VISION
● The eyes are composed of:
○ An optical component, which focuses
the visual image on the receptor cells
○ Neural component, which transforms the
visual image into a pattern of graded
and action potentials
Light
● Greater frequency, greater energy
● Shorter wavelength, greater energy
● Visible light roughly 400 nm- 700 nm
○ Red longest wavelength
○ Violet shortest wavelength
Anatomy of the eye
● Conjunctiva
○ Thin membrane covering the eye
○ Protection of the anterior portion of the
eye
○ Conjunctivitis— inflammation
● Sclera
○ White portion of the eye
● Cornea
○ Dome-shaped structure
○ Highest refractive index of all the
structures of the eye
○ Can bend rays at the acutest angle
○ Made up of dense transparent tissue
○ Uniconvex lense
○ Direction of refraction is converging
○ Middle portions streamlined because
there is no bending of the surface
○ Highest bending on the distal portion of
the cornea near the sclera
○ Focal point
○ Astigmatism— error in refraction
● First chamber/ Anterior chamber
○ Cornea to lens
○ Made up of substances called aqueous
humor
■ Exerts effort in the eye
■ If secreted in large volumes will
lead to glaucoma
○ Iris— gives color to the eye, no
physiological factor
○ Iris muscles connected to the ciliary
muscles
○ Ciliary muscles has zonular ligaments
that supports the lens
○ Lens more crystalline than the cornea
○ Lens is biconvex
○ Lens is very important in
accommodation
○ Center portion (proteinaceous material)
degenerates the most
■ Becomes the condition called
the cataract
○ Recti muscles need for convergence
■ Medial rectus contracted
■ Lateral rectus
■ Relaxed
○ Pupillary constriction
■ Radial sphincter muscle of the
iris is stimulated by
parasympathetic nerve
■ Zonular ligaments relaxed
■ Lens becomes more spherical
■ More bending/ convergence of
light rays
1
 ■ Focal point becomes nearer to The Optics of Vision: Refraction
the anterior portion
■ Hitting the fovea centralis for
more acute vision
○ In a relaxed state lens are stretched (flat
but still convex)
○ If the cornea is not that smooth, the
laser will correct
○ Laser will coagulate any bleeding inside
the eye
● Second chamber/ Posterior chamber
○ Inner portion of lens to retina
○ Vitreous humor
■ Made up of proteinaceous
material ● Retina puts it in invert position but perception
■ Hyaluronic acid corrects it to upright
○ From the vitreous humor, to the retina
■ Neuroepithelial portion of the
eye
■ Choroid layer
● Layer continuous to the
eyelid
● Has pigments
■ Retinal blood vessels
● Originate from the area
of the optic nerve
■ Optic disc
● Long axons coming
from the retina
● Does not have
photoreceptors
● AKA blind spot
■ Macula lutea
● Area where you find the
fovea centralis
● Presence of cones
● No rods

● Myopia/Near-sightedness
○ Eyeball is too long
○ Focal point rests near the retina
○ How to correct: use a lens that is
biconcave
○ Lenses are measured by its power
■ Aka Diopters(?)
● Presbyopia/Far-sightedness
○ Eyeball is too short,
○ Focal point too far from the retina
○ Biconvex lens
○ Reading glasses of old people

● Area of rods and cones

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 ○ Photoreceptors of the eye ○ Activate the cGMP phosphodiesterase
○ Facing the choroid that will inactivate cGMP
○ Placed in the back to ensure that any ○ Will become GMP
excess light will be absorbed by the ○ Deactivation of GMP
pigment layer ■ Less depolarization because
○ Horizontal cells less sodium ions
■ Multi-synapsing in this area ■ More hyperpolarization
○ Bipolar cells ● Dark adaptation
■ Special only to the eyes, ○ If light area turned off suddenly guanylyl
especially the retina cyclase should be reinforced
■ Axo-Axonic in its synapsing ● Light adaptation
○ Amacrine ○ Light too intense but eyes are still in
○ Ganglion cells dark mode
○ All converge to form the optic nerve ○ Will cause bleaching because it hits the
● Inner segments retina suddenly
○ Organelles of the eyes ○ Read the book
● If too dark, depolarization; if too bright,
Phototransduction hyperpolarization

● How the light is processed in the area of the

photoreceptor
● Photopigments have opsins and chromophore
● Lack vitamin A difficult in perceiving light
○ Fat-soluble, so it will incorporate in your
fat
○ Constant supply to help your eye so you
can see better
● Photopigments Neural Pathways of Vision
○ Red, blue, green ● Light signals are converted into action potentials
○ For day vision through the interaction of photoreceptors with
● Guanine cyclase bipolar cells and ganglion cells
○ Phototransduction mechanism ● Light signals are converted into action potentials
● Cyclic guanosine monophosphate (cGMP) through the interaction of photoreceptors with
○ Second messenger bipolar cells and ganglion cells
○ Opens cation channel ● Photoreceptor and bipolar cells only undergo
○ Depolarization graded responses because they lack the
● If light enters voltage-gated channels that mediate action
○ Opsin stimulates the transducin by the potentials in other types of neurons
light ● Ganglion cells are the first cells in the pathway
where action potentials can be initiated

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● Photoreceptors interact with bipolar and pigments in the objects of our visual
ganglion cells in two distinct ways, designated world reflect, absorb, or transmit
as “ON-pathways” and “OFF-pathways” ○ E.g. the object appears red
● In both photoreceptors are depolarized in the because it absorbs shorter
absence of light, causing the neurotransmitter wavelengths, which would be
glutamate to be released onto bipolar cells perceived as blue, while it
● Light striking the photoreceptors of either reflects the longer wavelengths,
pathway hyperpolarizes the photoreceptors, perceived as red, to excite the
resulting in a decrease in glutamate release onto photopigment of the retina most
bipolar cells sensitive to red.
● Two key differences in the pathway: ○ Light perceived as white is a
○ Bipolar cells of the ON-pathway mixture of all wavelengths, and
spontaneously depolarize in the black is the absence of all light
absence of input, while bipolar cells of ● Color vision begins with activation of the
the OFF-pathway hyperpolarize in the photopigments in the cone
absence of input photoreceptor cells.
○ Glutamate receptors of ON-pathway ● Human retinas have three kinds of
bipolar cells are inhibitory, while cones
glutamate receptors of OFF-pathway ○ L cones (responds optimally at
bipolar cells are excitator long wavelengths)
○ M cones (medium wavelengths)
○ S cones (short)

Color Blindness
● There are several types of defects in color vision
Color Vision
that result from mutations in the cone pigments
● The colors we perceive are related to
the wavelengths of light that the
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● Most common form of color blindness is red and
green (present predominantly in 1 out of 12
men)
● Men with red-green color blindness either lack
the red or the green cone pigments entirely or
have them in an abnormal form
● Because of this, the discrimination between
shades of these colors is poor
● Color blindness results from a recessive
mutation in one or more genes encoding the
cone pigments

5
MUSCLES Structure of Skeletal Muscle
Muscle Physiology
● Classification:
○ Skeletal
○ Smooth
○ Cardiac
● Each type of muscle has specific characteristics
and functions

Characteristics of a Skeletal Muscle Fiber

● Skeletal Muscle has some defining
characteristics ● A band made of actin and myosin filaments
○ Multinucleated ● M line bisects the A band
○ Contains many mitochondria ● H zone ends of the actin filaments in the middle
○ Has transverse tubules (T tubules) where you can find the M lines
○ Has myofibrils and sarcomeres ● Cross bridges stick out from the myosin
○ Has specific terms filaments
○ Attaches to the binding sites within the
Myofibrils actin
● Structures that give skeletal cardiac muscle their ● In the beads of the actin there is a concavity
characteristic striated appearance where the heads of the myosin attaches
● They are orderly arrangement of thick and thin ● Blue rope-like structures— tropomyosin
filaments
○ Actin (thin) Structure of the Sarcomere
■ Troponin and tropomyosin also
thin
○ Myosin (thick)
● Isotropic band (light band) and A band (dark
band)

● A band made up of only actin

● I band

6
Molecular Mechanisms of Skeletal Muscle
Contraction
● The term contraction does not necessarily mean
“shortening”
○ Isometric and isotonic contraction is
shortening
● It simply refers to activation of the force-
generating sites within muscle fibers—the cross-
bridges
● For example, holding a dumbbell at a constant
position require muscle contraction, but not
muscle shortening

● End Plate Potential (EPP)

Sliding Filament Mechanism
○ A graded potential
● In this model of contraction force generation
produces shortening of a skeletal muscle fiber,
Thin Filaments and Associated Proteins
the overlapping thick and thin filaments in each
● Actin
sarcomere move past each other, propelled by
○ Contractile protein
movements of the cross-bridges
○ Each G actin has a binding site for
○ Think of row boats or dragon boats
myosin
(boat - myosin, water - actin)
○ Think of pearls strung together on a
● The ability of a muscle fiber to generate force
string and then the strands of pearls are
and movement depends on the interaction of the
twisted together
contractile proteins actin and myosin
● Tropomyosin
○ Regulatory protein
○ Overlaps binding sites on actin for
myosin and inhibits interaction when in
the relaxed state
● Troponin
○ Regulatory protein
○ Forms a complex with the other proteins
of the thin filament (actin and
tropomyosin)
○ Troponin binds Ca2+ reversibly and
once bound changes conformation to
pull tropomyosin away from the myosin
interaction sites
○ Ca 2+ binding to troponin regulates
skeletal muscle contraction because it
moves the tropomyosin away and allows
● Relaxed state myosin to interact with the actin
○ No attachment
○ Moves out retaining the original length
● Shortened
○ With attachment
○ Pulls actin towards the z line

7
The Cross-bridge Cycle

● In the resting muscle, the cross bridge is

energized
○ Cleaving of ATP to form ADP PI ● Somatic nerve
○ Head is ready to attach to actin binding ○ Nerve attached to muscles
site ● Neuromuscular junction
● Ca2+ rises ○ Nerve and muscle are attached together
○ Found in the lateral sacs, cisternae ● ACh
■ Beside T tubules ○ Excitatory
● Attachment of actin to myosin ○ Main neurotransmitter
● Head pulls actin towards the center
○ Energy is utilized because there is Action Potentials and Contraction
movement
○ ADP and PI is lost
● Detachment of cross-bridge
○ ATP binds to myosin, causing cross-
bridge to detach
● Hydrolysis of ATP
○ Energizes the cross bridge to attach to
the next binding site
● Rigor mortis
○ Stiffening at death
○ ATP is lost because of loss of
metabolism
○ It will stay at the time of attachment
○ Softening will occur when decay occurs
Roles of Troponin, Tropomyosin, and Ca2+ in ● -90V resting membrane potential
Contraction ● Latent period
○ To have recruitment of muscle fibers

