestine
Motility
Stimulates ileum;
inhibits ileo-cecal
sphincter
Growth Stimulates
Large intestine Stimulates mass
movement

c. The three phases of gastrointestinal regulation --- cephalic, gastric, and intestinal --- are
named after the location of the stimulus that initiates the response.

48
2. Chewing breaks up food into smaller particles suitable for swallowing but is not essential for
eventual digestion and absorption of food.

3. Salivary secretion is stimulated by food in the mouth acting via chemo- and pressure receptors.
Both sympathetic and parasympathetic stimulation increases salivary secretion.

4. Food moved into the pharynx by the tongue initiates swallowing, which is coordinated by the
swallowing center in the medulla.
a. Food is prevented from entering the trachea by inhibition of respiration and closure of the
glottis.
b. The upper esophageal sphincter relaxes as food is moved into the esophagus and then clos-
es.
c. Food is moved through the esophagus toward the stomach by peristaltic waves. The lower
esophageal sphincter remains open throughout swallowing.
d. If food does not reach the stomach with the first peristaltic wave, distension of the esopha-
gus will initiate secondary peristalsis.

5. Acid secretion by parietal cells in the stomach occurs in three phases.

a. During the cephalic phase, sight, smell, taste, and chewing stimulate gastric HCl secretion.
Pathways to the parietal cells which secrete the acid, are the vagus nerves and the hormone
gastrin.

b. During the gastric phase, gastric distension, decreased acidity, and the presence of peptides
increase acid secretion. This is mediated by gastrin and long as well as short neural reflexes.

c. During the intestinal phase, duodenal distension, increased acidity, increased osmolarity, and
increased nutrient concentration in the intestine decreases gastric acid secretion. This is me-
diated by long and short neural reflexes, secretin, CCK, and other unspecified hor-
mones.

6. Pepsinogen, secreted by the gastric chief cells in response to most of the same reflexes that con-
trol acid secretion, is converted to the active proteolytic enzyme pepsin in the stomach's lumen
by acid and by pepsin itself.

7. Peristaltic waves sweeping over the stomach become stronger in the antrum, where most mixing
occurs. With each wave, only a small por
intestine through the pyloric sphincter.
a. The basic electrical rhythm (BER) generated by gastric smooth muscle, determines gastric
peristaltic wave frequency. Contraction strength depends on the frequency of action poten-
tials triggered by the slow waves.
b. The larger a meal, the faster the stomach empties. Distension of the small intestine, and fat,
acid, or hypertonic solutions in the intestinal lumen inhibit gastric contractions.

8. The exocrine portion of the pancreas secretes digestive enzymes and bicarbonate ions, which
reach the duodenum through the pancreatic duct.
a. The bicarbonate ions neutralize the acid entering the small intestine from the stomach.
b. Most of the proteolytic enzymes, including trypsin, are secreted by the pancreas in inactive
forms. Trypsin is activated by enterokinase located on the luminal membranes of the small
intestine cells and in turn activates other inactive pancreatic enzymes.
c. The hormone secretin, released from the small intestine in response to increased luminal
acidity, stimulates bicarbonate secretion. CCK is released from the small intestine in response
to the products of fat and protein digestion, and stimulates pancreatic enzyme secretion.
d. Parasympathetic stimulation increases pancreatic secretion.

9. The liver secretes bile, the major ingredients of which are bile salts, cholesterol, lecithin, bicar-
bonate ions, bile pigments, and trace metals.
a. Bile salts undergo continuous enterohepatic recirculation during a meal. The liver synthesizes
new bile salts to replace those lost in the feces.
b. The greater the bile salt concentration in the hepatic portal blood, the greater the rate of bile
secretion.

c. Bilirubin, the major bile pigment, is a breakdown product of hemoglobin and is absorbed
from the blood by the liver and secreted into the bile.
d. Secretin stimulates bicarbonate secretion by the cells lining the bile ducts in the liver.
e. Bile is concentrated in the gallbladder by the absorption of NaCl and water.
f. Following a meal, the release of CCK from the small intestine causes the gallbladder to con-
tract and the sphincter of Oddi to relax, thereby injecting concentrated bile into the intestine.

49
 10. In the small intestine, the digestion of polysaccharides and protein increases the osmolarity of
the luminal contents, producing an osmotic flow of water into the lumen.

11. Sodium, chloride, bicarbonate, and water are secreted by the small intestine. However, most of
these secreted substances, as well as those entering the small intestine from other sources, are
absorbed back into the blood.

12. Intestinal motility is coordinated by the enteric nervous system and modified by long and short
reflexes and hormones.
a. During and shortly after a meal, the intestinal contents are mixed by segmenting movements
of the intestinal wall.
b. After most of the food has been digested and absorbed, segmentation is replaced by the mi-
grating motility complex, which moves the undigested material into the large intestine by a
migrating segment of peristaltic waves.

13. The primary function of the large intestine is to store and concentrate fecal matter prior to defe-
cation.
a. Water is absorbed from the large intestine secondary to the active absorption of sodium,
leading to the concentration of fecal matter.
b. Flatus is produced by bacterial fermentation of undigested polysaccharides.
c. Three to four times a day, mass movements in the large intestine move its contents into the
rectum.
d. Distension of the rectum initiates defecation, which is assisted by a forced expiration against
a closed glottis.
e. Defecation can be voluntarily controlled through somatic nerves to the skeletal muscles of
the external anal sphincter.

III. GASTROINTESTINAL DISORDERS

A. Pathophysiology of the Gastrointestinal Tract.

1. The factors that normally prevent breakdown of the mucosal barriers and ulcers are (1) secretion
of an alkaline mucus, (2) tight junctions between epithelial cells, and (3) rapid replacement of
epithelial cells.
a. The bacterium Helicobacter pylori is a major cause of damage to the mucosal barrier leading
to ulcers.
b. Drugs that block histamine receptors or inhibit H-K, ATPase pump, inhibit acid secretion and
promote ulcer healing.

2. Vomiting is coordinated by the vomiting center in the medulla. Contractions of abdominal mus-
cles force the contents of the stomach into the esophagus (retching), and if the contractions are
strong enough, they force the contents of the esophagus through the upper esophageal sphincter
into the mouth (vomiting).

3. Precipitation of cholesterol or, less often, bile pigments in the gallbladder forms gallstones that
can block the exit of the gallbladder or common bile duct. In the latter case, the failure of bile
salts to reach the intestine causes decreased digestion and absorption of fat, and accumulation of
bile pigments in the blood and tissues causes jaundice.

4. Lactase, which is present at birth, undergoes a genetically determined decrease during childhood
in many individuals. In the absence of lactase, lactose cannot be digested, and its presence in
the small intestine can result in diarrhea and increased flatus production when milk is ingested
(lactose intolerance).

5. When bile salt is deficient (eg. sprue and Crohn's disease) malabsorption of fat and fat-soluble
vitamins occur and is clinically manifested as steatorrhea (fatty stool) and nutritional deficiency.

6. Constipation is primarily the result of decreased colonic motility. The symptoms of constipation
are produced by the overdistension of the rectum, not by the absorption of toxic bacterial prod-
ucts. The two most common causes of constipation are chronic voluntary suppression of defeca-
tion and chronic laxative abuse.

7. Megacolon (Hirschsprung's disease) develops in patients with a congenital absence of the

myenteric and submucosal nerve plexuses in a segment of the colon. Massive dilatation of the
colon occurs and feces collect proximal to the affected segment (obstipation).

8. Diarrhea is the opposite of constipation and is defined as an increase in stool volume, frequency,
or both. Three types of diarrhea may be distinguished.
50
 a. Osmotic diarrhea results when an osmotically active substance enters the bowel and is not
absorbed (eg. lactose intolerance, magnesium sulfate).
b. Secretory diarrhea results from secretion of fluid and electrolytes in excess of the colon's ab-
sorptive capacity. Cathartics such as bisacodyl and cholera infection produce secretory diar-
rhea.
c. Motor diarrhea results when bowel contents are moved rapidly through the intestines. In-
creased parasympathetic activity can produce this such as those seen in stress.

ENDOCRINE PHYSIOLOGY

I. HORMONES AND THEIR MECHANISMS OF ACTIONS

A. Chemical Structures and Synthesis

1. The amine hormones are the iodine-containing thyroid hormones thyroxine and triiodothyronine
-- and the catecholamines (mainly epinephrine) secreted by the adrenal medulla.

2. Most hormones are peptides and are synthesized as larger molecules that are then cleaved (e.g.
GH, insulin, and prolactin)

3. Steroid hormones are produced from cholesterol by the adrenal cortex and the gonads, and by
the placenta during pregnancy.
a. The most important steroid hormones produced by the adrenal cortex are the mineralocorti-
coid aldosterone, the glucocorticoid cortisol, and two androgens.
b. The ovaries produce mainly estradiol and progesterone, and the testes mainly testosterone.

B. Transport of Hormones in the Blood

1. Peptide hormones and catecholamines dissolve in the plasma water.

2. Steroid and thyroid hormones, being water-insoluble are, circulated mainly bound to plasma pro-
teins.

C. Hormone Metabolism and Excretion

1. The liver and kidneys are the major organs that remove hormones from the plasma by metaboliz-
ing or excreting them.

2. The peptide hormones and catecholamines are rapidly removed from the blood, whereas the ster-
oid and and thyroid hormones are removed more slowly.

3. After their secretion, some hormones are metabolized to more active molecules in their target
cells or other organs.

D. Mechanisms of Hormone Action and The Role of Second Messengers.

1. A hormone affects its target tissues by first activating target receptors in the tissue cells.

2. The receptors for steroid and thyroid hormones are inside the target-cells; those for the peptide
hormones and catecholamines are on the plasma membrane.

3. Receptors activated by peptide hormones and catecholamines utilize one or more of the signal
transduction mechanisms available to plasma membrane receptors; the result is altered activity
of proteins in the cell.
a. G proteins, which can either be stimulatory or inhibitory act by coupling hormone receptors
to adjacent effector molecules.

b. In the adenylate cyclase mechanism, the hormone binds to a receptor in the cell membrane.
If the receptor is coupled to a stimulatory G protein, then adenylate cyclase will be activated.
If the receptor is coupled to an inhibitory G protein, then adenylate cyclase will be inhibited.
(1) Activated adenylate cyclase then catalyzes the conversion of ATP to cyclic AMP.
(2) cAMP activates protein kinase A, which phosphorylates specific proteins, producing high-
ly specific physiologic actions.
(3) cAMP is degraded by phosphodiesterase. Phosphodiesterase is inhibited by caffeine and
theophylline, so these agents augment the physiologic actions of cyclic AMP.

c. With the IP3 mechanism, the hormone binds to a receptor in the cell membrane and, via a G
protein, activates phospholipase C.
51
 (1) Phospholipase C liberates diacylglycerol and IP3.
(2) IP3 mobilizes Ca++ from the endoplasmic reticulum. Together, Ca++ and diacylglycerol
activate protein kinase C, which phosphorylates proteins and causes specific physiologic
actions.

d. With the Ca++-calmodulin mechanism, the hormone binds to a receptor in the cell membrane
and, via a G protein, produces an increase in intracelllar [Ca++] via two effects: opening of
cell membrane calcium channels, and releasing Ca++ from endoplasmic reticulum. Ca++ binds
to calmodulin, and the Ca++-calmodulin complex produces physiologic actions.

4. Intracellular receptors activated by steroid and thyroid hormones combine with DNA in the nucle-
us and induce the transcription of DNA into mRNA; the result is increased synthesis of particular
proteins.
a. Steroid or thyroid hormones diffuse across the cell membrane and bind to either a cytosolic
(in the case of steroids) or nuclear (in the case of thyroid hormone) receptor.
b. In the nucleus, transcription is initiated, resulting in production of mRNA.
c. mRNA is translated in the cytoplasm and results in the production of specific proteins that
have physiologic actions (e.g., the Ca++-binding protein induced by 1,25-
dihydroxycholecalciferol).