Neuromuscular Junction

8
 Excitation-contraction coupling
Sarcoplasmic Reticulum
● Homologous to the endoplasmic reticulum
● Ca2+ is stored here and is released following
membrane excitation
● T-tubules and SR are connected with junctions
● Junctions involve two integral membrane
proteins
○ T-tubule membrane
○ Membrane of SR
● T-tubule protein is a modified voltage-sensitive
Ca2+ channel known as dihydropyridine (DHP)
receptor, which acts as a voltage sensor
● Protein embedded in the SR is known as
ryanodine receptor, which forms a Ca2+ channel
Motor Unit
● Muscle action potential propagated into the T-
tubules
● Action potential is sensed by a voltage sensor
(DHP receptor) that is attached to the
Ryanodine receptor
○ Extension of the Ca channel
● Opens the Ca channels
● Stored within the lateral sacs and will be
released into the cytosol
○ High cytosolic concentration
● Ca attached to troponin and moves myosin
away from the binding sites
● Exposes it to the cross-bridge of myosin(?)
● Relaxation
○ Calcium is removed from troponin
○ Tropomyosin will cover the heads of the
myosin to prevent further movement of
actin towards the N Line
○ Calcium is pushed back to the lateral
sacs
■ Needs ATP to be pumped back
● Defined as the motor neuron and the skeletal
muscle fibers it innervates
● One motor neuron innervates many muscle
fibers, but one muscle fiber is innervated by only
one motor neuron
● Within a whole muscle there are many motor
units
9
 Disruption of Neuromuscular Signaling
The Neuromuscular Junction
● Stimulation of the nerve fibers to a skeletal
muscle is the only mechanism by which action
potentials are initiated in skeletal muscle
● The nerve cells whose axon innervate skeletal
muscle fibers are known as motor neurons
(somatic efferent neuron) and their cell bodies
are located in either the brainstem or the spinal
cord
● Cell bodies are located in either the brainstem or
the spinal cord
● Axons of motor neurons are myelinated and are
the largest-diameter axons in the body
● They propagate action potentials at high
velocities, allowing signals from the CNS to
travel to skeletal muscle fibers with minimal
delay
● All neuromuscular junctions are excitatory
● In addition to receptors for ACh, the synaptic
junction contains the enzyme
acetylcholinesterase, which breaks down ACh
● Curare is a deadly arrowhead poison used by
indigenous peoples of South America
● Binds strongly to nicotinic ACh receptors and
does not open their ion channels, however, and
acetylcholinesterase does not destroy it
● When a receptor is occupied by curare, ACh
cannot bind to the receptor
● Therefore, although the motor nerves still
conduct normal action potentials and release
ACh, there is no resulting EPP in the motor end
plate and no contraction
● Because skeletal muscles responsible for
breathing, like all skeletal muscles, depend upon
neuromuscular transmission to initiate their
contraction, curare poisoning can cause death
by asphyxiation
● Neuromuscular transmission can also be
blocked by inhibiting acetylcholinesterase.
● Some organophosphates, which are main
ingredients in certain pesticides and “nerve
gases” inhibit this enzyme
● Results in skeletal muscle paralysis and death
from asphyxiation
● Nerve gases also cause ACh to build up at
muscarinic synapses, where parasympathetic
neurons inhibit cardiac pacemakers cells
● Thus, the antidote for organophosphate and
nerve gas exposure includes both pralidoxime,
which reactivates acetylcholinesterase and the
muscarinic receptor antagonist atropine
● The toxin produced by bacterium Clostridium
botulinum, blocks the release of of acetylcholine
from nerve terminals
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 ● Botulinum toxin is an enzyme that breaks down
proteins of the SNARE complex that are
required for binding and fusion of ACh vesicles
with the plasma membrane of the axon terminal
● This toxin, which produces the food poisoning
called botulism, is one of the most potent
poisons known because of the very small
amount necessary to produce an effect
● Application of botulinum toxin is increasingly
being used for clinical and cosmetic procedure,
including the inhibition of overactive extraocular
muscles, prevention of excessive sweat gland
activity, treatment of migraine headaches, and
reduction of aging-related skin wrinkles
Isometric and Isotonic Twitches:
● Isometric twitches do not generate tension but
do not shorten the muscles (load is greater than
the force generated by the muscle, i.e. postural
muscles)
● Isotonic twitches do shorten the muscle
Load Shortening Relationship
Load-velocity relationship
Frequency-tension Relationship
● Because a single action potential in a skeletal
muscle fiber lasts only 1 to 2 ms but the twitch
my last for 100 ms, it is possible for a second
action potential to be initiated during the period
of mechanical activity
● When a stimulus is applied before a fiber has
completely relaxed from a twitch, it induces a
contractile response with a peak tension greater
than that produced in a single twitch (S3 and S4)
● The increase in muscle tension from successive
action potentials occurring during the phase of
mechanical activity is known as summation
● A maintained contraction in response to
repetitive stimulation is known as a tetanus
(tetanic contraction)
Length-tension Relationship
● The spring-like characteristic of the protein titin
is responsible for mouth of the passive elastic
properties of relaxed muscle fibers
● With increased stretch, the passive tension in a
relaxed fiber increases, not from active cross-
bridge movements but from elongation of the
titin filaments
11
 ● If the stretched fiber is released, it will return to
an equilibrium length, much like what occurs ● Creatine primase will create creatine and this
when releasing a stretched rubber band will excrete the body
● By a different mechanism, the amount of active ○ Different from creatinine
tension a muscle fiber develops during ● Oxidative phosphorylation in the mitochondria
contraction can also be altered by changing the ○ Phosphorylate ATP
length of the fiber ● If oxygen is depleting, the other sources will be
● If you stretch a muscle fiber to various lengths used to produce ATP
and tetanically stimulate it at each length, the ○ Gluconeogenesis
magnitude of active tension will vary with length ■ Production of ATP using a non-
● The length at which the fiber develops the carbohydrate source
greatest isometric active tension is termed the ● Fatty acids will be the first to be burned through
optimal length, L0 OxPhos
○ Only happens after 30 minutes of
exercise

Muscle Fatigue
● When a skeletal muscle fiber is repeatedly
stimulated, the tension the fiber develops
eventually decreases even though the
stimulation continues
● This decline in muscle tension as a result of
previous contractile activity is known as muscle
fat icy
● Additional characteristics of fatigued muscle
○ Decreased shortening velocity
○ Slower rate of relaxation
● The onset of fatigue and its rate of development
Skeletal Muscle Energy Metabolism depend on:
● As we have seen, ATP performs three functions ○ Type of skeletal muscle fiber that is
directly related to muscle fiber contraction and active
relaxation ■ Physiologically, the muscle is
● There are three ways a muscle fiber can form divided into a high myosin
ATP: muscle and low myosin
○ Phosphorylation of ADP by creatine ○ Intensity and duration of contractile
phosphate activity
○ Oxidative phosphorylation of ADP in the ■ The more you exert effort, the
mitochondria (aerobic respiration) faster your muscle will fatigue
○ Phosphorylation of ADP by the glycolytic ○ Degree of an individual’s fitness
pathway in the cytosol (anaerobic) ■ If you are into practicing fitness,
you train the muscle to have the
greater power/velocity, which
eventually decreases the
chances of fatigue
■ Athletes have lesser chances of
getting fatigue
■ Low intensity sports
(endurance) - swimming,
running
■ High intensity (power) -
weightlifting

12
Muscle Fatigue Causes
● Many factors can contribute to the fatigue of
skeletal muscle
● Fatigue from high-intensity, short-duration
exercise is thought to involve at least three
different mechanisms
1. Conduction Failure
● The muscle action potential can fail to
be conducted into the fiber along the T-
tubules, which halts the release of Ca2+
from the SR
● This results from the build up K ions in
the small volume of the T-tubule during
the depolarization of repetitive action
potentials
● Elevated external K ion concentration
leads to a persistent depolarization of
the membrane potential
● Eventually causes a failure to produce
action potentials in the T-tubular
membrane
● Cramps
○ Stiffening or hardening of the
muscle
○ Lost of water or potassium (due
to sweat)
2. Lactic Acid Buildup
● Elevated hydrogen ion concentration
alters protein conformation and activity
● Thus, the acidification of muscle by
lactic acid may alter a number of muscle
proteins, including the proteins involved
in Ca2+ release
○ Acts on the channels
● The function of Ca2+ -ATPase pumps of
the SR is also affected, which in part
explain the impaired relaxation of
fatigued muscle
○ Lactic acid - acidification of
myosin and actin filaments
3. Inhibition of Cross-bridge cycling
● The buildup of ADP and Pi within
muscle fibers during intense activity may
directly inhibit cross-bridge
○ Not much phosphorylation
● Slowing the rate of this step delays
cross-bridge detachment from actin, and
thus slows the overall rate of cross-
bridge cycling
● These changes contribute to the
reduced shortening velocity and
impaired relaxation observed in muscle
fatigue resulting from high-intensity
exercise
Central Command Fatigue
● Another type of fatigue quite different from
muscle fatigue occurs when the appropriate
regions of the cerebral cortex fails to send
excitatory signals to the motor neurons
● This may cause a person to stop exercising
even though the muscles are not fatigued
● An athlete’s performance depends not only on
the physical state of the appropriate muscles but
also upon the “will to win”— that is, the ability to
initiate central’s commands to muscles during a
period of increasingly distressful sensations
● Tetanus
○ Continuous and synchronous
contraction of the muscle
Types of Skeletal Muscle Fibers
● Skeletal muscle fibers do not all have the same
mechanical and metabolic characteristics
● Fibers are classified based on:
○ Their maximal velocities of shortening
(fast or slow)
○ The major pathway that use to form
ATP— oxidative or glycolytic
● Fast and slow fibers contain forms of myosin
that differ in the maximal rates at which they use
ATP
○ Slow usually use oxidative pathway
○ Slow is more fatigue resistant
● This determines the maximal rate of cross-
bridge cycling and thus the maximal shortening
velocity
● The second means of classifying skeletal
muscle fibers is according to the type of
enzymatic machinery available for synthesizing
ATP
● Some fibers contain numerous mitochondria and
thus have a high capacity for oxidative
phosphorylation
13
 ○ Classified as oxidative fibers
● Most of the ATP such fibers produce is
dependent upon blood flow to deliver oxygen
and fuel molecules to the muscle and contain
myoglobin
○ Myoglobin - equivalent to hemoglobin
○ ____ tends to be more oxidative than
glycolytic
● In contrast, glycolytic fibers have few
mitochondria but possess a high concentration
of glycolytic enzymes and a large store of
glycogen
○ More for power (e.g. chest muscles)
● On the basis of these two characteristics, three
principal types of skeletal muscle fibers can be
distinguished:
○ Slow-oxidative fibers (Type I) combine
low myosin-ATPase activity with high
oxidative capacity
○ Fast-oxidative-glycolytic fibers (Type IIa)
combine high myosin-ATPase activity
with high oxidative capacity and
intermediate glycolytic capacity
○ Fast-glycolytic fibers (Type IIb) combine
high myosin-ATPase activity with high
glycolytic capacity
● Note that the fourth theoretical possibility—
slow-glycolytic fibers— is not found
○ You can’t have low velocity if you have
slow fibers