E. Types of Inputs that Control Hormone Secretion

1. There are 3 ways of controlling secretion of a hormone.

a. By the plasma concentration of an ion or nutrient that the hormone regulates,
b. By the neural input to the endocrine cells.
c. By a tropic hormone.

2. The autonomic nervous system is the neural input controlling many hormones, but the hypotha-
lamic and posterior-pituitary hormones are controlled by neurons in the brain.

II. THE ROLE OF THE HYPOTHALAMUS AND PITUITARY

1. Control Systems Involving the Hypothalamus and Pituitary

1. The pituitary gland, comprising the posterior pituitary and anterior pituitary, is connected to the
hypothalamus by a stalk containing nerve fibers and blood vessels.

2. The nerve fibers, which originate in the hypothalamus and terminate in the posterior pituitary, se-
crete oxytocin and vasopressin (ADH).
a. ADH increases the permeability of the renal tubules to water thereby promoting water reab-
sorption. It is synthesized mainly in the supraoptic nuclei of the hypothalamus.
(1) ADH deficiency causes pituitary diabetes insipidus which is characterized by excessive
thirst, large urine volume, and very dilute urine. This is ameliorated by ADH administra-
tion.
(2) When the kidney is unresponsive to the ADH even when present in adequate amount the
condition is called nephrogenic diabetes insipidus. ADH administration does not help in
this case.
(3) Hypersecretion of ADH manifests clinically as water retention, hypoosmolality of plasma,
and very concentrated urine. The condition is called syndrome of inappropriate ADH se-
cretion (SIADH).

b. Oxytocin stimulates the contraction of the myoepithelial cells of the lactating breast (milk let-
down). It is synthesized mainly in the paraventricular nuclei of the hypothalamus.

3. Of the cells in the anterior pituitary:

a. The acidophilic chromophils synthesize the prolactin and growth hormone.
b. The basophilic chromophils synthesize TSH, ACTH, LH, FSH, and -LPH.

4. The anterior pituitary secretes growth hormone (GH), thyroid-stimulating hormone (TSH), adre-
nocorticotropic hormone (ACTH), prolactin, and two gonadotropic hormones--follicle stimulating
hormone (FSH) and luteinizing hormone (LH).
a. ACTH stimulates the synthesis and release of cortisol by the adrenal cortex.
b. TSH stimulates the uptake of iodine and the release of thyroxine and triiodothyronine by the
thyroid gland.
c. FSH stimulates the development of the Graafian follicles and the secretion of estrogen in the
female. It promotes spermatogenesis in the male.

52
 d. LH (ICSH) prompts ovulation and the luteinization of the mature ovarian follicles and subse-
quent release of progesterone in the female. It stimulates the production and release of tes-
tosterone by the Leydig cells in the male.
e. Prolactin stimulates breast development and milk production.
f. GH (somatotropin) stimulates growth and influences organic metabolism in many tissues and
secretion of insulin-like growth factor (IGF-I), also called, somatomedin C by the liver.
(1) Physiologic effects of GH include:
a. Stimulation of bone growth, and cartilage and connective tissue development.
Somatomedins mediate its actions.
b. Anabolism by promoting protein synthesis.
c. Ketogenesis by virtue of its overall catabolic actions on adipose tissue (fatty acid mo-
bilization).
d. Diabetogenesis (anti-insulin action), which results from its lipolytic and gluconeogenic
actions.
e. Promotion of sodium, calcium, and phosphate retention by the kidneys.

(2) Hyposecretion of GH produces stunting of growth (dwarfism) and this is often accompa-
nied by sexual immaturity, hypothyroidism, and adrenal insufficiency.

(3) Hypersecretion of GH during adolescence (giantism) or during adulthood (acromegaly) is

characterized by coarse facial features, frontal bosses, prognathism, massive hands and
feet, enlarged organs and, if it starts before the fusion of the epiphysial plates of the long
bones, excessive tallness.

5. The anterior pituitary also produces -lipoprotein and -endorphin along with ACTH, all being por-
tions of the parent pro-opiomelano-cortin molecule.

6. Secretion of the anterior pituitary hormones is controlled mainly by hypothalamic releasing hor-
mones secreted into capillaries in the median eminence and reaching the anterior pituitary via
the portal vessels connecting the hypothalamus and anterior pituitary.
a. CRH stimulates the secretion of ACTH.
b. TRH stimulates the secretion of TSH and prolactin.
c. PRH stimulates the secretion of prolactin only
d. GHRH stimulates the secretion of GH.
e. GIH or somatostatin inhibits the secretion of GH and TSH.
f. PIH inhibits the secretion of prolactin.

III. THE THYROID GLAND

A. The Thyroid Gland

1. The thyroid gland secretes two hormones namely calcitonin from the parafollicular or C cells, and
the thyroid hormones (T3 and T4) from the follicular cells.

2. Calcitonin is involved in plasma ionic calcium regulation and is discussed together with the para-
thyroid hormone somewhere in this book.

3. The thyroid follicle (acinus) performs two parallel functions in the synthesis of thyroid hormones.
They are:
a. Synthesis of thyroglobulin which is a glycoprotein that serves as matrix for thyroid hormone
formation. It is the storage form of thyroid hormone.
b. Accumulation of inorganic iodide. Ninety five percent are stored in the colloid as thyroglobulin
(iodotyrosine 2/3; thyronines 1/3) and five percent are pooled inside the follicular cells.

4. The synthesis of thyroid hormones are divided into 4 steps all of which are stimulated by TSH.
a. Active iodide uptake occurs at the basal membrane of the follicular cell.
b. Oxidation of iodide is mediated by peroxidase converting it either to iodinium ion, or a free
radical of iodine or iodine (I2).
c. Iodination of the preformed thyroglobulin is catalyzed by peroxidase and produces mono- and
diiodotyrosine.
d. Coupling (condensation) of iodotyrosines occurs to form the biologically active thyronines (T3
and T4). Peroxidase also catalyzes this reaction. T4 results from the fusion of two
diiodotyrosine molecules, and T3 results from the condensation of a monoiodo-tyrosine with a
diiodotyrosine molecule.

53
 5. The secretion of the hormone begins with endocytosis of the colloid at the apical border of the
acinar cell which leads to the hydrolysis of thyroglobulin by lysosomal proteases inside the cell.
The freed iodothyronines are then secreted into the blood at the basal border of the acinar cell.

6. The molar activity ratio of T3 to T4 is about 4:1. The secretory ratio of T4 to T3 is about 15:1.
The plasma concentration ratio of free T4 to free T3 is 2:1.

7. While T4 comes directly from the thyroid gland, T3 aside from being secreted is also produced by
the peripheral monodeiodination of T4.

8. The thyroid hormones are transported in the blood mainly bound to proteins.

9. Thyroid hormone secretion is influenced by hypothalamic TRH, pituitary TSH, plasma concentra-
tion of the hormone (negative feedback). Stress and cold increases its secretion.

10. Antithyroid substances such as thiocyanates and perchlorates block iodide trapping. Drugs like
propylthiouracil and methimazole block coupling reaction. Iodide deficiency increases TSH secre-
tion. All of these are goitrogenic substances and thus cause enlargement of the thyroid gland
(goiter). Excess iodide (e.g. 100 times plasma level) inhibits TSH effects and causes reduction in
gland size and vascularity.

11. Effects of thyroid hormone include:

a. Increased BMR of most cells (except in gonads, brain, lungs, lymph nodes and spleen). Ther-
mogenesis and enzymatic activity are increased.
b. Promotion of maturation of nervous tissue (nerve myelinization and arborization) and growth
of bone. It is also essential for normal lactation.
c. Potentiation of insulin activity and anabolism at physiologic concentrations. In pharmacologic
doses it is a hyperglycemic, catabolic, and lipolytic hormone.

12. In hyperthyroidism the patient exhibits weight loss inspite of excellent appetite, warm and moist
skin, heat intolerance, insomnia, hyperactivity, irritability, diarrhea, rapid heart rate, palpitation,
low plasma triglycerides, cholesterol and phospholipids, high plasma free fatty acids. The protein-
bound iodine in the blood is high and the uptake of radioactive iodine is also elevated.

13. Symptoms opposite to those mentioned above are seen in hypothyroidism. In children mental and
growth retardation is seen (cretinism).

IV. The Pancreas and the Islets of Langerhans

A. The islet has three cell types.

1. Alpha cell is the source of glucagon.
2. Beta cell is the source of insulin.
3. Delta cell is the source of somatostatin.

B. The metabolic effects of insulin

1. Carbohydrate metabolism
a. Stimulation of glucose uptake by cells
b. Stimulation of glycolysis
c. Stimulation of glycogen synthesis
d. Inhibition of glycogen catabolism
e. Inhibition of gluconeogenesis
f. The net result is a decrease in plasma glucose concentration; increases in glucose utilization
and glycogen storage. There is also net glucose uptake, rather than release, by liver.

2. Lipid metabolism
a. Stimulation of triacylglycerol synthesis
b. Inhibition of triacylglycerol catabolism
c. Stimulation of endothelial-cell lipoprotein lipase
d. The net result is a decrease in the plasma concentrations of glycerol and free fatty acids.
There is also net fat storage and decreased utilization of fat for energy

3. Protein metabolism
a. Stimulation of amino acid uptake by cells
b. Stimulation of protein synthesis
c. Inhibition of protein catabolism
d. The net result is decreased plasma concentrations of amino acids and net protein anabo-
lism
54
C. Control of Insulin Secretion
1. Glucose is the primary stimulus for insulin release.
2. Gastrin, secretin, CCK, and GIP augments insulin release
3. Glucagon stimulates insulin release

D. Physiologic Effects of Glucagon

1. Its major site of action is in the liver.
2. It stimulates hepatic glycogenolysis and is a hyperglycemic hormone.
3. It promotes hepatic gluconeogenesis (increased amino acid oxidation).
4. It is a lipolytic hormone because it activates glucagon-sensitive lipase in fat cells.
5. It causes an elevation of plasma levels of fatty acids and glycerol.
6. It has a net proteolytic effect in the liver.
7. It has an antianabolic effect.

E. Control of Glucagon Secretion

1. Hypoglycemia stimulates and hyperglycemia inhibits glucagon secretion.
2. Amino acids (eg. arginine and alanine) stimulate glucagon secretion.
3. CCK, gastrin, secretin, and GIP stimulates glucagon secretion

F. Diabetes Mellitus is due to Insulin Deficiency

1. Basic biochemical defects include:
a. Decreased glucose uptake by cells which leads to:
(1) Hyperglycemia
(2) Glycosuria
(3) Osmotic diuresis
(4) Urinary loss of sodium and potassium
(5) Dehydration if water intake is prevented
b. Increased protein catabolism which increases:
(1) Plasma amino acid concentration
(2) Nitrogen loss in the urine
c. Increased lipolysis which leads to:
(1) Increased plasma FFA
(2) Ketonemia and ketonuria
(3) Metabolic acidosis
(4) Respiratory compensation which lowers PCO2
d. Increased glycogenolysis
e. Increased gluconeogenesis

2. Clinical Signs and Symptoms of Diabetes Mellitus

a. Polyuria, nocturia, and polydipsia
b. Polyphagia with weight loss
c. Dehydration in cases of failure to drink water
d. Acetone breath, vomiting and abdominal pain
e. Kussmaul breathing: rapid and deep breathing (air hunger)
f. Stupor and coma and death

3. Treatment of diabetes mellitus includes:

a. Insulin
b. Hypoglycemic drugs
c. Bicarbonate in acidosis

V. PTH, Calcitonin, Vitamin D, and Calcium Metabolism

A. Calcium Distribution
1. More than 99 percent of the total body calcium is stored in the skeleton. Bone calcium is in the
form of hydroxyapatite crystals.
2. Plasma calcium is about 10 mg% or about 2.5 mmol/L. It is present in the plasma as:
a. Ionized or free (45%) and is regulated by PTH, calcitonin, and vitamin D.
b. Complexed with phosphate or bicarbonate (10%)
c. Bound to protein (primarily albumin) (45%)

3. The exchangeable pool of calcium is in equilibrium with the ECF and act as a buffer to prevent
plasma calcium ion fluctuation.