14
Whole-muscle contraction Control of Shortening Velocity
● Shortening velocity of a whole muscle depends
upon the load on the muscle, the types of motor
units in the muscle, and the number of motor
units recruited to work against the load

Muscle Adaptation to Exercise

● An increase in the amount of contractile activity
increases the size of muscle fibers and
increases their capacity for ATP production
● “Use it or lose it.” Muscles that are not used will
atrophy
● There are 2 types of atrophy:
○ Disuse atrophy (like an arm in a cast)
○ Denervation atrophy (nerve damage =
loss of function)

Muscle movements

● Hyperplasia - increase in muscle volume

● Hypertrophy - increase in muscle mass

Control of Muscle Tension

● The total tension a muscle can develop depends
upon two factors:
○ The amount of tension developed by
each fiber
○ The number of fibers contracting at any
time
● By controlling these two factors, the nervous
system controls whole-muscle tension as well as
shortening velocity

15
 of skeletal muscle and may result in death due
to respiratory failure

Muscle Cramps
● Involuntary tetanic contraction of skeletal
muscles
● During cramping, action potentials fire at
abnormally high rates, a much greater rate than
occurs during maximal voluntary contraction
● The specific cause of this high activity is
uncertain, but it is probably related to electrolyte
imbalances in the extracellular fluid surrounding
both the muscle and nerve fibers
● These imbalances may arise from overextended
or persistent dehydration, and they can directly
induce action potentials in motor neurons and
muscle fibers
● Another theory is that chemical imbalances
within the muscle stimulate sensory receptors in
the muscle, and the motor neurons to the area
are activated by reflex when those signals reach
the spinal cord

Hypocalcemic Tetany
Muscle Cramps ● Involuntary tetanic contraction of skeletal
● Stretch your muscles muscles that occurs when the extracellular Ca2+
● Ice and elevate your muscle concentration falls to about 40% of its normal
● value
Lever Action of Muscles and Bones ● This may seem surprising, because we have
seen that Ca2+ is required for excitation-
contraction coupling. However,

Structure of Smooth Muscle

● Each smooth muscle cell is spindle-shaped with
a diameter between 2 and 10 um, and length
ranging from 50 to 400 um
● They are much smaller than skeletal muscle
fibers, which are 10 to 100 um wide and can be
tens of centimeters long
● Smooth muscle cells (SMC) have a single
nucleus and have the capacity to divide
throughout life of an individual
● SMCs have thick myosin-containing filaments
Skeletal Muscle Disorders
and thin actin-containing filaments, and
● A number of conditions and diseases can affect
tropomyosin but no troponin
the contraction of skeletal muscle
● The thin filaments are anchored either to the
● Many of them are cause by defects in the parts
plasma membrane or to cytoplasmic structures
of the nervous system that control contraction of
known as dense bodies
the muscle fibers rather than by defected in the
● The thick and thin filaments are not organized
muscle fibers themselves
into myofibrils, and there are NO sarcomeres,
● For example, poliomyelitis, is a viral disease that
which accounts for the for the absence of a
destroys motor neurons, leading to the paralysis
banding pattern
16
 ● Smooth muscle contraction occurs by a sliding-
filament mechanism
● Smooth muscles surround hollow structures and
organs that undergo changes in volume with
accompanying changes in volume with
accompanying changes in the lengths of the
smooth muscle fibers in their walls

Smooth Muscle Contraction and its Control

Smooth Muscle Contraction and its Control

Cross-Bridge Activation
● Cross-bridge cycling in smooth muscle is
controlled by a Ca2+ regulated enzyme that
phosphorylate myosin
● Only the phosphorylated form of smooth muscle
myosin can bind to actin and undergo cross-
bridge cycling
● This is done by myosin light chain kinase
(MLCK)
● To relax a contracted smooth muscle, myosin
must be dephosphorylated because
dephosphorylate myosin is unable to bind to
actin
● This dephosphorylation is mediated by the
enzyme myosin light-chain phosphatase (MLCP)

Sources of Cystolic Ca2+

● Two sources of Ca2+ contribute to the rise in
cystolic Ca2+ that initiates smooth muscle
contraction:
○ The sarcoplasmic reticulum
○ Extracellular Ca2+ entering the cell
through plasma membrane Ca2+
channels
● To relax, the Ca2+ has to be removed from
either the SR or back to the extracellular fluid

Membrane Activation
● Smooth muscle response can be graded
● Input to smooth muscle can be either excitatory
or inhibitory
17
Cross-bridge Activation ● A given neurotransmitter may produce opposite
effects in different smooth muscle tissues
○ Norepinephrine, the neurotransmitter
released from most postganglionic
sympathetic neurons, enhances
contraction of most vascular smooth
muscle by acting on alpha-adrenergic
receptors, but produces relaxation of
airway (bronchiolar) smooth muscle by
acting on beta-2-adrenergic receptors
● Thus the type of response (excitatory or
inhibitory) depends not on the chemical
messenger per se, but on the receptors the
chemical messenger binds to in the membrane
and on the intracellular signaling mechanism
those receptors activate

Local Factors
● Can also alter smooth muscle tension
● Include:
○ Paracrine signals
○ O2 and CO2 levels
○ Osmolarity
○ Ion composition of extracellular fluid
● Response to local factors provide a means for
altering smooth muscle contraction in response
Nerves and Hormones
to changes in the muscle’s immediate internal
● The contractile activity of smooth muscles is
environment, independent of long distance
influenced by neurotransmitters released by
nerves and hormones
autonomic neuron endings
● Many of these local factors induce smooth
● Unlike skeletal muscle fibers, smooth muscle
muscle relaxation
cells do not have a specialized motor end-plate
○ Nitric oxide (NO) which produces
region. They have swollen regions known as
smooth muscle relaxation in a paracrine
varicosities
manner
● Each varicosity contains many vesicles filled
● Some smooth muscles can also respond by
with neurotransmitter, some of which are
contracting when they are stretched
released when an action potential passes the
● Stretching opens mechanosensitive ion
varicosity
channels, leading to membrane depolarization
● Varicosities from a single axon may be located
● Resulting contraction opposes the forces acting
along several muscle cells, and a single muscle
to stretch the muscle
cell may be located near varicosities belonging
to postganglionic fibers of both sympathetic and
Spontaneous Electrical Activity
parasympathetic neurons
● Some types of smooth muscle cells generate
● Therefore, a number of smooth muscle cells are
action potentials spontaneously in the absence
influence by the neurotransmitter released by a
of any neural or hormonal input
single neuron, and a single smooth muscle cell
● The membrane potential change occurring
may be influenced by neurotransmitters from
during the spontaneous depolarizations to
more than one neuron
threshold is known as a pacemaker potential
● Whereas some neurotransmitters enhance
● Slow waves
contractile activity, other decrease contractile
○ Membrane potential drifts up and down
activity
due to regular variation in the ion flux
across the membrane
18
 ● Pacemaker cells are found throughout the
gastrointestinal tract Cellular Structure of Cardiac Muscles
○ Gut smooth muscle tends to contract
rhythmically even in the absence of
neural input
● Some cardiac muscle fibers and a few neurons
in the central nervous system also have
pacemaker potentials and can spontaneously
generate action potentials in the absence of
external stimuli

Types of Smooth Muscle

Excitation-Contraction Coupling in Cardiac Muscles
● Single-unit smooth muscles respond to stimuli
as a single unit because cells are connected by
gap junctions
● Multi-unit smooth muscles contain cells that
respond to stimuli independently and they
contain few gap junctions

Cardiac Muscle
● Have one or two nuclei that are centrally located
● Striated and use the sliding filament mechanism
to contract
● Branching cells with intercalated discs with
Desmos ones and gap junctions
○ Gap junctions are critical to the heart’s
ability to be electrically coupled
● Have large mitochondria that produce the
energy needed to prevent the heart from
fatiguing
● Automaticity/Autorhythmicity
○ Node cells have the ability to stimulate
their own action potentials
● Absolute refractory period is about 250 ms
○ Prevents tetanic contractions which
would interfere with the heart’s ability to
pump

19
Skeletal vs. Cardiac Muscle

*sarcomere— other filament, titin filament attaches

the myosin
Print separate table in page 295, table 9.6

20
CARDIOVASCULAR
System Overview
Blood
● Composed of formed elements (cells and cell
fragments suspended in a liquid called plays
plasma
● Erythrocytes (RBC)
○ One of the blood cells
○ More than 99 % of blood cells
○ Carry oxygen to tissues and carbon
dioxide from tissues
● Leukocytes (WBC)
○ Other type of blood cell
○ Protect against infection and cancer
● Platelets
○ Cell fragments
○ Function in blood clotting
● Hematocrit
○ Percentage of blood volume that is
erythrocytes
○ 45% in men and 42% in women
Plasma
● Consist of a large number of organic and
inorganic substances dissolved in water
● Plasma proteins
○ Constitute most of plasma solutes by
weight
○ Role in exerting osmotic pressure that
favors the absorption of extracellular
fluid into capillaries
○ Three broad groups
■ Albumin
● Most abundant
● Synthesized in liver
■ Globulins
■ Fibrinogen
● Clotting
● Serum
○ Plasma with fibrinogen and other
clotting proteins removed
Blood Cells
● Multipotent hematopoietic stem cells
○ Progenitor of blood cells
○ Undifferentiated cells capable of giving
rise to precursors of any blood cells
● Once stem cell divides may produce:
○ Bone marrow lymphocyte precursor
cells
■ Gives rise to lymphocytes
○ “Committed” stem cells
■ Progenitors of all the other
varieties
Erythrocytes
● Functions in gas transport
○ Carry oxygen take in by the lungs and
carbon dioxide produced by the cells
● Carry protein hemoglobin to which oxygen and
carbon dioxide reversible bund
○ Oxygen binds to Fe2+ in the hemoglobin
molecules
● Biconcave disk
○ Shape and small size allows for a high
surface-area-to-volume ratio so that
oxygen and carbon dioxide can diffuse
rapidly to and from the interior of the cell
● Produced in the red bone marrow
● Ultimately lose nuclei and organelles
● Reticulocytes
○ Young erythrocytes
● Can neither reproduce nor maintain normal
structure for long
● Destruction of damaged or dying erythrocytes
occurs in the spleen and liver
● Bilirubin
○ Major breakdown product of hemoglobin
○ Gives plasma yellowish color
● Ferritin
○ Protein that stores iron
● Transferrin
○ Iron-transport plasma protein
○ Delivers iron to bone marrow
● Folic acid
○ Essential for formation of DNA and
normal cell division
○ Fewer erythrocytes produced when folic
acid is deficient
● Vitamin B12 (cobalamin)
○ Cobalt-containing molecule
○ Require for action of folic acid
○ Needs the protein intrinsic factor,
secreted by the stomach, to be
absorbed
○ Deficiency causes pernicious anemia
● Erythropoietin
○ Hormone that controls erythropoiesis
○ Secreted by the kidney
○ Acts on the bone marrow to stimulate
proliferation of erythrocytes progenitor
cells and their differentiation to mature
erythrocytes
○ Release also stimulated by testosterone
● Anemia
○ Decrease in ability of blood to carry
oxygen due to:
21
 ■ Decrease in total number of Circulation
erythrocytes
■ Diminished concentration of
hemoglobin per erythrocyte
■ Combination of both
● Sickle cell
○ Genetic mutation which alters one
amino acid in hemoglobin chain
○ Abnormal hemoglobin react with each
other causing the cell to form sickle
shapes
○ May cause blockage of capillaries,
tissue damage, and anemia
● Polycythemia
○ More erythrocytes than Norma
○ Increases hematocrit therefore
increasing blood viscosity
Platelets
● Produced when cytoplasmic portions of large
bone marrow cells, megakaryocytes, pinch off
and enter the circulation

Blood Flow
● Unidirectional
● Bulk flow
○ Rapid flow of blood produced by
pressures created by pumping action of
hear
● Nutrients and metabolic end products moved
between capillary blood and interstitial fluid via
● Closed loop
diffusion
○ Blood is pumped out of the heart
● Movement between interstitial and cell interior
through one set of vessels and returns
via diffusion and mediated transport
to the heart by a different set
● Systemic circulation
○ Left atrium—> Left ventricle—> other
organs
○ Blood leaves left ventricular via aorta
○ Aorta divides to arterioles
○ Arterioles branch to capillaries
○ Which branch to venues
○ Collectively termed as micro circulation
○ Venues unite to form veins
○ Veins unite to inferior vena cava,
collects blood below heart, and superior
vena cava, collect blood above the heart
○ Return to the right atrium
● Pulmonary circulation
○ Right atrium → Right ventricle → lungs
→ left atrium
○ Blood leaves right ventricle via
pulmonary trunk

22
 ○ Which divides into two pulmonary ■ If normal, it’s not a big factor
arteries (one for left and one for right unless you have very thick
lungs) blood (high RBC like
○ Arteries—> arterioles—> capillaries—> polycythemia) which can
venules—> vein increase velocity
○ Blood leaves lungs via four pulmonary ○ Vessel length
veins ■ How much tubing is needed
● Arteries ○ Blood vessel diameter
○ Vessels carrying blood away from the ■ Vasoconstriction, vasodilation
heart ■ Biggest contributor
● Veins ● Resistance is directly proportional to both fluid
○ Vessels carry blood from the body viscosity and vessel length and inversely
organs and tissues back to the heart proportional to the fourth power of the vessel’s
● Blood in the pulmonary veins, left side of the radius
heart, and systemic artery have high oxygen
content The Heart Anatomy
● Systemic venous and pulmonary arterial blood
have low oxygen content
● Arrangement
○ Guarantees systemic tissues receive
freshly oxygenated blood
○ Allows for independent regulation of
blood flow through different tissues as
their metabolic activities change

Pressure, Flow, and Resistance

● Collectively termed as hemodynamics
● Blood flow is always from a region of higher
pressure to lower pressure
● Hydrostatic pressure
○ Pressure exerted by any fluid ● Interventricular septum
● Pressure denotes force exerted by the blood ○ Separates the two ventricles
● Force generated by contraction of the heart and ○ Gives the framework of the heart
its magnitude varies
● Force will expand the wall of the blood vessels Heart Layers
(arteries) ● Pericardium
● Systolic pressure exerted during contraction, ○ Protective fibrous sac that encloses the
diastolic during relaxation heart
● Resistance to flow greatly enhances changes in ● Epicardium
blood vessels ○ Outer layer (superficial)
○ Visceral layer of the serous pericardium
Resistance ● Myocardium
● Capacity to flow, ability to flow within a vessel ○ Middle layer of the heart muscle
● How difficult it is for blood to flow between two ○ Composed of cardiac muscle
points at a given pressure difference ○ Forms the bulk of the heart mass
● Measure of friction that impede flow ○ Layer that contracts
● Flow rate directly proportional to pressure ● Endocardium
difference between two points and inversely ○ Thinnest, most superficial
proportional to the resistance ○ Rests on a thin layer of connective
● Factors that affect resistance tissue
○ Blood viscosity ○ Continuous with the lining of the blood
vessels entering and leaving the heart
23

Heart Valves
● Atrioventricular valves
○ Located between the atrium and
ventricle
○ Permit blood flow from the atrium to the
ventricle but not backflow
○ Tricuspid valve
■ Right AV valve
■ Has three fibrous flaps/cusps
○ Bicuspid/Mitral valve
■ Left AV valve
■ Has two flaps and resembles a
bishop’s headgear
○ Opening and closing of valves results
from pressure differences across the
valves (pressure gradient)
■ When blood pressure on atrium
is greater, valve is pushed open
■ When contracting ventricle
achieves internal pressure
greater than the atrium, valve is
forced closed
● Prolapse
○ Condition wherein the AV valves are
pushed up and opens backward into the
atria when ventricles are contracting
● Chordae tendineae and papillary muscles
○ Fibrous strands (CT) which fastens
valves to muscular projections (PM) in
the ventricular wall
○ Papillary muscles part of main muscle
bulk of myocardium
○ Holds valves in place to prevent
prolapse/backflow
○ Papillary muscles do not open or close
valve
■ Act only to limit valve’s
movement and prevent backflow
● Semilunar valves
○ Named due to the half-moon shape of
their cusps
○ Pulmonary valve
■ Opening of the right ventricle
into the pulmonary trunk
○ Aortic valve
■ Opening of left ventricle into the
aorta
○ Allow blood to flow into the arteries
during ventricular contraction but
prevent blood from moving in the
opposite direction during ventricular
relaxation
● No valve between pulmonary vein and left
atrium and between vena cava and right atrium
because by gravity, it will just fall into the left
atrium
● Left ventricle more muscular than right
○ Blood of the right is just near the lungs
so the effort to the lungs is lesser than
the left ventricle
○ Left has to pump the blood throughout
the body for systemic circulation
○ Pulmonary semilunar valve
○ Looks like a half-moon
○ Between a ventricle and great vessel
○ Between big vessel and artery
● Heart sounds
○ Closure of AV valve (tricuspid and
mitral)
○ Closure of semilunar valve (aortic and
pulmonic)
○ Both close at the same time
● Stenosis (heart murmur)
○ Narrowing of the valve
○ Infectious
● Flaccid
○ Valve is inefficient
○ Regurgitation
Blood Vessels (INCOMPLETE)
● Muscular bigger than conduit
● If away from the heart, artery and to the heart,
vein
24
Cardiac Muscle ● Receptors for NE on cardiac muscles are mainly
● Cardiac muscle cells of the myocardium are beta-adrenergic
arranged in layers that are tightly bound together ● Cholinergic receptors (muscarinic) on the node
and completely encircle the blood-filled and adrenergic receptors in the node
chambers
● When the walls of a chamber contract, they
come together like a squeezing fist and exert
pressure on the blood they enclose
● Every heart cell contracts with every beat of the
heart, so these cells do not get much rest
● Heart has only a limited ability to replace its
muscle cells
● 1% of heart muscle cells are replaced per year
● Electrically excitable tissue that converts
chemical energy stored in the bonds of ATP into
force generation
● Action potentials propagate along cell
membranes, Ca2+ enters the cytosol and the Blood supply
cycling of force generating cross-bridges is ● Blood being pumped through the heart
activated chambers does not exchange nutrients and
metabolic end products with the myocardial cells
Cardiac Communication ● Receive blood supply via arteries that branch
● 1% of cardiac cells do not function in contraction from the aorta
but have specialized features that are essential ● Coronary arteries
for normal heart excitation ○ Arteries supply in the myocardium
○ Will form cardiac conjunction for the ● Coronary blood flow
pacemakers ○ Blood flowing through the coronary
● Constitute a network known as the conducting arteries
system of the heart and are in electrical contact ● Coronary artery exit from behind the aortic valve
with the cardiac muscle cells via gap junctions cusps
● Conducting system initiates the heartbeat and ● Then lead to a branching network of small
helps spread the impulse rapidly throughout the arteries, arterioles, capillaries, venules, and
heart veins
● Heart is also an endocrine organ because it ● Most cardiac veins drain into the single large
secretes a hormone at the wall of the atrium vein, coronary sinus, and empties into the right
(atrial atrium
● Pacemakers ● Myocardium first to be affected by
○ SA node atherosclerosis
■ Main pacemaker of the heart
■ Dictates the rhythm
■ Main source
○ AV node connected to bundle of His