55
 4. The degree of protein-binding of calcium depends upon the pH value of the blood: it rises in alka-
losis and sinks in acidosis (by about 0.21 mmol/l Ca++ per pH unit). This is the reason why alkalo-
sis (e.g. by hyperventilation) may lead to tetany.

B. Calcium Regulating Hormones

1. Parathyroid hormone or PTH is secreted by the chief cells of the parathyroid glands.
a. PTH is a hypercalcemic hormone and it regulates only the plasma concentration of the ionic
form of calcium.
b. When plasma calcium falls the secretion of PTH increases, as calcium rises PTH secretion de-
creases.

2. Calcitonin is secreted by the parafollicular cells of the thyroid gland.

a. It is a hypocalcemic hormone
b. A rise in the plasma calcium stimulates its secretion.

3. Vitamin D is a steroid hormone (the largest steroid hormone in the body).

a. UV light converts the 7-dehydrocholesterol in the skin into cholecalciferol (vitamin D3). D3 (al-
so the D3 found in the diet) is converted in the liver into 25-cholecalciferol and then in the
kidney this in turn is converted to 1,25-dihydrcholecalciferol(calcitriol).
b. PTH enhances the conversion occuring in the kidney.
c. 1,25-dihydroxycholecalciferol (calcitriol) is the active form of vitamin D.

C. Cellular Aspects of Bone Metabolism.

1. Osteoblasts are bone-forming cells that synthesize and secrete collagen. They contain abundant
alkaline phosphatase activity.
2. Osteocytes are osteoblasts that have become buried in the bone matrix. Osteocytes have an
osteolytic activity which is stimulated by PTH.
3. Osteoclasts contain lysosomes that mediate bone resorption at bone surfaces. They contain acid
phosphatase and are stimulated by PTH to form acids that cause bone dissolution.

D. Physiologic Actions of PTH

1. PTH increases mobilization of calcium and phosphate from the nonreadily exchangeable calcium
pool (bone dissolution).
2. PTH stimulates the activity of osteoclasts and osteocytes and inhibits osteoblastic activity.
3. PTH promotes the active reabsorption of calcium by the distal tubules and at the same time inhib-
its phosphate reabsorption in the proximal tubules (phosphaturic effect).
4. PTH by activating vitamin D promotes calcium and phosphate absorption in the gut.
5. The unopposed effects of PTH include:
a. Hypercalcemia
b. Hypophosphatemia
c. Initial hypocalciuria later followed by hypercalciuria
d. Hyperphosphaturia

E. Physiologic Actions of Calcitonin

1. Calcitonin inhibits osteoclastic activity and the osteolytic action of osteocytes.
2. It is associated with an increase in alkaline phosphatase synthesis by osteoblasts.
3. It inhibits jejunal absorption of calcium and phosphate.
4. It promotes urinary excretion of phosphate, calcium and NaCl.

F. Physiologic Actions of Calcitriol

1. Calcitriol acts synergistically with PTH to cause bone dissolution.
2. It promotes intestinal absorption of calcium and phosphate.
3. It promotes distal tubular reabsorption of calcium and unlike PTH it promotes reabsorption of
phosphate in the kidneys.

G. Hyperparathyroidism is associated with:

1. Hypercalcemia with CNS and peripheral nervous depression.
2. Muscle weakness, peptic ulcer, cardiac diastolic arrest.
3. Osteitis fibrosa cystica.
4. Metastatic calcification of soft tissues and renal stones

H. Hypoparathyroidism is associated with hypocalcemia and tetany.

1. Inadvertent removal of the parathyroid glands during thyroidectomy causes hypoparathyroidism.
2. Its treatment includes vitamin D and calcium.

I. Rickets is a condition characterized by bone demineralization.

1. Dietary vitamin D deficiency or renal disease (D-resistant rickets) can cause it. Osteomalacia is the
term used for rickets in the adults.
2. Inadequate vitamin D activity produces hypocalcemia and this may lead to tetany.
56
 3. Alkaline phosphatase level rises because of increased osteoblastic activity.
4. It is treated with vitamin D AND calcium.

VI. Adrenal Cortex

A. Adrenocortical Hormones.

1. Mineralocorticoid (Aldosterone; secreted by the zona glomerulosa)

2. Glucocorticoids (Cortisol, corticosterone, and cortisone; secreted by the zona fasciculata and
reticularis)
3. Androgenic hormone (Dehydroepiandrosterone or DHEA; secreted by the zona reticularis)

B. Adrenocorticosteroids are synthesized from acetyl co-A (10%) and from cholesterol (90%) preformed
somewhere else in the body.

Cholesterol

Pregnenolone -Hydroxypregnenolone {Dehydroepiandrosterone(DHEA)}

Progesterone -Hydroxyprogesterone [Androstenedione] [Testosterone]

Corticosterone 11-Deoxycortisol (Estrone) (Estradiol)

{Aldosterone} {Cortisol}

[ ] occurs in the testis; ( ) occurs in the ovary; { } occurs in adrenal

Figure 1. Summary of steroidogenesis in the adrenal cortex, testis, and ovary. Notice that there is no
interconversion between mineralocorticoids and glucocorticoids.

C. Aldosterone Secretion.
1. Potassium concentration is the major regulator of aldosterone secretion. An increase in potassium
ion concentration increases its secretion.
2. The renin-angiotensin system when activated also stimulates aldosterone secretion.
3. Hypovolemia and lowered plasma concentration increases secretion.
4. ACTH also stimulates the formation of aldosterone.

D. Physiologic Actions of Aldosterone.

1. It stimulates sodium reabsorption in the distal and collecting tubules.
2. It increases the renal excretion of potassium (sodium-potassium countertransport).
3. It increases renal reabsorption of anions particularly chloride.
4. It increases ECF volume by drawing water with sodium.
5. It increases NaCl reabsorption in the salivary and sweat glands.

E. Glucocorticoid Secretion.
1. Stress and its attendant release of catecholamines by inducing ACTH secretion increases glucocor-
ticoid secretion.
2. CRH and its effect on ACTH promotes the secretion of glucocorticoids. In addition ACTH helps
maintain the structure of the adrenal cortex and the availability of the substances from which the
hormones are synthesized.
3. A spontaneous night-day rhythm (circadian or diurnal) in the release of CRH is responsible for a
similar rhythm in ACTH and cortisol release.
4. The plasma cortisol concentration reaches peak at about six in the morning and is at its ebb at
about ten oclock in the evening. This however may be reversed in those who work at night and
sleep during daytime.

F. Physiologic Actions of Glucocorticoids.

1. Cortisol stimulates gluconeogenesis and blocks glucose uptake by cells (anti-insulin action).
2. It decreases protein stores in almost all tissues EXCEPT the liver where protein synthesis is en-
hanced.
3. It promotes fatty acid mobilization from adipose tissue (lipolytic and ketogenic effects).
4. It increases gastric acid secretion.
57
 5. It is a potent anti-inflammatory and immunosuppressive substance. Its action includes:
a. Stabilization of the lysosomal membrane
b. Inhibition of leukocytic activity and decreasing capillary permeability.
c. Involution of the lymphoreticular system and reduction of antibody production.
d. Reduction of the numbers of circulating lymphocytes, monocytes, eosinophils, and basophils.
6. It increases the total blood count by increasing the numbers of neutrophils, red blood cells, and
platelets.
7. Cortisol in pharmacologic doses enhances the pressor effect of norepinephrine on blood vessels.
8. Cortisol in large doses delay wound healing by inhibiting fibroblastic activity.
G. Hyperaldosteronism is characterized by hypokalemic metabolic alkalosis whereas hypoaldosteronism
is characterized by hyperkalemic acidosis.

H. Hypoadrenalism (eg. Addison's disease) may manifest with:

1. Increased melanin pigmentation of the skin (an ACTH effect).
2. Chronic hypotension and decreased cardiac size.
3. Susceptibility to stress
I. Hyperadrenalism (eg. Cushing's disease) may manifest with:
1. Centripetal distribution of fat (moon facies, buffalo hump, potbelly, truncal obesity).
2. Protein catabolism (thin extremeties, weak muscles, osteoporosis, and easy bruisability).
3. Poor wound healing and abdominal striae.
4. Hirsutism
5. Hypertension and hyperglycemia (insulin-resistant diabetes).

J. Congenital abnormality - 21 -hydroxylase deficiency- adrenogenital syndrome and is characterized by

the following:
1. Decreased cortisol and aldosterone (from enzyme block upstream)
2. Increased progesterone (resulting from buildup behind the enzyme block)
3. Increased ACTH (resulting from decreased feedback)
4. Hyperplasia of zona fasciculata and zona reticularis (due to ACTH)
5. Increased adrenal androgens (17-hydroxyprogesterone is their precursor)
6. Virilization in females and pre-pubertal males
7. Early acceleration of linear growth and early appearance of pubic and axillary hair
8. Suppression of gonadal function in males and females
9. Elevated 17-ketosteroids (derived from androgens) in the urine is diagnostic.

VII. Male Reproductive Physiology

A. Spermatogenesis.

1. The male gonads, the testes, produce sperm in the seminiferous tubules and secrete testos-
terone from the Leydig cells.
2. The meiotic divisions of spermatogenesis result in each sperm containing 23 chromosomes, com-
pared to the original 46 of the spermatogonia.
3. The developing germ cells are intimately associated with the Sertoli cells which perform the fol-
lowing functions:
a. Provision of blood-testis barrier to chemicals.
b. Nourishment of the developing sperm.
c. Secretion of androgen-binding protein.
d. Secretion of chemical messengers (when stimulated by testosterone and FSH) that stimulate
sperm production and maturation.
e. Secretion of inhibin which inhibits FSH secretion
f. Phagocytosis of defective sperm.
g. Secretion of H-Y antigen responsible for induction of testicular organogenesis.
h. Secretion of MDIF (mullerian duct-inhibiting factor) that causes regression of the mullerian
duct system.
i. Secretion of fluid that transports sperm.
j. Synthesis of estradiol from androgenic precursors.

B. Transport of Sperm
1. From the seminiferous tubules, the sperm pass through the epididymis, where they mature and
are concentrated.
2. The epididymis and vas deferens store the sperm, and the seminal vesicles and prostate secrete
the bulk of the semen.
3. Erection of the penis occurs because of vascular engorgement accomplished by relaxation of the
arterioles and passive occlusion of the veins.
4. Ejaculation includes emission--emptying of semen into the urethra --followed by expulsion of the
semen from the urethra.