Innervation of the Heart

● Heart is innervated by both sympathetic and
parasympathetic nerve fibers the latter
contained in the vagus nerves
● SNS innervates the entire heart muscles and
node cells and release NE, whereas the PSNS
innervates the node cells and release primarily
ACh

25
Heartbeat Coordination ● Relaxation
● When atria is contracted or depolarized, the
ventricles are relaxed or not in a state of
excitation. Never the same action at the same
time
○ Systole contraction (ventricles) -
excitatory
○ Diastole contraction (atrial) - relaxation

Cardiac Action Potential

● The heart pumps blood separately—but

simultaneously— into the systemic and
pulmonary vessels
● Atria contracts first that followed almost
immediately by ventricles
● Contraction triggered by depolarization
● Gap junctions allow action potentials to spread
● Sinoatrial (SA) node
○ Where initial depolarization arises
○ Located in the right atrium near the
entrance of the superior vena cava

Excitation of the Heart

● Signal starts in the SA node (normal: 75 signals
/ min)
● Heart rate > 100 = tachycardia
● Heart rate < 60 = bradycardia
● The purkinje fibers also supply the papillary
muscles

Sequence of Excitation

Node Cells
● SA node is the pacemaker and controls the
electrical impulses which cause contraction
● Any damage to the SA node or to the heart walls
can damage this circuit and cause problems
● Graded potential

● Atrial begins SA node and spreads right and left

atrium, completed when everything is
depolarized
● It will spread into the ventricular septum, passing
in the atrial valve (ventricular excitation)
26
Excitation of the SA Node
Excitation-Contraction Coupling
Clinical Issues
● Arrhythmias are the uncoordinated atrial and
ventricular contractions caused by a defect in
the conduction system
EKGs
● Tool for evaluating the electrical events within
the heart
● When action potentials occur simultaneously in
many individual (contractile) myocardial cells,
currents are conducted through the body fluids
around the heart and can be detected by
recording electrodes at the surface of the skin
● P Wave
○ First deflection
○ Current flow during atrial depolarization
● QRS Complex
○ Second deflection
○ Occurs approx. 0.15 sec later
○ Result of ventricular depolarization
○ Complex because
■ The paths taken by the wave of
depolarization through the thick
ventricular walls differ from
instant to instant
■ Currents generated in the body
fluids change direction
accordingly
● T wave
○ Final deflection
○ Result of ventricular repolarization
○ Atrial repolarization is usually not
evident on the ECG because it occurs at
the same time as the QRS complex
● Typical ECG makes use of multiple
combinations of recording locations on the limbs
and chest (aka ECG leads)
● ECG is not a direct record of the changes in
membrane potential across individual cardiac
muscle cells
● It is a measure of the currents generated in the
extracellular fluid by the changes occurring
simultaneously in many cardiac cells
● Powerful tool for diagnosing certain types of
heart diseases (through electrical activity of the
heart)
● The small amount of extracellular Ca2+ entering
through L-type Ca2+ channels during the
plateau of the action potential triggers the
release of a larger quantity of Ca2+ from the
ryanodine receptors in the SR membrane
● Ca2+ activation of the thin filaments and cross-
bridge cycling lead to generation of force
● Contraction ends when Ca2+ is returned to the
SR and extracellular fluid by Ca2+-ATPase
pumps and Na+/Ca2+ countertransporters
● Amount of cytosolic Ca2+ concentration
increases during excitation = major determinant
of the strength of cardiac muscle contraction
● Amount of Ca2+ released from the SR in cardiac
muscle during resting heartbeat is not usually
sufficient to saturate all troponin sites
● Number of active cross-bridges can be
increased if more Ca2+ is released from the
sarcoplasmic reticulum
27
Refractory Period of the Heart
● Cardiac muscle is incapable of undergoing
summation of contractions like that occurring in
skeletal muscle
● If a prolonged tetanic contraction were to occur
in the heart, it would cease to function as a
pump
○ Ventricles can only adequately fill with
blood while they are relaxed
● Absolute refractory period
○ Result from inability of the heart to
generate tetanic contractions
○ Period during and following an action
potential when an excitable membrane
cannot be re-excited
● Main mechanism: inactivation of Na+ channels
● Because of the prolonged, depolarized plateau
in the cardiac muscle action potential
○ Absolute refractory period of cardiac
muscle lasts almost as long as the
contraction
○ Muscle cannot be re-excited multiple
times during an ongoing contraction
■ Stroke volume (SV) - volume of
blood ejected from each
ventricle during systole
○ Isovolumetric Ventricular Relaxation
■ First part of diastole
■ Ventricles begin to relax and
aortic and pulmonary valves
close
■ AV valves are also closed
■ No blood is entering or leaving
the ventricles, so ventricular
volume doesn’t change
○ Ventricular filling (Diastole)
■ Blood flows in from the atria
■ AV valves open
■ Atrial contraction occurs at the
end of the diastole
■ Ventricle receives blood
throughout most of diastole
■ 80% of ventricular filling occurs
before atrial contraction

Cardiac Cycle
● Divided into two phases
○ Systole - ventricular contraction and
blood ejection
○ Diastole - ventricular relaxation and
blood filling
● Typical heart rate of 72 beats/min
● Systole and diastole can be subdivided into two
discrete periods
○ Isovolumetric ventricular contraction
■ First part of systole
■ Ventricles are contracting but all
valves in the heart are closed
(no blood is ejected)
■ Ventricular volume is constant
■ Muscle develops tension but
does not shorten
○ Ventricular ejection (Systole)
■ When increasing pressure in the
ventricles exceeds that in the
aorta and pulmonary trunk
■ Aortic and pulmonary valves
open
■ Blood is forced into the aorta
and pulmonary trunk as
contracting ventricular muscle
fibers shorten
28

Mid-Diastole to Late Diastole (Refer to Picture)
1. Left atrium and ventricle are both relaxed (atrial
pressure is higher than ventricular because
atrium is filling with blood from veins)
2. AV valve is held open by pressure difference;
blood from atrium continues into ventricle
3. Aortic valve is closed because aortic pressure is
higher than ventricular pressure
4. Throughout diastole, aortic pressure is
decreasing because blood is moving out of the
arteries and through the vascular system
5. Ventricular pressure is increasing because blood
entering the relaxed ventricle from atrium
(expansion of ventricular volume)
6. Nearing the end of diastole: SA node discharges
and atria depolarize (P wave)
7. Contraction of atrium (increases atrial pressure)
8. Increased atrial pressure = small additional
volume of blood into the ventricle (atrial kick)
9. End of ventricular diastole (end-diastolic volume
(EDV) = amount of blood in the ventricle at this
time)
Systole
10. From AV node: depolarization waves passes
into and through the ventricular tissue (QRS
complex) = ventricular contraction
11. Ventricle contracts = rapid increase in ventricular
pressure, exceeds atrial pressure
12. Pressure forces AV valve to close (prevents
backflow into atrium)
13. Aortic valve remains closed (because aortic
pressure > ventricular at this time) and ventricle
cannot empty; all valves are closed; backward
bulging of closed AV valves causes a small
upward deflection in atrial pressure wave
14. Rapid increase of ventricular pressure > aortic
pressure
15. Pressure forces aortic valves to open and
ventricular ejection begins
16. Ventricular volume curve shows initial rapid then
slow down of ejection
17. End-systolic volume (ESV) = amount of blood
remaining in the ventricle after ejection
● Ventricle does not empty completely
○ SV = EDV - ESV
18. Blood flows into aorta, aortic pressure increases
with ventricular pressure. Small pressure
difference exist between the two since open
aortic valve offers little resistance to flow
19. Peak ventricular and aortic pressure are
reached before end of ventricular ejection; both
pressures start to decrease at last part of systole
because strength of ventricular contraction
diminishes
20. Force reduction = reduced rate of blood ejection
during last part of systole
21. Volume and pressure in aorta decreases as rate
of blood ejected from ventricles becomes slower
than rate of blood draining out of the arteries
Early Diastole
22. T wave corresponds to ventricular repolarization
23. As ventricles relax, ventricular pressure
decreases below aortic pressure (increased due
to volume of blood that entered); aortic valve
closes because of change in pressure; elastic
29
 recoil of aorta + blood rebounding against valve ● Normal blood flow through valves and vessels
= rebound of aortic pressure (aka dicrotic notch) follow a laminar flow
24. AV valve remains closed because ventricular ○ Flows in smooth concentric layers
pressure > atrial pressure; valves are closed ● Turbulent flow can be caused by
again during isovolumetric ventricular relaxation ○ Blood flowing rapidly in the usual
25. Rapidly decreasing ventricular pressure < atrial direction through an abnormally
pressure narrowed valve (stenosis)
26. Opening of AV valve (change in pressure ○ Blood flowing backward through a
gradient) damaged, leaky valve (insufficiency)
27. Venous blood accumulates in the atrium since ○ Blood flowing between the two atria or
AV valve is closed two ventricles through a small hole in
28. Rate of blood flow is enhanced during the initial the wall separating them (septal defect)
filling phase by rapid decrease in ventricular
pressure.
○ Occurs because the ventricle’s previous
contraction compressed the elastic
elements of the chamber in a way that
the ventricle actually tends to recoil
outward once systole is over
○ This expansion lowers ventricular
pressure more rapidly than would
otherwise occur and may even create
negative pressure

Pulmonary Circulation Pressures

● Pressure changes in right ventricle and
● Exact timing and location of the murmur provide
pulmonary arteries are qualitatively similar to left
the physician with a powerful diagnostic clue
ventricle and aorta pressure
○ E.g. murmur during systole could be
● Quantitative differences
stenotic pulmonary or aortic valve,
○ Pulmonary arterial systolic and diastolic
insufficient AV valve, or hole in IV
pressures are 25 to 10 mmHg
septum
respectively
○ E.g. murmur in diastole could be
● Pulmonary circulation is a low-pressure system
stenotic AV valve or insufficient
● Difference is reflected in the ventricular anatomy
pulmonary or aortic valve
○ Right ventricular wall is much thinner
than the left
Cardiac Output
● Volume of blood each ventricle pumps as a
Heart Sounds
function of time
● Two heart sounds resulting from cardiac
● Expressed in liters per minute
contraction are heard through the stethoscope
● In a steady state, cardiac output in systemic and
● First sound: lub
pulmonary circuits is the same
○ Closure of the AV valves
● Typical value for resting adult = 5.0 L/min
○ Occurs at the onset of systole
● Two factors that affect cardiac output:
● Second sound: dup
○ Heart rate
○ Closure of the pulmonary and aortic
○ Stroke volume
valves
● Both factors do not always change in the same
○ Onset of diastole
direction
● Sounds are caused by the closing valves
○ E.g. stroke volume decrease flowing
● Heart murmurs
blood loss, whereas heart rate increases
○ Sign of heart disease
○ Produced by heart defects that cause
blood flow turbulence
30
Control of Heart Rate
● Inherent autonomous discharge rate of SA node
= 100 beats/min
○ Heart rate slower or faster due to
constant influence of nerve and
hormones
● A large number of parasympathetic and
sympathetic postganglionic neurons end on the
SA node
● Chronotropic effects
○ Activity in the parasympathetic neurons
(which travels in the vagus nerves)
decreases heart rate
○ Activity in the sympathetic neurons
increases heart rate
● In resting state more parasympathetic activity
● Normal heart rate= 70-75 beats/min
Control of Stroke Volume
● Sympathetic stimulation increases the slope of
the pacemaker potential by increasing the F-
type channel permeability
○ Main current through these channels is
Na+ entering the cell
○ Faster depolarization occurs
○ SA node cells reaches threshold more
rapidly therefore increasing heart rate
● Increasing parasympathetic input on the other
hand decreases the slope of the pacemaker
potential due to reduction of inward current
○ Threshold is reached more slow and
heart rate decrease
○ Hyperpolarizes plasma membrane of SA
nodes increasing its permeability to K+
● Epinephrine speed the heart by acting on the
same beta-adrenergic receptors in the SA node
as norepinephrine released from the neuron
● Heart rate is also sensitive to the following
factors
○ Changes in body temperature
○ Plasma electrolyte concentrations
○ Hormones other than epinephrine and
adenosine
● Mentioned factors not as important as input from
the cardiac nerves
● Dromotropic effects
○ Sympathetic stimulation increases
conduction velocity in the entire cardiac
conducting system
○ Parasympathetic stimulation decreases
rates of spread of excitation through the
atria and AV node
● Stroke volume
○ Volume of blood each ventricle ejects
during each contraction
● A more forceful contraction of the ventricle can
produce an increase in stroke volume by
causing a greater emptying
● Factors that changes force during ejection of
stroke volume
○ Changes in the end-diastolic volume
■ Volume of blood in the
ventricles before contraction,
aka preload
○ Changes in the magnitude of
sympathetic nervous system input to the
ventricles
○ Changes in afterload
■ Arterial pressures against which
the ventricles pump
31
Relationship between Ventricular End-Diastolic Volume end-diastolic volume and therefore
and Stroke Volume: Frank-Starling Mechanism stroke volume
● Stroke volume increases as the end-diastolic
volume increases Sympathetic Regulation
● Ventricular function curve ● NE acts on beta-adrenergic receptors to
○ Graphic illustration of mentioned increase ventricular contractility (strength of
relationship contraction at any given end-diastolic volume
● Frank-Starling Mechanism ● Ionotropic effects
○ Relationship between stroke volume ○ Extrinsic factors that increase the force
and end-diastolic volume of contraction at a given end-diastolic
● Length-tension relationship accounts for this volume
mechanism
○ The greater the end diastolic volume,
the greater the stretch
● Normal point for cardiac muscle in a resting
individual is not at its optimal length for
contraction unlike in the skeletal muscle