58
C. Hormonal Control of Male Reproductive Function.
1. Hypothalamic GnRH stimulates the anterior pituitary to secrete FSH and LH, which then act on
the testes.
a. FSH act on the Sertoli cells to stimulate spermatogenesis and inhibin secretion.
b. LH act on the Leydig cells to stimulate testosterone secretion.
(1) Testosterone exerts a negative-feedback inhibition on both the hypothalamus and the
anterior pituitary to reduce LH secretion.
(2) Inhibin exerts a negative-feedback inhibition on FSH secretion.
2. Testosterone, acting locally on the Sertoli cells, is essential for maintaining spermatogenesis.
Sperm represents 10% of the ejaculate volume.
a. Euspermia: 40 to 100 million sperm/ml of ejaculate.
b. Oligospermia: 5 to 20 million sperm/ml of ejaculate.
c. Azoospermia: less than 5 million sperm/ml of ejaculate.

D. Synthesis of testosterone (see Figure 1)

1. Testosterone is the major androgen synthesized and secreted by the Leydig cells of the testis.
2. Leydig cells do not contain 21 -hydroxylase or 11 -hydroxylase (in contrast to the adrenal cor-
tex) and do not synthesize glucocorticoids or mineralocorticoids.
3. LH increases testosterone synthesis by stimulating cholesterol desmolase.
4. In the developing male fetus, the stimulus for testosterone synthesis is chorionic gonadotropin, a
placental hormone).
5. Accessory sex organs contain 5 -reductase, which converts testosterone to dihydrotestosterone
(the active form).
6. -reductase inhibitors (finasteride) may be used in the treatment of benign prostatic hypertro-
phy because they block the activation of testosterone to dihydrotestosterone in the prostate.

Figure 1. Testosterone synthesis.

Cholesterol (LH-stimulated) -- pregnenolone -- 17-Hydroxypregnenolone -- DHEA --

Androstenedione (17 -OH-steroid dehydrogenase) -- -reductase) --
Dihydrotestosterone

E. Functions of testosterone
1. Maintains the accessory reproductive organs
2. Growth of facial, chest, axillary, and pubic hair.
3. Recession of hairline
4. Enlargement of the larynx and the penis
5. Thickening of the vocal cords (low pitched-voice)
6. Linear bone growth then fusion of epiphysial plates
7. Wolffian duct system differentiation (during fetal life)
8. Descent of the testis into the scrotum during the third trimester of pregnancy
9. Muscularity (broad shoulders and narrow hips)
10. Thickening of the skin and acne
11. Libido
12. In many of its target cells it must undergo transformation to dihydrotestosterone or (in the brain)
to estrogen to be effective.

VIII. Female Reproductive Physiology

A. Ovarian Function.

1. The female gonads, the ovaries, produce ova and secrete estrogen, progesterone, inhibin, and
relaxin.
2. The two meiotic divisions of oogenesis result in each ovum having 23 chromosomes, in contrast
to the 46 of the original oogonia.
3. The follicles surrounding the ova consist of inner layers of granulosa cells and outer layers of the-
ca cells.
4. At the beginning of each menstrual cycle, several follicles begin to develop into antral follicles,
but soon only the largest (dominant) follicle continues its development to full maturity and ovula-
tion.
5. Following ovulation the remaining cells of that follicle are trans formed into a corpus luteum,
which lasts about 10 to 14 days if pregnancy does not occur.
6. The menstrual cycle can be divided, according to ovarian events, into a follicular phase and a lu-
teal phase, which are approximately 14 days each and separated by ovulation.

B. Control of Ovarian Function.

59
 1. During the early and middle follicular phases.
a. FSH stimulates the granulosa cells to proliferate and secrete estrogen.
b. LH stimulates the theca cells to proliferate and produce the androgens that the granulosa
cells use to make estrogen.
c. During this period, estrogen exerts a negative feedback on the hypothalamus and anteri-
or pituitary to inhibit the secretion of GnRH and the gonadotropins (LH and FSH).
2. During the late follicular phase, plasma estrogen becomes high enough to elicit a surge of LH,
which then causes, via the granulosa cells, completion of the oocyte's first meiotic division and
cytoplasmic maturation, ovulation, and formation of the corpus luteum.
3. During the luteal phase, under the influence of small amounts of LH, the corpus luteum secretes
progesterone and estrogen. Regression of the corpus luteum results in a cessation of the secre-
tion of these hormones.

C. Uterine Changes in the Menstrual Cycle.

1. The ovarian follicular phase is equivalent to the uterine menstrual and proliferative phases, the
first day of menstruation being the first day of the cycle. The ovarian luteal phase is equivalent to
the uterine secretory phase.
2. Menstruation occurs when the plasma progesterone and estrogen levels fall as a result of the re-
gression of the corpus luteum.
3. During the proliferative phase, estrogen stimulates growth of the endometrium and myometrium
and causes the cervical mucus to be readily penetrable by sperm.
4. During the secretory phase, progesterone converts the estrogen-primed endometrium to a secre-
tory tissue and makes the cervical mucus relatively impenetrable to sperm.

D. Synthesis of estrogen and progesterone (see Figure 2)

1. Theca cells produce mostly androgens (stimulated by LH).
2. The androgens diffuse to the granulosa cells, which contain aromatase and convert androgen to
estrogen (stimulated by FSH).

Figure 2. Estrogen and progesterone synthesis.

Cholesterol (LH-stimulated in theca cells) pregnenolone Progesterone 17-Hydroxypregnenolone

DHEA Androstenedione (17 -OH-steroid dehydrogenase) Testosterone (aromatase in granulosa
cells and stimulated by FSH) 17 -Estradiol

3. Physiologic Effects of Estrogen.

a. Stimulates ovary and follicle growth.
b. Stimulates growth of smooth muscle and epithelial linings of reproductive tract. In addition:
(1) Uterine tubes increases contractions and ciliary activity.
(2) Uterus increases myometrial contractions.
(3) Stimulates secretion of abundant, clear cervical mucus (spinnbarkheit sign) with crystal-
lization (ferning pattern).
(4) Prepares endometrium for progesterone's actions by inducing progesterone receptors.
c. The vagina increases "cornification" (layering of epithelial cells).
d. Stimulates external genitalia growth.
e. Stimulates breast growth, particularly ducts and fat deposition.
f. Stimulates female body configuration development; narrow shoulders, broad hips, female fat
distribution.
g. Stimulates a more-fluid sebaceous gland secretion ("antiacne effect")
h. Stimulates development of female pubic hair pattern (growth of pubic and axillary hair is an-
drogen-stimulated).
i. Stimulates bone growth and ultimate cessation of bone growth (closure of epiphyseal plates);
protects against osteoporosis.
j. Vascular effects (deficiency produces "hot flashes").
k. Has feedback effects on hypothalamus and anterior pituitary.
l. Stimulates retention of fluid.
m. Stimulates prolactin secretion but inhibits prolactin's milk-inducing action on the breast.

4. Physiologic Effects of Progesterone.

a. Stimulates endometrial glands to secrete.
b. Induces thick, sticky cervical mucus.
c. Decreases contractions of uterine tubes and myometrium.
d. Decreases vaginal cornification.
e. Stimulates breast growth, particularly the lobulo-alveolar glands.
f. Inhibits milk-inducing effects of prolactin.
g. Has feedback effects on hypothalamus and anterior pituitary.
h. Increases body temperature.

60
 5. The Menstrual Cycle Summary.
--------------------------------------------------------------------------------------------------------------------------------
----------------------------
Day(s) Major Events
_____________________________________________________________________________________
____________________
1 5 Estrogen and progesterone are low because the previous corpus luteum has completely
regressed.
Therefore: (a) Endometrial lining sloughs
(b) Secretion of FSH and LH is released from inhibition, and their plas-
ma concentrations rise. Therefore: Several follicles are stimulated to
enlarge.
_____________________________________________________________________________________
________
7 Dominant follicle is selected.
7 12 Plasma estrogen rises because of secretion by the dominant follicle.
Therefore: Endometrium is stimulated to proliferate.
12-13 LH surge is induced by high plasma estrogen.
Therefore: (a) Oocyte is induced to complete its first meiotic division and undergo
cytoplasmic maturation.
(b) Follicle is stimulated to secrete lytic enzymes and prosta-
glandin.
14 Ovulation is mediated by follicular enzymes and prostaglandin.
15-25 Corpus luteum forms and, under the influence of LH, secretes estrogen and progester-
one, and so plasma concentrations of these hormones increase.
Therefore: (a) Secretory endometrium develops.
(b) Secretion of FSH and LH is inhibited, lowering their plasma concen-
trations.
Therefore: No new follicles develop.
25-28 Corpus luteum degenerates.
Therefore: Plasma estrogen and progesterone concentrations decrease.
Therefore: Endometrium begins to slough at end of
day 28, and a new cycle begins.

61
BLOOD

I. Introduction
A. Composition
1. Blood is composed of cells (erythrocytes, leukocytes, and platelets) suspended in plasma.
2. More than 99% of the cells are erythrocytes (red blood cells), which are oxygen-carrying cells of
the blood.
3. Leukocytes (white blood cells) protect against infection and cancer whereas the platelets function
in blood clotting.
4. The percentage of blood that is erythrocytes is called hematocrit and this is determined by centri-
fuging a blood sample. Normal hematocrit is about 45% in men and 42% in women.
5. Roughly, total blood volume is equal to total erythrocyte volume plus plasma volume
(TBV=TEV+PV).

B. Plasma
1. Plasma, the liquid portion of the blood, consists of organic (proteins, nutrients, and metabolic
waste products) and inorganic substances (mineral electrolytes) dissolved in water.
2. Proteins (albumin, globulins, fibrinogen) account for about 7% of the total weight of plasma. Al-
bumins are the most abundant proteins and are synthesized by the liver.
3. Serum is plasma from which fibrinogen and other proteins involved in clotting have been re-
moved as a result of clotting. Serum does not clot.

II. ERYTHROCYTES (Red Blood Cells)

A. The Cell and Hemoglobin

1. Erythrocytes are biconcave disks with high surface-to-volume ratio, which allows rapid diffusion
of oxygen and carbon dioxide through its membrane.
2. The membrane also contains specific proteins that differ from person to person, and these confer
upon the blood its so-called blood type.
3. Red blood cells contain hemoglobin which binds oxygen taken in by the lungs.
4. Each hemoglobin molecule is made up of four subunits, each subunit consisting of an organic
molecule known as heme attached to a polypeptide. The four identical polypeptides of hemoglo-
bin molecule are bound together and collectively called globin. Each of the four heme portions of
a hemoglobin molecule contains one atom of iron (Fe), which binds oxygen.

B. Red cell production (Erythropoiesis)

1. Red cells are synthesized in the bone marrow. They descend from cells that contain no hemoglo-
bin but do have nuclei and are therefore capable of cell division.
2. After several divisions, immature erythrocytes begin to acquire hemoglobin. As maturation con-
tinues, more hemoglobins are formed and at the same time their nuclei and organelles gradually
disappear.
3. Newly produced erythrocytes (reticulocytes) still contain a few ribosomes, which produce a web-
like or reticular appearance on staining.
4. On complete maturation the cells do not have nucleus and organelles anymore and these are the
ones that leave the bone marrow and enter the blood.
5. A small amount of reticulocytes however, about 1% of the total red cell count, is seen in the pe-
ripheral blood. The appearance of a large amount of reticulocytes in the blood (reticulocytosis)
indicates an abnormally rapid red cell production (e.g. hemolytic anemia).
6. The average life span of a red cell is about 120 days. Almost 1% of the body's red cells are de-
stroyed and replaced everyday (about 100 billion cells per day!). Destruction occurs in the
spleen.
7. Erythrocyte production needs amino acids, iron, folic acid and vitamin B12.

C. Iron Metabolism, Folic Acid, and Vitamin B12

1. The iron in our diet replaces the iron that we lose daily. The average daily iron loss is about 0.6
mg in adult males and higher, about 1.3 mg, in adult females because of menstruation.

2. The total body iron is 4 gms. About 60% is in hemoglobin, 15% to 30% is bound to protein ferri-
tin in the liver (storage iron), 5% in myoglobin and other heme-containing proteins.
3. Dietary iron is absorbed in ferrous form mainly in the duodenum. This is transported in the
plasma attached to an iron-transport protein called transferrin. Iron released from destroyed red
cells are also bound to transferrin (recycling).
4. The iron is delivered to the bone marrow for red cell production and some are stored in the liver
and other tissues.
5. Folic acid, a vitamin, is involved in the synthesis of the pyrimidine, thymine which is essential for
DNA formation and for normal cell division. Deficiency in folic acid produces anemia in which red
cells are few and abnormally large (megaloblastic or macrocytic anemia).
62
 6. Vitamin B12 (cyanocobalamin) is required for the action of folic acid. Unlike folic acid, it is not
synthesized in the body and so its supply depends upon dietary intake (animal products, not in
vegetables).
7. Absorption of vitamin B12 in the GIT (ileum) requires a substance secreted by the parietal cells of
the stomach, the intrinsic factor.
8. Intrinsic factor deficiency leads to poor absorption of vitamin B12 and so maturation failure oc-
curs in red cells. B12 deficient diet also causes maturation failure. The cells are characteristically
large, few and fragile (megaloblastic anemia or pernicious anemia).
9. Since vitamin B12 is needed for myelin formation neurological symptoms accompany the anemia.

D. Regulation of Erythrocyte Production

1. The direct control of erythropoiesis is exerted by a hormone called erythropoietin which is syn-
thesized and secreted by the kidneys and, to a lesser extent the liver.
2. The secretion of erythropoietin is primarily stimulated when the blood flowing to the kidneys is
low in oxygen.
3. Erythropoietin stimulates red cell proliferation and maturation in the bone marrow.
4. Testosterone also stimulates the release of erythropoietin, which accounts, in part, for the higher
hemoglobin concentration in men than in women (16 g/dL blood versus 14 g/dL).

E. Anemia
1. Anemia is defined as (1) a decrease in the total number of erythrocytes, each having a normal
quantity of hemoglobin, or (2) a diminished concentration of hemoglobin per erythrocyte, or (3) a
combination of both.
2. Causes of anemia include:
a. Dietary deficiency of iron, vitamin B12, or folic acid.
b. Bone marrow failure (aplasia) due to toxic drugs and cancer.
c. Excessive blood loss from the body leading to iron deficiency.
d. Inadequate secretion of erythropoietin in renal disease.
e. Excessive destruction (hemolysis) of erythrocytes.
3. Laboratory Diagnosis of Anemia
a. Laboratory evaluation of anemia starts with analysis of a blood sample for the number of
erythrocytes, the average cell size, and the hemoglobin concentration.
b. In normal men the average number of red cells per cubic millimeter is 5,200,000 (±300,000)
and in normal women 4,700,000 (±300,000).
c. In normal men the average value of hemoglobin concentration is 16 grams per deciliter and
in normal women is 14 grams per deciliter of whole blood.
d. The average size of the red blood cell is 83 cubic micrometers.
e. The normal hematocrit (packed red cell volume) is 40 to 45 percent.
f. The average cell size determination is useful since it correlates well with several common
type of anemias. Microcytosis (small cells) most commonly occurs in iron deficiency,
normocytosis (normal size) accompanies acute blood loss, and macrocytosis (large size) is
characteristic of vitamin B12 or folic acid deficiency. Macrocytosis is due to delayed cell divi-
sion because of DNA deficiency.

III. BLOOD GROUPS AND TRANSFUSIONS

A. The ABO Blood Groups

1. Red cells contain antigens (agglutinogens) on the surface of their membranes.

2. The antigens are determined by three allelomorphic genes (i.e. A, B, and O) and, therefore, six
genotypes are possible. They are AA, AO, BB, BO, AB, and OO.
3. Genes A and B are dominant over the gene O, therefore only group specific substances A and B
can act as agglutinogens whereas group specific substance O cannot.
4. Antibodies against agglutinogens are called agglutinins for they cause agglutination or clumping
of red cells.
5. Anti-A is the agglutinin reacting with agglutinogen A and anti-B is the agglutinin reacting with
agglutinogen B. No anti-O exists.
6. Using antisera, humans can be typed into four major blood groups, namely groups A (genotypes
AA and AO), B (genotypes BB and BO), AB (genotype AB), and O (genotype OO).
7. The prevalence of ABO blood types is as follows: type O (47%); type A (41%); type B (9%); and
type AB 3%).
8. Agglutinins specific for agglutinogens A and B develop in the plasma spontaneously early in life, if
the red cells in the blood do not have the agglutinogens. They are absent if the cells have the
agglutinogens (Landsteiner's proposal).
9. Group O blood has both anti-A and anti-B, group A has anti-B only, group B has anti-A only, and
group AB has neither anti-A nor anti-B.

63
 10. Blood typing is done by slide technique, in which a blood sample is tested for agglutination with
anti-A and -B sera. The expected results are demonstrated in the table below.

Table 3-1. ABO characteristics of blood

Blood Red cell Plasma Reaction w/ Reaction w/

Genotypes Groups Agglutinogens Agglutinins Anti-A serum Anti-B serum
OO O None anti-A, anti-B (-) no clumping (-) no clumping
AA or AO A A anti-B only (+) clumping (-) no clumping
BB or BO B B anti-A only (-) no clumping (+) clumping
AB AB A and B none (+) clumping (+) clumping

11. Since a person's genotypes are contributions of both his biological mother and father, one can
have an idea of the parent's possible blood types once his blood type is known. If the parent's
blood types are known one can also determine the possible blood types of their children.
12. With this heredity principle in mind paternity determination is therefore possible with blood typ-
ing. For example a man with blood type O can never be a father to an AB child since he cannot
possibly supply either the A or the B gene.

B. The Rhesus Groups

1. Three genes, each commonly responsible for two alternate forms, determine the Rh genotype.
2. The commonly occuring factors (antigens) are C, D, and E or Rho, Rh, and Rh". By far the most
important is the gene D and when a person is said to be Rh-positive it is with reference to this
gene. Rh-negative means the red cell has no agglutinogen D.
3. The most common antibody seen in cases of hemolytic disease of the newborn is against D.
4. Unlike the ABO system, anti-D agglutinins are NOT NATURALLY present in the plasma of the
blood whose red cells have no D agglutinogens. But an Rh-negative person may develop anti-D
antibodies if exposed to D antigens previously.
5. Development of anti-D antibodies occur in the following conditions:
a. Transfusion of Rh-negative person with Rh-positive blood.
b. An Rh-negative woman bearing an Rh-positive child.

C. Blood Transfusion
1. Blood transfusion is indicated in:
a. Severe hemorrhage
b. Severe anemia
c. Thrombocytopenia
d. Blood clotting factors deficiencies

2. Hazards of blood transfusion include:

a. Incompatibility. Most cases of hemolytic reactions are due to ABO incompatibility.
b. Sensitization. An Rh negative person when given Rh-positive blood will develop anti-D anti-
bodies.
c. Pyrogenic reaction. This may be due to an immune response to the donor's blood proteins
and manifests as chills and fever.
d. Anaphylatic shock. This is due to massive histamine release as part of an allergic reaction.
e. Disease transmission. Hepatitis and AIDS virus can be transmitted to recipients.
f. Hyperkalemia. Stored blood may have high plasma potassium concentration as the red cells
age and hemolyse.
g. Hypocalcemia and tetany. This is due to the introduction of anticoagulants used to keep the
stored donor's blood fluid.

3. Transfusion of mismatched blood can cause renal shutdown.

a. Renal blood flow is compromised when toxic substances cause constriction of renal arterioles;
when widespread vasodilation produce hypotension; and when hemoglobin precipitates in
the tubules to cause blockage.
b. When the kidney fails anuria sets in and is followed by uremia due to the accumulation of ni-
trogenous substances in the blood.

D. Hemolytic Disease of the Newborn - Erythroblastosis Fetalis

1. This occurs when an Rh-negative woman bears an Rh-positive child. The Rh factor is inherited by
the child from the Rh-positive, biological father.
2. The mother develops anti-D antibodies (IgG type), which can cross the placental barrier and re-
act with the fetus's red cells to cause hemolysis.

64
 3. The severity of the hemolytic reaction increases with the number of pregnancies. The first and
second children usually do not suffer the disease.
4. The consequences of full blown HDN (erythroblastosis fetalis) include:
a. Anemia with severe reduction in hemoglobin level.
b. Jaundice. Yellowish discoloration of the skin due to elevated bili-rubin concentration in the
blood.
c. Hepatomegaly and spleenomegaly. The liver and spleen are activated to produce and release
into the blood a lot of red cells including nucleated blast cells. The observed erythroblasts in
the peripheral blood gave rise to the name of the disease.
d. Death
e. Permanent mental impairment in survivors. This is due to the precipitation of bilirubin in the
neuronal cells of the brain (kernicterus).
5. Prevention and Treatment of Erythroblastosis Fetalis
a. The injection of anti-D antibodies (RhoGam) to the mother within 36 to 72 hours of giving
birth reduces the incidence of Rh immunization in subsequent pregnancies.
b. The anti-D antibodies are intended to destroy the fetal red cells that managed to reach the
maternal circulation during delivery so that they will not evoke sensitization and anti-D anti-
bodies production.
c. Replacement of the infant's blood with Rh-negative blood by exchange transfusion will mini-
mize the rise of bilirubin level in the blood which is a consequence of hemolysis.

IV. LEUKOCYTES

A. Characteristics of leukocytes. Leukocytes are classified according to their structure and affinity for
dyes.
1. The polymorphonuclear granulocytes have multilobed nuclei and abundant granules. Three types
of granulocytes are seen. Those with granules that show no dye preference are called neutro-
phils, those that take up red eosin are called eosinophils, and those that take up basic dyes are
called basophils.
2. A fourth type of leukocyte is the monocyte and the fifth type is the lymphocyte.
3. All of the leukocytes are produced in the bone marrow.
a. The normal leukocyte count is 7000 cells per microliter of blood.
b. Neutrophils constitute 50 to 70 percent of the total leukocytes, lymphocytes 20 to 40 per-
cent, monocytes 2 to 8 percent, eosinophils 1 to 4 percent, and basophils 0.1 percent.
4. Neutrophils are phagocytic and release chemicals involved in inflammation. Phagocytosis is the
engulfment of particulate materials (eg. microbes) by endocytosis and their destruction inside the
phagocyte.
a. Neutrophils during inflammation stick to the inner surface of the capillary endothelium
(margination) in the infected area. They form pseudopodia which allow them to move
(ameboid movement).
b. These projections can insinuate through spaces between two endothelial cells (diapedesis)
and soon thereafter the entire neutrophil squeezes through the capillary wall and into the
interstitium.
c. The entire process starting with margination is called chemotaxis and any mediator that
causes it is called chemotaxin.
d. Chemical factors produced in the body can bind the phagocyte to microbes and markedly en-
hances phagocytosis. These factors are called opsonins and the process is termed
opsonization.
5. Basophils are precursors of tissue mast cells. They release histamine and other chemicals in-
volved in inflammation.
6. Eosinophils are weak phagocytes that destroy parasitic worms. They proliferate and migrate to
tissues in which allergic reactions have occured.
7. Monocytes are precursors of tissue macrophages and functions like macrophages while in the
blood.
8. Macrophages are phagocytic cells found in virtually all tissues (the first line of defense in
inflammation). They process and present antigens to lymphocytes. Macrophages also secrete
protein messengers such as interleukin 1 and tumor necrosis factor (monokines) involved in in-
flammation, activation of helper T cells, and systemic responses to infection or injury (the acute
phase response).