● Stretching of cardiac muscle cells to optimum

length causes:
○ Overlap of thick and thin filaments
○ Decreases spacing between thick and
thin filaments
● (a) stroke volume is increased at any given end-
■ Allow more cross-bridges to
diastolic volume
bind during a twitch
● (b) both the rate of force development and the
○ Increases sensitivity of troponin for
rate of relaxation increase as does the maximum
binding Ca2+ and increases Ca2+
force developed
release from the sarcoplasmic reticulum
● Green curve= ventricular function curve
● Venous return
● Orange curve = sympathetic nerve stimulation
○ Flow of blood from the veins into the
● Increased contractility leads to a more complete
heart
ejection of the end-diastolic ventricular volume
● Significance of Frank-Starling mechanism
● Ejection fraction
○ At any given heart rate, an increase in
○ Quantification of contractility
venous return automatically forces an
○ Ratio of stroke volume and end-diastolic
increase in cardiac output by increasing
volume
32
 ○ Average value under resting conditions:
50%-75%
● Increased sympathetic stimulation also causes
contraction and relaxation of ventricles to occur
more quickly
○ Important because increased
sympathetic activity also increases heart
rate
● As heart rate increases time for diastolic filling
decreases
○ Problem compensated by quicker
contraction and relaxation due to
sympathetic neurons
● Cellular mechanisms involved in sympathetic
regulation:
● Adrenergic receptors activate a G-protein-
coupled cascade that includes the production of
cAMP and activation of protein kinase
● Proteins involved in excitation-contraction
coupling are phosphorylated by kinase
enhancing contractility
● Proteins include:
○ L-type Ca2+ channels in plasma
membrane
○ Ryanodine receptor and associated
proteins in SR
○ Thin filament proteins— in particular
troponin
○ Thick filament proteins associated with
cross-bridges
○ Proteins involved in pumping Ca2+ back
into SR
● There is little parasympathetic innervation in the
ventricles there it is negligible
Afterload
● Increased arterial pressure reduces stroke
volume
● Afterload
○ How hard the heart must work to eject
blood
● The greater the load, the less contracting
muscle fibers can shorten at a given contractility
Summary
Measurement of Cardiac Function
● Echocardiography
○ Used to obtain 2D and 3D images of
heart throughout the entire cardiac cycle
○ Ultrasonic waves are beamed at the
heart and returning echoes are
electronically plotted by the computer to
produce images
○ Detect abnormal functioning of cardiac
valves or contractions of cardiac walls
and measure ejection fraction
○ Non-invasive
● Cardiac angiography
○ Requires temporary threading of thin,
flexible tube called a catheter through
an artery or vein into the heart
33
 ○ Liquid containing radiopaque contrast
material is injected through the catheter
during high-speed x-ray videography
○ Useful for evaluating cardiac function
and identifying narrowed coronary
arteries
Arteries
● Can be viewed most conveniently as elastic
tubes
● Their large radii primarily functions as low-
resistance tubes conducting blood to the various
organs
● Second major function acts as a pressure
reservoir for maintaining blood flow through the
tissues during diastole
Arterial Blood Pressure
● Compliance = Change Volume / Change
Pressure
● Greater compliance = more easily it can be
stretch
● Contraction of the ventricles ejects blood into the
arteries during systole
● If an equal quantity of blood were to
simultaneously drain out of the arteries into the
arterioles during systole, total volume of blood in
arteries would remain constant and pressure
would not change
● Only ⅓ of the stroke volume leaves the arteries
during systole
● Rest of the stroke volume remains in the arteries
during systole (increases arterial pressure)
● As ventricular contraction ends, stretched
arterial walls recoil passively and blood
continues to be driven into the arterioles during
diastole
● As blood leaves the arteries, the arterial volume
and pressure slowly decreases.
● Next ventricular contraction occurs while the
artery walls are still stretched by the remaining
blood (arterial pressure does not decrease to
zero)
● Aortic pressure pattern is typical of the pressure
changes that occur in all the large systemic
arteries
● Systolic pressure (SP)
○ Maximum arterial pressure reached
during peak ventricular ejection
● Diastolic pressure (DP)
○ Minimum arterial pressure that occurs
before ventricular ejection begins
● Arterial pressure is generally recorded as
systolic/diastolic (120/80 mmHg)
● Systolic and diastolic average about 10 mmHg
lower in females than in males
● Pulse pressure
○ Difference between systolic and
diastolic pressure
○ Pulsation or throb in the arteries of the
wrist or neck with each heartbeat
○ During diastole, nothing is felt over the
artery
○ Rapid pressure on the next systole
pushes out the artery wall (expansion of
blood vessel) that produces the
detectable pulse
● Factors determining the magnitude of pulse
pressure
○ Stroke volume
○ Speed of ejection of stroke volume
○ Arterial compliance
● Pulse pressure produced by a ventricular
ejection is greater if
○ Volume of blood ejected increases
○ Speed at which it is ejected increases
○ Arteries are less compliant
● Arteriosclerosis
○ Last phenomenon that occurs
34
 ○ Stiffening of the arterial walls that
progresses with age
○ Accounts for the increase in systolic and
decrease in diastolic pressures
○ Resultant increase in pulse pressure
that often occurs after the age of 40
years
● Arterial pressure is continuously changing
throughout the cardiac cycle
● Mean arterial pressure (MAP)
○ Average pressure during cardiac cycle
○ Not merely the value halfway between
systolic and diastolic pressure (diastolic
lasts twice as long as systole)
○ MAP = DP + ⅓(SP - DP)
○ Important parameter because it is the
average pressure driving blood into the
tissues averaged over the entire cardiac
cycle
● Arterial compliance does not have a major
influence on the mean arterial pressure
○ Change in compliance = change in
systolic and diastolic pressures but in
opposite directions
Measurement of Systemic Arterial Pressure
● Sphygmomanometer
○ Inflatable cuff containing a pressure
gauge wrapped around the upper arm
○ Stethoscope is placed over the brachial
artery below the cuff
● How it works
○ Cuff is inflated to a pressure greater
than systolic blood pressure
○ High pressure in cuff is transmitted
through the tissue of the arm and
completely compresses the artery under
the cuff which prevents blood flow
through the artery
○ Air in cuff is slowly released, which
decreases pressure in the artery
○ Artery opens slightly and allows blood to
flow when cuff pressure is below systolic
pressure
○ Blood flow through the partially
compressed artery occurs at a very high
velocity because of the small opening
and the large pressure difference across
the opening
○ Korotkoff’s sounds
■ High velocity blood flow is
turbulent and produces this
vibration in the stethoscope
○ First sound heard after decrease in cuff
pressure is the systolic blood pressure
○ As pressure in cuff decreases further,
duration of blood flow through the artery
in each cycle becomes longer
○ When cuff pressure reaches the
diastolic blood pressure, sound stops
becauses flow is non turbulent and
continuous
○ Diastolic pressure = when sound
disappears
Arterioles
● Two major functions
○ Arterioles in individual organs are
responsible for determining the relative
blood flows to those organs at any given
mean arterial pressure
○ The arterioles all together are the major
factor in determining mean arterial
pressure itself
● Flow (F) = change in pressure gradient (delta P)
/ resistance to flow (R)
● All large arteries of the body can be considered
a single pressure reservoir
● Arteries branch within each organ and turns into
smaller arteries and branch into arterioles
● Smallest arteries are narrow enough to offer
significant resistance to flow, but the narrower
arterioles are the major sites of resistance
○ Decrease in mean pressure as blood
flows through the arterioles
○ Pulse pressure also decreases in the
arterioles, so flow is much pulsatile in
downstream capillaries, venules, and
veins
● Arterioles contain smooth muscle, which can
either relax and cause the vessel radius to
increase (vasodilation), or contract and
decrease the vessel radius (vasoconstriction)
● Pattern of blood-flow distribution depends upon
the degree of arteriolar smooth muscle
contraction within each organ and tissue
● Differing resistances in various organs
determines the distribution of blood flow at rest
● Intrinsic tone
○ aka basal tone
○ Arteriolar smooth muscle possesses a
large degree of spontaneous activity
35
 ○ Sets a baseline level of contraction that
can be increased or decreased by
external signals (e.g. neurotransmitters,
circulating hormones)
○ The signals act by inducing changes in
cytosolic Ca2+ concentration of the
vascular smooth muscle cells
● Increase in contractile force above the intrinsic
tone causes vasoconstriction
● Decrease in contractile force causes
vasodilation
● Mechanisms controlling vasoconstriction and
vasodilation in arterioles fall into two categories
○ Local controls
○ Extrinsic (or reflex) controls
Local Controls
● Denotes mechanisms independent of nerves or
circulating hormones by which organs and
tissues alter their own arteriolar resistance
○ Self-regulates blood flow
● Includes changes caused by autocrine and
paracrine agents
● Self-regulation is apparent in phenomena like
active hyperemia, flow autoregulation, reactive
hyperemia, and local response to injury
Active Hyperemia
● Hyperemia
○ Increased blood flow
● Active hyperemia is where organs and tissues
have hyperemia when metabolic activity is
increased
● E.g. exercising skeletal muscles experience an
increase in blood flow and is directly proportional
to the increased activity of the muscle
● Direct result of arteriolar dilation in the most
active organ or tissue
● Local chemical changes in the extracellular fluid
surrounding the arterioles cause arteriolar
smooth muscle to relax in active hyperemia
● Most obvious change is when there is a
decrease in the local concentration of oxygen
● Chemical factors that increase when metabolism
increases:
○ CO2
○ Hydrogen ions (e.g. lactic acid)
○ Adenosine
○ K+ ions, accumulated from repeated
action potential repolarization
○ Eicosanoids
○ Osmotically active products from the
breakdown of high-molecular-weight
substances
○ Bradykinin
■ Peptide generated locally from a
circulating protein (kininogen) by
the action of an enzyme
(kallikrein), produced locally and
in the plasma from its precursor
(prekallikrein) secreted by the
liver
○ Nitric oxide
■ Gas released by endothelial
cells
■ Acts on the immediately
adjacent vascular smooth
muscle
● All these factors have been shown to cause
arteriolar dilation under controlled experimental
conditions
● It is likely that additional important local factors
remain to be discovered
● Active hyperemia is most highly developed in
skeletal muscles, cardiac muscles, and glands
● Ability of each vascular bed to regulate its own
blood flow locally is a highly efficient way to
distribute blood flow to the tissues that need it
Flow Autoregulation
● Change in the resistance is in the direction of
maintaining blood flow nearly constant despite
the pressure change
● E.g. Arterial pressure to an organ is reduced
because of a partial blockage in the artery, so
blood flow is reduced. Response: arteriolar
vasodilation
● Mechanisms of flow autoregulation: decrease in
arterial pressure
○ Reduces blood flow to an organ, supply
of oxygen in organ diminishes, and local
extracellular oxygen concentration
decreases
○ Local metabolic changes occurring
during decreased blood supply at
constant metabolic activity are similar to
those that occur during increase
metabolic activity
○ This is because in both situations, there
is an imbalance between blood supply
and level of cellular metabolic activity
○ Vasodilation of active hyperemia and of
flow autoregulation at low arterial
36
 pressure involve the same metabolic
mechanisms
● Not limited to circumstances in which arterial
pressure decreases
● Mechanism of flow autoregulation: Arterial
pressure increases
○ Initial increase in flow removes the local
vasodilator chemical factors faster than
they are produced
○ Increases local concentration of oxygen
○ This causes arterioles to constrict, which
maintains a relatively constant local flow
despite the increased pressure
● Mechanism of flow autoregulation: Myogenic
responses
○ Arteriolar smooth muscle respond
directly by contracting at increased
arterial pressure
○ Vascular smooth muscles decrease as
arterial pressure decreases
○ Myogenic responses are caused by
changes in Ca2+ movement into the
smooth muscle cells through Ca2+
channels in the plasma membrane
Reactive Hyperemia
● When an organ or tissue has had its blood
supply completely occluded, a profound
transient increase in its blood flow occurs if flow
is reestablished
● Essentially an extreme form of flow
autoregulation
● Arterioles in the affected organ or tissue dilate
during a period of no blood flow
● As occlusion to arterial flow is removed, blood
flow increases greatly through these wide-open
arterioles
● E.g. Removing adhesive bandages that was
wrapped too tightly around a finger will make the
finger turn bright red because of the increase in
blood flow
Response to Injury
● Tissue injury causes eicosanoids and a variety
of other substances to be released locally from
cells or generated from plasma precursors
● These make arteriolar smooth muscle relax and
cause vasodilation in an injured area
(inflammation)
Extrinsic Controls
Sympathetic Neurons
● Most arterioles are richly innervated by
sympathetic postganglionic neurons
● Mainly release norepinephrine, which binds to
alpha-adrenergic receptors on the vascular
smooth muscle to cause vasoconstriction
● Receptors for norepinephrine on heart muscle
(and conducting system) are mainly beta-
adrenergic
● B-adrenergic antagonists block the actions of
norepinephrine on the heart but not the
arterioles and vice versa for a-adrenergic
antagonists
● Control of the sympathetic neurons to arterioles
can also be used to produce vasodilation
● Sympathetic neurons always cause some
degree of tonic constriction in addition to the
vessels’ intrinsic tone
● Decrease in sympathetic activity can achieve
dilation
● E.g. At room temperature, skin arterioles are
already under the influence of a moderate rate
of sympathetic discharge. Appropriate stimulus
causes reflex (e.g. cold, fear, loss of blood)
enhancement of sympathetic discharge, and
arterioles constrict further.
● Primary function of sympathetic neurons to
blood vessels are concerned with the reflexes
that serve whole-body needs
● Most common reflex is that which regulates
arterial blood pressure by influencing arteriolar
resistance throughout the body
Parasympathetic Neurons
● There is little to no important parasympathetic
innervation of arterioles
● Great majority of blood vessels receive
sympathetic input.
Noncholinergic, Nonadrenergic, Autonomic Neurons
● Noncholinergic, nonadrenergic neurons do not
release ACh nor norepinephrine
● They release other vasodilator substances,
particularly nitric oxide
37
 ● These neurons are particularly prominent in the
enteric nervous system
○ Contributes significantly to the control of
the GI system’s blood vessels
● These neurons innervate arterioles in other
locations (e.g. penis and clitoris where they
mediate erection)
● Some drugs used to treat erectile dysfunction in
men (e.g. sildenafil aka Viagra and tadalafil aka
Cialis) work by enhancing the nitric oxide
signaling pathway
Hormones
● Epinephrine can bind to a-adrenergic receptors
on arteriolar smooth muscle and cause
vasoconstriction
● Many arteriolar smooth muscle cells possess the
beta2 subtype of adrenergic receptors and the
a-adrenergic receptors
● Binding of epinephrine to beta2 receptors
causes the muscle cells to relax rather than
contract
● Existence of beta2-adrenergic receptors on
vascular smooth muscle is of little to any
importance
● This is because the alpha-adrenergic receptors
greatly outnumber them
● Arterioles in skeletal muscles are an important
exception because they have a significant
number of Beta2-adrenergic receptors
○ This can cause the circulating
epinephrine to contribute to vasodilation
in muscle vascular beds
● Angiotensin II
○ Constricts most arterioles
○ Part of the renin-angiotensin system
○ Drugs that prevent its action or
formation are a major therapy for
treating high blood pressure
● Vasopressin
○ Causes arteriolar constriction
○ Released into the blood by posterior
pituitary response to decrease in blood
pressure
● Atrial Natriuretic Peptide
○ Hormone secreted by the cardiac atria
○ Vasodilator
○ Influence blood pressure by regulating
Na+ balance and blood volume
Endothelial Cells and Vascular Smooth Muscle
● Many of the substances mentioned can act
directly on the arteriolar smooth muscle
● Others act indirectly via the endothelial cells
adjacent to the smooth muscle
● Endothelial cells
○ Secrete several paracrine agents that
diffuse to the adjacent vascular smooth
muscle
○ Induce either relaxation or contraction
(vasodilation or vasoconstriction)
● Nitric oxide
○ Very important paracrine vasodilator
released by endothelial cells
○ Different from the neuronal endings
mentioned previously
○ Released continuously in significant
amounts by endothelial cells in the
arterioles
○ Contributes to arteriolar vasodilation in
the basal state
○ Its secretion rapidly and markedly
increases in response to a large number
of the chemical mediators involved in
both reflex and local control of arterioles
● Prostacyclin
○ Also called prostaglandin I2 (PGI2)
○ Vasodilator the endothelial cells release
○ An eicosanoid
○ Little basal secretion of PGI2
○ Secretion can increase markedly in
response to various inputs
● Endothelin-1 (ET-1)
○ One of the important vasoconstrictor
paracrine agents that the endothelial
38
 cells release in response to certain
mechanical and chemical stimuli
○ Under certain circumstances, it can also
achieve high enough concentrations in
the blood to function as a hormone (can
cause arteriolar vasoconstriction)