V. IMMUNOLOGY

A. Cells Mediating Immune Responses

1. Immune responses may be nonspecific, in which the identity of the target is not recognized, or
specific, in which it is recognized.

65
 2. The cells of the immune system are leukocytes (neutrophils, eosinophils, basophils, monocytes,
and lymphocytes), plasma cells, macrophages, macrophage-like cells, and mast cells. The leuko-
cytes use the blood for transportation but function mainly in the tissues.
3. Cells of the immune system (as well as some other cells) secrete protein messengers that regu-
late immune responses and are collectively termed cytokines.

Table 5-1. Cells Mediating Immune Defenses

Name Site produced

Leukocytes (white blood
cells) Bone marrow
Neutrophils Bone marrow
Basophils Bone marrow
Eosinophils Bone marrow
Monocytes Bone marrow, thymus, and peripheral lymphoid organs
Lymphocytes
B cells
T cells
Cytotoxic T cells
Helper T cells
? Suppressor T
cells
NK cells
Plasma cells Peripheral lymphoid organs differentiate from B lymphocytes during immune
responses
Macrophages Almost all tissues and organs differentiate from monocytes
Macrophage-like cells Dendritic cells are produced in almost all tissues, and microglia in the central
nervous system
Mast cells Almost all tissues and organs; differentiate from bone marrow cells

B. Nonspecific Immune Responses

1. External barriers to infection are the skin, anti-microbial chemicals in glandular secretions,
the linings of the respiratory and GI tracts, and the cilia of these linings.

2. Inflammation, the local inflammatory response to injury or infection, includes vasodilation, in-
creased vascular permeability to protein, phagocyte chemotaxis, destruction of the invader via
phagocytosis or extracellular killing, and tissue repair.
a. The mediators controlling these processes are either released from cells or from plasma pro-
teins. They are summarized in the table below.

Table 5-2. Inflammatory mediators.

Mediator Source

Kinins Plasma proteins

Complement Plasma proteins
Products of blood clotting Plasma proteins
Histamine Mast cells
Eicosanoids Many cell types
Platelet-activating factor Many cell types
Cytokines, including chemokines. Monocytes, macrophages, neutrophils, lympho-
Examples are interleukin 1, tumor necrosis fac- cytes, and several nonimmune cell types, includ-
tor, and interleukin 6 ing endothelial cells and fibroblasts
Lysosomal enzymes, nitric oxide, and other oxygen Neutrophils and macrophages
derived substances

b. The cells that function as phagocytes are neutrophils, monocytes, macrophages and macro-
phage-like cells. They also secrete many inflammatory mediators.
c. One group of inflammatory mediators--the complement family of plasma proteins, activated
during nonspecific inflammation by the alternate pathway--not only stimulates many of the
steps of inflammation but, mediates extracellular killing via its membrane attack complex
(MAC).
d. The sequence of events in a local inflammatory response to bacteria occurs in the following
manner.
(1) Initial entry of bacteria into tissue.
(2) Vasodilation of the microcirculation in the infected area, leading to increased blood flow
(3) Marked increase in protein permeability of the capillaries in the infected area, with re-
sulting diffusion of protein and filtration of fluid into the interstitial fluid, causing edema

66
 (4) Chemotaxis: exit of leukocytes into the interstitial fluid of the infected area.
(5) Destruction of bacteria in the tissue either through phagocytosis or by mechanisms not
requiring prior phagocytosis.
(6) Tissue repair.
e. Manifestations of inflammation are local redness, swelling, heat, and pain.
f. The end result of infection or tissue damage is complete repair, with or without a scar, or
formation of a granuloma.

3. Interferon stimulates the production of intracellular proteins that nonspecifically inhibit viral repli-
cation.

C. Specific Immune Defenses

1. Lymphocytes mediate specific immune responses.

2. Specific immune responses occur in three stages (see figure 5-1).
a. A lymphocyte programmed to recognize a specific antigen encounters it and binds to it via
plasma-membrane receptors specific for the antigen.
b. The lymphocyte undergoes activation-a cycle of cell divisions and differentiation.
c. The multiple active lymphocytes produced in this manner launch an attack all over the body
against the specific antigens that stimulated their production.
3. The lymphoid organs are categorized as primary (bone marrow and thymus) or secondary (lymph
nodes, spleen tonsils, and lymphocyte collections in the linings of the body's tracts).
a. The primary lymphoid organs are the sites of maturation of lymphocytes that will then be
carried to the secondary lymphoid organs, which are the major sites of lymphocyte cell divi-
sion and specific immune responses.
b. Lymphocytes undergo a continuous recirculation among the secondary lymphoid organs,
lymph, blood, and all the body's organs and tissues.

Figure 5-1. Summary of roles of B, cytotoxic T, and helper T cells in immune responses. The two other
less well understood lymphocyte populations are suppressor T cells, which inhibit B cells and cytotoxic T
cells, and NK cells, which function similarly to cytotoxic T cells.

4. The three broad populations of lymphocytes are B, T, and NK cells.

a. B cells mature in the bone marrow and are carried to the secondary lymphoid organs, where
additional B cells arise by cell division.
b. T cells leave the bone marrow in an immature state, are carried to the thymus and undergo
maturation there. These cells then travel to the secondary lymphoid organs and new T cells
arise from them by cell division.
c. NK cells originate in the bone marrow.
5. B cells and T cells have different functions.
a. B cells, upon activation, differentiate into plasma cells, which secrete antibodies. Antibody-
mediated responses constitute the major defense against bacteria, viruses, and toxins in the
extracellular fluid.
b. Cytotoxic T cells directly attack and kill virus-infected cells and cancer cells, without participa-
tion of antibodies.
c. Helper T cells stimulate B cells and cytotoxic T cells via the cytokines they secrete. With few
exceptions, this help is essential for activation of the B cells and cytotoxic T cells.

67
 6. B cell surface plasma membrane receptors are copies of the specific antibody (immunoglobulin)
that the cell is capable of producing.
a. Any given B cell or clone of B cells produces antibodies with a unique antigen binding site.
b. Antibodies are composed of four interlocking polypeptide chains; the variable regions of the
antibodies are the sites that bind antigen.
7. T cell surface plasma-membrane receptors are not immunoglobulins, but they do have specific
antigen binding sites that differ from one T cell clone to another.
a. The T-cell receptor binds antigen only when the antigen is complexed to one of the body's
own plasma-membrane major histocompatibility complex (MHC) proteins.
b. Class I MHC proteins are found on all nucleated cells of the body, whereas class II MHC pro-
teins are found only on macrophages, B cells, and macrophage-like cells.
(1) Cytotoxic T cells require antigen to be complexed to class I proteins.
(2) Helper T cells require class II proteins.
8. Antigen presentation is required for T cell activation.
a. Only macrophages, B cells, and macrophage-like cells function as antigen-presenting cells
(APCs) for helper T cells. The antigen is internalized by the APC and hydrolyzed to peptide
fragments, which are complexed with class II MHC proteins. This complex is then shuttled to
the plasma membrane of the APC, which also delivers a nonspecific costimulus to the cell and
secretes interleukin 1.
b. A virus-infected cell or cancer cell can function as an APC for cytotoxic T cells. The viral anti-
gen or cancer-associated antigen is synthesized by the cell itself and hydrolyzed to peptide
fragments, which are complexed to class I MHC proteins. The complex is then shuttled to the
plasma membrane of the cell.

9. NK cells have the same targets as cytotoxic T cells, but they are not antigen-specific; their mech-
anism of target identificationis not understood.
10. Immune tolerance is the result of clonal deletion and clonal inactivation.
11. In antibody-mediated responses, the membrane receptors of a B cell bind antigen, and at the
same time a helper T cell also binds antigen in association with a class II MHC protein on a mac-
rophage or other APC (see figure 5-2).
a. The helper T cell, activated both by the antigen and by IL-1 secreted by the APC, se-
cretes IL-2, which then causes the helper T cell to proliferate into clone of cells that secrete
additional cytokines.
b. These cytokines then stimulate the antigen-bound B cell to proliferate and differentiate into
plasma cells, which secrete antibodies. Some of the activated B cells become memory cells,
which are responsible for active immunity.
c. There are five major classes of secreted antibodies: IgG, IgM, IgA, IgD, and IgE. The first
two (IgG and IgM) are the major antibodies against bacterial and viral infection.
d. The secreted antibodies are carried throughout the body by the blood and combine
with antigen. The antigen-antibody complex enhances the inflammatory response mainly by
activating the complement system. Complement proteins mediate many steps of inflamma-
tion, act as opsonins, and directly kill antibody-bound cells via the membrane attack complex.
e. Antibodies of the IgG class also act directly as opsonins and also link target cells to NK cells,
which directly kill target cells.
f. Antibodies also neutralize toxins and extracellular viruses.

68
Figure 5-2. Summary of events by which a bacterial infection leads to antibody synthesis in peripheral
lymphoid organs and the secreted antibodies travel by the blood to the site of infection where they bind
to bacteria of the type that induced the response.

12. Virus-infected cells and cancer cells are killed by cytotoxic T cells, NK cells, and activated macro-
phages (see figure 5-3).
a. A cytotoxic T cell binds, via its membrane receptor, to cells bearing a viral antigen or cancer-
associated antigen in association with a class I MHC protein.
b. Activation of the cytotoxic T cell also requires cytokines secreted by helper T cells, them-
selves activated by antigen presented by a macrophage. The cytotoxic T cell then releases
perforin, which kills the attached target cell by making it leaky.
c. NK cells and macrophages are also stimulated by helper T cell cytokines, particularly IL-2 and
interferon-gamma, to attack and kill virus-infected or cancer cells.

D.
1. The body's capacity to resist infection is influenced by nutritional status, the presence of
other diseases, psychological factors, and the intactness of the immune system.
2. AIDS is caused by a retrovirus that destroys helper T cells and therefore reduces the
ability to resist infection and cancer.
3. Antibiotics interfere with the synthesis of macromolecules by bacteria.

Figure 5-3. Summary of events in the killing of virus-infected cells by cytotoxic T cells. The released virus
can then be phagocytized. The sequence would be similar if the inducing cell were a cancer cell rather
than a virus-infected cell.

E. Harmful Immune Responses

1. Rejection of tissue transplants is initiated by MHC proteins on the transplanted cells and is medi-
ated mainly by cytotoxic T cells.
2. Transfusion reactions are mediated by antibodies.
a. Transfused erythrocytes will be destroyed if the recipient has natural antibodies against the
antigens (type A or type B) on cells.
b. Antibodies against Rh-positive erythrocytes can be produced following exposure of an Rh-
negative person to such cells.
3. Allergy (hypersensitivity reactions), caused by allergens, is of several types.

69
 a. In delayed hypersensitivity, the inflammation is due to the interplay of helper T cell cytokines
and macrophages. Immune complex hypersensitivity is due to complement activation by an-
tigen-antibody complexes.
b. In immediate hypersensitivity, antigen binds to IgE antibodies, which are themselves bound
to mast cells. The mast cells then release inflammatory mediators such as histamine that
produce the symptoms of allergy. The late phase of immediate hypersensitivity is mediated
by eosinophils.
4. Autoimmune Disease
a. The body does not normally attack its own tissues because clones of lymphocytes bearing re-
ceptors against proteins found in the body are either destroyed early in life or sup-
pressed.
b. Under abnormal circumstances, antibodies or killer cells can attack normal tissues and
produce autoimmune disease.
c. Excessive inflammation and immune-complex disease can also cause destruction of normal
body tissues.

VI. HEMOSTASIS: PREVENTION OF BLOOD LOSS

A. Major Events of Hemostasis

1. The initial response to blood-vessel damage is vasoconstriction and sticking together of the op-
posed endothelial surfaces.
2. The next events are formation of a platelet plug followed by blood coagulation (see figure 6-1).

Figure 6-1. Sequence of events leading to vasoconstriction

and formation of a platelet plug following damage to a
blood-vessel wall. Note the two positive feedbacks in the
pathways.

B. Formation of a Platelet Plug

1. Platelets adhere to exposed collagen in a damaged
vessel and release the contents of their secretory
vesicles.
a. These substances help cause platelet activation
and aggregation.
b. This process is also enhanced by von Willebrand
factor, secreted by the endothelial cells, and by
thromboxane A2, produced by the platelets.
c. Fibrinogen forms the bridges between aggre-
gating platelets.
d. Contractile elements in the platelets compress
and strengthen the plug.

2. The platelet plug does not spread along normal en-

dothelium because the latter secretes prostacyclin,
which inhibits platelet aggregation.

C. Blood Coagulation: Clot Formation

1. Blood is transformed into a solid gel when, at the
site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which bind to each
other to form a mesh.
2. This reaction is catalyzed by the enzyme thrombin, which also activates factor XIII, a plasma pro-
tein that stabilizes the fibrin meshwork.
3. The formation of thrombin from the plasma protein prothrombin is the end result of a cascade of
reactions in which an inactive plasma protein is activated and then enzymatically activates the
next protein in the series.
a. Thrombin exerts a positive feedback stimulation of the cascade by activating platelets and
several clotting factors.
b. Activated platelets, which display platelet factor and binding sites for several activated plas-
ma factors, are essential for the cascade.
4. In the body, the cascade usually begins via the extrinsic clotting pathway when tissue factor
forms a complex with factor VIIa. This complex activates factor X, which then catalyzes the con-
version of small amounts of prothrombin to thrombin. This thrombin then recruits the intrinsic
pathway by activating factor XI and factor VIII, as well as platelets, and this pathway (intrinsic)
then generates a larger amount of thrombin.
a. In the intrinsic clotting pathway, the cascade begins with the activation of factor XII by con-
tact with collagen underlying a damaged vessel. Factor XIIa then catalyzes the activation of
factor XI to factor XIa, which activates factor IX to factor IXa. This last factor then activates
70
 factor X to factor Xa, which is the enzyme that converts prothrombin to thrombin (see Figure
6-2).
b. The thrombin that is rapidly formed via the extrinsic pathway, however, is enough to drive
the intrinsic pathway to completion by activating factors XI and VIII and the platelets (indi-
cated by the arrow proceeding from thrombin in the diagram in Figure 6-1). In essence, the
thrombin produced via the extrinsic pathway eliminates the need for factor XII.
c. Both calcium and a platelet phospholipid PF3, are required at several steps in the cascade.

5. The inactive plasma proteins fibrinogen, prothrombin, labile factor (factor V), stable factor
(factor VII), plasma thromboplastin component (factor IX), and Stuart-Prower factor (factor X)
are synthesized in the liver.
6. Vitamin K is required by the liver for the synthesis of the plasma proteins serving as precursors
for factors II, VII, IX, and X (Vitamin K dependent factors).

Figure 6-2. Two clotting pathways called intrinsic and extrinsic merge and can lead to the generation
of thrombin. Under most physiological conditions, however, factor XII and the contact activation step that
begin the intrinsic pathway probably play little, if any roles in clotting. Rather clotting is initiated solely by
the extrinsic pathway.

D. Maintenance of Blood Fluidity

1. Spontaneous clotting of blood is prevented by:
a. Smoothness of vascular endothelium
b. Negatively charged endothelial surface
2. Circulating anticoagulants which limit clotting are:
a. Fibrin threads which has antithrombin action by adsorbing thrombin
b. Antithrombin III (antithrombin-heparin co-factor) which binds to heparin on endothelial cells
and inactivates thrombin.
c. Heparin which by itself has minimal anticoagulant property, but when it combines with
antithrombin III the effectiveness of antithrombin III is increased a thousandfold.
d. Alpha2-Macroglobulin which binds many coagulation factors so that they cannot participate in
clotting.

E. Lysis of Blood Clots

1. Clots are dissolved by the fibrinolytic system, in which the plasma proenzyme, plasminogen, is
activated by plasminogen activators to plasmin, which digests fibrin.
2. Tissue plasminogen activator or t-PA is secreted by endothelial cells and is activated by fibrin in a
clot.
3. Thrombin inactivates a plasma inhibitor of tissue plasminogen activator.
4. Lysis of clot allows slow clearing of extraneous clotted blood once clotting has served its physio-
logic usefulness.

71
F. Conditions with Bleeding Tendencies
1. Liver disease
2. Vitamin K deficiency
3. Classical hemophilia due to Factor VIII deficiency
4. Parahemophilia due to Factor IX and Factor XI deficiency
5. Thrombocytopenia leads to spontaneous bleeding when platelet concentration is below
50,000/cubic mm and is characterized by capillary fragility and easy bruisability (petechiae, ec-
chymosis, and purpura).

G. Excessive Clotting Tendencies

1. Thromboembolism may be caused by overactivity of the clotting system or underactivity of the
plasmin system; injury or inflammation of the veins (thrombophlebitis); and blood stasis.
2. A thrombus is a solid mass (e.g. clot) in the heart or vessel.
3. An embolus is a detached clot which flows with the blood and may obstruct small vessels (e.g.
pulmonary embolism)
4. Thromboembolism is treated with anticoagulants.
a. Heparin which acts immediately. It is inactivated by protamine.
b. Coumarin which inhibits the synthesis of vitamin K-dependent factors but produces its effect
only 12 hours after administration.

NERVOUS SYSTEM
I. THE AUTONOMIC NERVOUS SYSTEM

A. Two Divisions.
1. Sympathetic Nervous System
2. Parasympathetic Nervous System

B. Sympathetic Division.
1. Physiologic Anatomy
a. Made up of preganglionic and postganglionic neurons (in series).
b. Cell bodies of preganglionic neurons lie in intermediolateral horn of the T1 to L2 segment of
the spinal cord (thoracolumbar outflow)
c. Postganglionic neurons originate in either the:
(1) sympathetic chain ganglia or
(2) prevertebral ganglia (eg. celiac, messenteric ganglia)
d. Preganglionic fiber is shorter than postganglionic fiber

2. Physiologic Characteristics
a. Preganglionic fibers secrete acetylcholine (cholinergic fibers).
b. Most postganglionic fibers secrete norepinephrine (adrenergic) which binds to alpha and beta
receptors found on membranes of many cells
c. A few postganglionic fibers secrete acetylcholine (cholinergic) supplying thermoregulatory
sweat glands and blood vessels of skeletal muscles. The acetylcholine binds to muscarinic re-
ceptors producing:
(1) dilation of blood vessels
(2) increased sweating
d. Some preganglionic fibers end directly on cells of adrenal medulla which in turn secrete epi-
nephrine (80%) and norepinephrine (20%)
e. Neurotransmitter of postganglionic adrenergic neurons is norepinephrine
f. Synthetic steps of norepinephrine in adrenergic neurons
(1) Tyrosine hydroxylated to DOPA
(2) DOPA decarboxylated to Dopamine (transported to vesicles)
(3) Dopamine hydroxylated to Norepinephrine

In the adrenal medulla steps 1, 2, and 3 occur followed by one more step i.e.
(4) Norepinephrine methylated to Epinephrine
g. Norepinephrine (NE) is removed from its action site by:
(1) active reuptake by the nerve endings (50 to 80%)
(2) diffusion away from tissues and into the blood (20 - 40%)
(3) Monoamine oxidase (MAO) in nerves and Catechol-O-methyl transferase (COMT) in liver
destroy some of the NE
h. Mainly concerned with exercise, stress, and fight-or-flight conditions (see table 1-3 at the end
of this section).

Table 1-1. Characteristic of some important adrenoceptors in the ANS.

72
 3. Receptor Types in the Sympathetic Nervous System (see Table 1-1).
a. Adrenergic receptors
(1) 1 receptors:
(a) are located on smooth muscle (except bronchial smooth muscle).
(b) produce excitation
(c) are equally sensitive to norepinephrine and epinephrine, but only norepinephrine is
present in concentrations that are high enough to activate receptors.
(d) when activated leads to the formation of inositol triphosphate (IP3) and increase in
intracellular [Ca++].
(2) 2 receptors:
(a) are located in presynaptic nerve terminals, platelets, fat cells, and smooth muscle
(b) often produce inhibition
(c) when activated leads to inhibition of adenylate cyclase and decrease in cAMP)
(3) 1 receptors:
(a) are located in the heart and fat cells
(b) produce excitation
(c) are sensitive to both norepinephrine and epinephrine, and are more sensitive than
the receptors
(d) when activated leads to activation of adenylate cyclase and increase in cAMP
(4) 2 receptors:
(a) are located on vascular smooth muscle, bronchial smooth muscle, and in the GIT.
(b) produce relaxation
(c) are more sensitive to epinephrine than to norepinephrine
(d) are more sensitive to epinephrine than is the receptor. Thus when small amounts
of epinephrine are released from the adrenal medulla, vasodilation ( 2) occurs;
when larger amounts of epinephrine are released from the adrenal medulla, vaso-
constriction ( ) occurs.
(e) when activated leads to activation of adenylate cyclase and increase in cAMP

4. Pharmacology
a. Examples of drugs acting on adrenergic receptors (sypathomimetics)
(1) Norepinephrine and epinephrine
(2) Phenylephrine - alpha receptor agonist
(3) Isoproterenol - beta1 and beta2 receptor agonist
(4) Albuterol - beta2 selective agonist
b. Drugs that cause release of norepinephrine (indirect agonists)
(1) Ephedrine
(2) Tyramine
(3) Amphetamine
c. Drugs that block adrenergic activity (sympatholytics)
(1) Reserpine - blocks synthesis and storage of NE
(2) Guanethidine - blocks release of NE
(3) Phenoxybenzamine & phentolamine - alpha-blockers
(4) Propranolol and metoprolol - beta-blockers

C. PARASYMPATHETIC DIVISION

1. Physiologic Anatomy
a. Made up of preganglionic and postganglionic neurons (in series)
b. Preganglionic fibers originate either from:
(1) cranial nerve nuclei of CN III, VII, IX, X or
(2) lateral horn cells located in S2-S4 segment of spinal cord
(3) a and b comprise the cranio-sacral outflow
c. Postganglionic fibers originate from:
(1) ciliary ganglion to supply pupillary sphincter (circular muscle) and ciliary muscle of the
eye (CN III)
(2) sphenopalatine ganglion to supply the lacrimal gland (CN VII)
(3) submandibular ganglion to supply the salivary gland (CN VII)
73
 (4) otic ganglion to supply the parotid gland (CN IX)
(5) terminal ganglia located within the visceral organs supplied by the vagus (CN X)
(6) terminal ganglia located within the visceral organs supplied by the pelvic nerves
d. Preganglionic fibers are longer than postganglionic fibers.

2. Physiologic Characteristics
a. Both pre- and postganglionic fibers secrete acetylcholine (cholinergic)
b. Does not supply sweat glands, blood vessels (except the external genitalia), and hair follicles.
c. Primarily concerned with restorative and vegetative functions such as digestion and rest (see
1-3 at the end of this section).

Table 1-2. Characteristics of the most important cholinergic receptors in the ANS.

3. Cholinergic receptors (see table 1-2).

a. Nicotinic receptors:
(1) are located in autonomic ganglia and at the neuromuscular junction. The receptors at
the two locations are similar but not identical.
(2) are activated by acetylcholine (Ach) or nicotine
(3) produce excitation
(4) ganglionic blockers (e.g. hexamethonium, trimethaphan) block the nicotinic receptor for
ACh in the autonomic ganglia but not at the neuromuscular junction
(5) are ion channels for Na+ and K+

b. Muscarinic receptors:
(1) are located in the heart, smooth muscle (except vascular smooth muscle), and glands
(2) are activated by ACh or muscarine
(3) are inhibitory in the heart (by inhibition of adenylate cyclase and opening of K + channels
and excitatory in smooth muscle and glands (by formation of IP3 and increase in intra-
cellular [Ca++]
(4) are blocked by atropine

5. Pharmacology
a. Parasympathomimetics acting on muscarinic receptors (agonists)
(1) Pilocarpine - a miotic and ciliary muscle stimulant (contraction for near vision)
(2) Methacholine
b. Anticholinesterase drugs (indirect acting agonists)
(1) Neostigmine
(2) Pyridostigmine
c. Antimuscarinic drugs (muscarinic blockers)
(1) Atropine
(2) Scopolamine
(3) Dicycloverine

74
Table 1-3. Direct effects of autonomic nerve activity and autonomic drugs on some organ sys-
tems.

75
 II. SPECIAL SENSES

A. Taste and Olfaction.

1. The receptors for taste lie in the taste buds throughout the mouth, principally on the tongue.
a. The cells composing the taste buds are innervated by the glossopharyngeal and facial nerves.
b. A particular taste bud is most sensitive to one of the four taste modalities: sweet, sour, bit-
ter, and salty.
c. Taste buds most sensitive to one modality are located in particular regions of the tongue;
(sweet at tip, sour at sides, bitter at back, and salty over most of the tongue).

2. Olfactory receptors, which are part of the afferent olfactory neurons (CN I), lie in the mucosa in
the upper nasal cavity.
a. Odorant molecules, once dissolved in the mucus, are transported to the receptors by odorant
binding proteins.
b. Olfactory pathways go to the limbic system.

B. Vision

1. Light is described by its wavelength or frequency.

2. Convex lens converges, whereas concave lens diverges light rays.
3. Light enters the cornea, passes through the pupil, and then through the lens, from which it is
projected to the retina.
a. Light rays are refracted by the cornea and lens.
b. Because of refraction, the image on the retina is upside down and right to left.
c. The right half of the visual field is projected to the left half of the retina in each eye, and vice
versa.
d. Lesions in the different parts of the visual pathway manifest visual field defects.

Figure 2-1. Visual pathways. Transection of

the pathways at the sites indicated by the
letters causes the visual field defects shown
in the diagrams on the right.

4. Accomodation is the ability to main-

tain a focus on the retina when the
distance between the object and the
eyes is changed. Accomodation is
produced by changes in the shape
and refractive power of the lens.
a. When the muscles of the ciliary
body are relax-ed, the suspenso-
ry liga-ment is tight and the lens
is in its least convex form. The

for distance vi-sion.

b. As an object is brought closer
than 20 feet from the eyes, the
ciliary body contracts, the sus-
pensory ligaments becomes less
tight, and the lens becomes
more convex and adapted for
near vision.

5. Visual acuity refers to the sharpness of the image and depends in part on the ability of the lens
to bring the image to a focus on the retina.
a. People with myopia have an eyeball that is too long, so that the image is brought to a focus
in front of the retina; this is corrected by a concave lens.
b. People with hyperopia have an eyeball that is too short, so that the image is brought to a fo-
cus behind the retina; this is corrected by a convex lens.
c. Astigmatism is the uneven refaction of light around 360 degrees of a circle, caused by une-
ven curvature of the cornea and/or lens.

76
 Figure 2-2. Organization of the retina. Photoreceptors converge on bipolar cells, which converge
on ganglion cells. All of the receptors that convey information to a ganglion cell are part of that

6. The retina contains rods and cones. The photopigments of the rods and cones are made up of a
protein component (opsin) and a chromophore.
a. When light strikes the rods, it causes the photodissociation of rhodopsin into retinene and
opsin (bleaching reaction).
b. Photodissociation is caused by the conversion of the 11-cis to the all-trans form of retinene,
which cannot bond to opsin.
c. In the dark, more rhodopsin can be produced and contained in the rods, so that the eyes be-
come more sensitive to light; this is responsible for one component of dark adaptation.
d. The rods provide black-and-white vision under conditions of low light intensity; at higher light
intensity the rods are bleached out and the cones provide color vision.
e. In the dark, there is constant movement of Na into the rods and rods are depolarized (dark
current) and release their neurotransmitter.
f. When light causes the dissociation of rhodopsin, the Na+ channels become blocked and the
rods become hyperpolarized in comparison to their membrane potential in the dark. Hyperpo-
larization of the rods results in their release of less neurotransmitter at their synapses with
bipolar cells.
g. The rods and cones synapse on bipolar cells, which synapse on ganglion cells.
(1) Ganglion cell axons form the optic nerves, which lead to the brain.
(2) Half the optic nerve fibers cross to the opposite side of the brain in the optic chiasm. Fi-
bers from the optic nerves terminate in the lateral geniculate nuclei of the thalamus,
which send fibers to visual cortex.
(3) Visual information is also relayed to areas of the brain dealing with biological rhythms.
(4) Some fibers from the ganglion cells, instead of synapsing in the geniculate body syn-
apse in the superior colliculus of the midbrain, which controls eye movements. This
tectal system enables the eyes to move and track an object; it is also responsible for the
pupillary reflex and the changes in lens shape that are needed for accomodation.
h. According to the trichomatic theory of color vision, there are three systems of cones, each of
which responds to one of three colors; red, blue, and green.
i. The colors we perceive are related to the wavelength of light. Different wavelengths excite
one of the three cone photopigments most strongly.
j. The fovea centralis contains only cones; more peripheral parts of the retina contain both
cones and rods.
k. Each cone in the fovea synapses with one bipolar cell, which in turn synapses with one gan-
glion cell.
(1) The ganglion cell that receives input from the fovea thus has a visual field equal to only
that part of the retina which activated its cone.
(2) As a result of this 1:1 ratio of cones to bipolar cells, visual acuity is high in the fovea but
sensitivity to low light levels is less than in other regions of the retina.
l. In other regions of the retina, where rods predominate, there are a large number of rods that
provide input to each ganglion cell (there is great convergence); visual acuity, as a result, is
impaired, but sensitivity to low light levels is improved.

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 7. Six skeletal muscles control eye movement.
a. Scan the visual field for objects of interest.
b. Keep the fixation point focused on the fovea centralis despite movements of the object or
head.
c. Prevent adaptation of the photoreceptors.
d. Move the eyes during accommodation.

8. Individual extraocular muscles have different functions in moving the eyeball (see Table below).

MUSCLE DIRECTION INNERVATION

Internal rectus Inward III (Oculomotor)
External rectus Outward VI (Abducens)
Superior rectus Up and In III (Oculomotor)
Inferior rectus Down and In III (Oculomotor)
Superior oblique Down and IV (Trochlear)
Inferior oblique Out III (Oculomotor)
Up and Out

C. Hearing

1. Sound energy is transmitted by movements of pressure waves.

a. The sound wave frequency determines pitch.
b. The sound wave amplitude determines loudness.

2. The outer ear funnels sound waves of a given frequency (measured in hertz) and intensity
(measured in decibels) to the tympanic membrane, causing it to vibrate.

Figure 2-3. Sounds of low frequency cause pressure waves of perilymph to pass through the
gh the cochlear
duct. This causes displacement of the basilar membrane, which is central to the transduction of
sound waves into nerve impulses.

3. Vibrations of the tympanic membrane cause movement of the ossicles-malleus, incus, and sta-
pes-which in turn produces vibrations of the oval window of the cochlea.

4. Vibrations of the oval window set up a travelling wave of perilymph in the scala vestibuli.
a. This wave can pass around the helicotrema to the scala tympani, or it can reach the scala
tympani by passing through the scala media (cochlear duct).
b. The scala media is filled with endolymph.
(1) The membrane of the duct facing the scala vestibuli is called the vestibular membrane.
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 (2) The one facing the scala tympani is called the basilar membrane.

5. The sensory structure of the cochlea is called the organ of Corti.

a. The organ of Corti consists of sensory hair cells on the basilar membrane.
(1) The hairs of the hair cells project upward into an overhanging tectorial membrane.
(2) The hair cells are innervated by the vestibulocochlear (VIII) nerve.
b. Sounds of high frequency cause maximum displacement of the basilar membrane closer to its
base near the stapes; sounds of lower frequency produce maximum displacement of the
basilar membrane closer to its apex near the helicotrema.

6. Displacement of the basilar membrane causes the hairs to bend against the tectorial membrane
and stimulate the production of nerve impulses.

7. Pitch discrimination is thus dependent on the region of the basilar membrane that vibrates maxi-
mally to sounds of different frequencies.

D. Vestibular Apparatus and Equilibrium

1. The structures for equilibrium as well as for hearing are located in the inner ear in the membra-
nous labyrinth.
a. The structure involved in equilibrium, known as the vestibular apparatus, consists of the
otolith organs (utricle and saccule) and the semicircular canals.
b. The utricle and saccule provide information about linear acceleration, whereas the semicircu-
lar canals provide information about angular acceleration.
c. The sensory receptors for equilibrium are hair cells that have stereocilia and one kinocilium.
(1) When the stereocilia are bent in the direction of the kinocilium, the cell membrane be-
comes depolarized.
(2) When the stereocilia are bent in the opposite direction, the membrane becomes hy-
perpolarized.

2. The hairs of the hair cells in the utricle and saccule protrude into the endolymph of the membra-
nous labyrinth and are embedded within a gelatinous otolith membrane.
a. When the person is upright, the hairs of the utricle are oriented vertically and those of the
saccule are oriented horizontally.
b. Linear acceleration causes a shearing force between the hairs and the otolith membrane,
thus bending the hairs and electrically stimulating the sensory endings.

3. The three semicircular canals are oriented at right angles to each other, like the faces of a cube.
a. The hair cells are embedded within a gelatinous membrane called the cupula, which projects
into the endolymph.
b. Movement along one of the planes of a semicircular canal (angular acceleration) causes the
endolymph to bend the cupula and stimulate the hair cells.
c. Stimulation of the hair cells in the vestibular apparatus activates sensory neurons of the
vestibulocochlear nerve, which projects to the cerebellum and the vestibular nuclei of the
medulla oblongata.
(1) The vestibular nuclei in turn send fibers to the oculomotor center, which controls eye
movements.
(2) Spinning and then stopping abruptly can thus cause oscillatory movements of the eyes
called nystagmus.

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(3) When a person seated on a revolving chair is rotated, the endolymph in his semicircu-
lar canals flow; first in the direction opposite to the rotation, then in the direction of
the rotation. This biphasic movement produces certain reflex responses and certain
sensations. These are nystagmus, vertigo, and post-rotating reactions.

(a) Nystagmus: During the rotation the eyes fix upon, and keep in view, a certain
object; the eyes, therefore move in the direction opposite to that of the body (the
so called "slow component" of nystagmus). When the eyes have turned as far as
possible and the object can no longer be seen, the eyes quickly move in the direc-
tion of the body rotation (the so called "quick component" of nystagmus) and fix-
ate another object, and thus the process is repeated. On stopping the rotation,
the nystagmus reverses its directions. This is due to inertia of the endolymph.

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(b) Vertigo: The sensation of moving in space (even when the body is still!) after the
rotation has stopped is also due to the inertia of endolymphatic flow. This leads to
compensatory movements in the opposite direction.
(c) Post-rotating reactions: These are manifested by pointing error, falling, and nau-
sea.

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