Arteriolar Control in Specific Organs

Anatomy of the Capillary Network

Refer to table 12.7 for the key features of arteriolar

control in specific organs

Capillaries
● At any given moment, approximately 5% of the
circulating blood is flowing through the
capillaries
● This 5% performs the ultimate function of the
system— exchange of nutrients, metabolic end
products, and cell secretions
● Found in every tissue of the body except the
cornea
● Angiogenesis
○ Growth and development of capillaries
● Vascular endothelial cells are critically involved
in the building of new capillary network via cell
locomotion and division
● Angiogenesis factors
○ Stimulates vascular endothelial cells to
function
○ E.g. vascular endothelial growth factor
(VEGF) secreted by various tissue cells
like fibroblasts and endothelial cells
● Structure varies from organ to organ
○ Cancer cells also secrete angiotensin
● Typical structure:
factors
○ thin-walled tube of endothelial cells one
● Angiostatin
layer thick resting on a basement
○ Peptide that occurs naturally in the body
membrane
and inhibits blood vessel growth
○ No surrounding smooth muscle or
○ Administering exogenous angiostatin
elastic tissue
has been found to reduce tumors in
● Capillaries in several organs can have a 2nd set
mice of cells that surround the basement membrane
○ Function in restricting the ability of
substances to diffuse across the
capillary wall

39
● Intercellular clefts Velocity of Capillary Blood Flow
○ Water-filled spaces that separate the flat
cells of the endothelial wall of the
capillaries
● Fused-vesicle channels
○ Fusion of endocytotic and exocytotic
vesicle of the endothelial cells
● Blood flow dependent on other vessels of
microcirculation
○ Vasodilation of arterioles supplying
capillaries cause increased capillary
flow
○ Arteriolar vasoconstriction reduces
capillary flow
● Metarterioles
○ Vessel where blood enters if it doesn't
come directly from the arterioles
○ Connects arterioles to venules
○ Contain scattered smooth muscle cells
like arterioles
● Precapillary sphincter
○ Site where a capillary exits from a
metarteriole
○ Surrounded by a ring of smooth muscle
○ Relaxes or contracts in response to
local metabolic factors
○ When contracted, closes the entry to the
capillary completely
○ The more active the tissue the more
precapillary sphincters are open at any
moment
○ Therefore more capillaries are receiving
blood
○ Also exist where capillaries exit from
arterioles

● A series of 1 cm diameter balls is being pushed

down a single tube that branches into six
narrower tubes
● In the wide tube, each ball moves 3 cm/min
○ However slows progressively in the
arteries and arterioles
○ Slows markedly as blood passes
through the huge cross-sectional area of
the capillaries
■ Maximize time available for
substances to exchange
between blood and interstitial
fluid
40
 ● Velocity of blood progressively increases in the
venules and veins
○ Due to decrease in cross-sectional area
● Blood velocity dependent not on proximity to the
heart but on cross-sectional area of the vessel
type
Diffusion Across the Capillary Wall: Exchanges of
Nutrients and Metabolic End Products
● Three basic mechanism that allow substances to
move between interstitial and plasma:
○ Diffusion
○ Vesicle transport
○ Bulk flow
● Mediated transport occurs in capillaries of some
tissues including the brain
● In all capillaries, excluding the brain, diffusion is
the only important means by which net
movement of nutrients, oxygen, and metabolic
end products occurs across the capillary walls
● Lipid-soluble substances, including oxygen and
carbon dioxide, easily diffuse through the
plasma membrane of the capillary endothelial
cells
● Ions and other polar molecules are poorly
soluble in lipid and must pass through small,
water-filled channels in the endothelial lining
● Water-filled channels in the capillary walls allows
the rate of movement of ions and small polar
molecules across the wall to be quite high
although not as high as that of lipid-soluble
molecules
○ Channels in the intercellular clefts
○ Fused-vesicle channels that penetrate
the endothelial cells
● These channels allow only small amounts of
protein to diffuse through them
● Small amounts of specific proteins (e.g.
hormones) can be transported via vesicle
transport
○ Endocytosis of plasma at the luminal
border
○ Exocytosis of the endocytotic vesicle at
the interstitial side
● Tight capillaries of the brain
○ No intercellular clefts, only tight
junctions
○ Water-soluble substances can only
enter or exit brain interstitial space by
carrier-mediated transport through blood
brain barrier
● Liver capillaries
○ Large intercellular clefts
○ Large fused-vesicles channels through
endothelial cells
○ Protein molecules can readily pass
○ Important due to function of liver in
synthesis of plasma proteins and
metabolism of substance bound to
plasma proteins
● Leakiness of capillaries and tissues of most
organs lies between these two extremes
● Transcapillary diffusion gradient for oxygen and
nutrients occur as a result of cellular utilization of
the substance
● For metabolic products, it arises as a result of
cellular production of the substance
● Glucose [from interstitial to muscle = carrier-
mediated transport mechanisms
● Oxygen [from interstitial to muscle] = diffusion
● Removal of glucose and oxygen from interstitial
fluid creates gradient for their diffusion from the
capillary into the interstitial fluid
○ Gradient formed from the lowering of
interstitial fluid concentrations below
those in capillary plasma
● Carbon dioxide [from muscle to interstitial] =
diffusion
○ Carbon dioxide in interstitial greater that
in capillary
○ Gradient formation for diffusion from
interstitial to capillary
● For substance moving in both directions, local
metabolic rate establishes transcapillary
diffusion gradients
● If tissue increases metabolic rate, more nutrients
needed from blood and elimination of more
metabolic end products must be done
● Mechanism for this:
○ Active hyperemia
41
 ○ Increased diffusion gradients between
plasma and tissue
■ Increased cellular utilization of
oxygen and nutrients lowers
tissue concentrations
■ Increased production of carbon
dioxide and other end products
raises tissue concentrations
Bulk Flow Across the Capillary Wall: Distribution of
the Extracellular Fluid
Effect of Solutes
● Bulk flow of protein-free plasma
○ Function in the distribution of
extracellular fluid volume
Filtration
● In presence of a hydrostatic pressure
differences across the capillary wall, it behaves
like a porous filter
● Allows protein-free plasma to move by bulk flow
from capillary plasma to interstitial fluid through
water-filled channels
● The concentrations of all the plasma solutes
except protein are virtually the same in the
filtered fluid as in plasma
● Magnitude of bulk flow determined partly by the
difference between the capillary blood pressure
and interstitial fluid hydrostatic pressure
○ Normally former is higher than the latter
● Considerable hydrostatic pressure difference
exists to filter protein-free plasma out of the
capillaries into the interstitial fluid with protein
remaining behind in the plasma
● Plasma doesn’t filter out into the interstitial due
Starling Forces
to the hydrostatic pressure difference favoring
filtration is being offset by an osmotic force
opposing filtration
Osmosis
● Movement of water from a solution of high water
concentration to a solution of low water
concentration
● Osmotic flow of water “drags” along with it
solutes that can penetrate the membrane
● A difference in water concentration secondary to
different concentration of non penetrating solute
on the two sides of a membrane can result in the
movement of a solution containing both water
and penetrating solutes in a manner similar to
the bulk flow produced by a hydrostatic pressure
difference
● Crystalloids
○ Low molecular weight solutes
○ Found in plasma in the capillary and the
interstitial fluid
○ In large quantities
○ E.g. Na+, Cl-, K+
● Concentrations of crystalloids in plasma and
interstitial fluid are the same
● Presence of crystalloids causes no significant
difference in water concentrations
● Unlike crystalloids, plasma proteins (colloids)
are unable to move through capillary pores and
have very low concentrations in interstitial fluid
● This difference cause the water concentration of
plasma to be lower (0.5%) than the interstitial
● This creates an osmotic force that tends to
cause the flow of water from the interstitial to the
capillary
● Because the crystalloids in the interstitial fluid
move along with water, flow that is driven by
either osmotic or hydrostatic pressures across
the capillary wall does not alter crystalloid
concentrations in either plasma or interstitial
fluid
● An increased filtration of fluid from plasma to
interstitial fluid increase the volume of the
interstitial fluid and decreases the volume of
plasma, even though no changes in the
crystalloid concentrations occur
● Opposing forces act to move fluid across the
capillary wall:
○ The difference between capillary blood
and hydrostatic pressure and interstitial
42
 fluid hydrostatic pressure favors filtration
out of the capillary
○ The water concentration difference
between plasma and interstitial fluid,
which results from differences in protein
concentration, favors the absorption of
interstitial fluid into the capillary
● Net filtration pressure (NFP) is the sum of:
○ Capillary hydrostatic pressure (favoring
fluid movement out of the capillary) Pc
○ Interstitial hydrostatic pressure (favoring
fluid movement into the capillary) PIF
○ Osmotic force due to plasma protein
concentration (favoring fluid movement
into the capillary) πc
○ Osmotic force due to interstitial fluid
protein concentration (favoring fluid
movement out of the capillary) πIF
○ NFP = Pc + πIF - PIF - πc
○ Positive values for forces directed out of
the capillary
○ Negative values for inward-directed
forces
● Collectively termed as Starling forces
Regional Difference in Capillary Pressure
● Arterial blood pressure has already dissipated
as the blood flows through the arterioles
● Hydrostatic pressure tending to push fluid out of
the arterial end of a typical capillary is only about
35 mmHg
● Interstitial fluid protein. concentration would
produce a flow of fluid out of the capillary
equivalent to a hydrostatic pressure of 3 mmHg
● Interstitial fluid hydrostatic pressure is virtually 0
● Only inward force is osmotic pressure due to
plasma proteins at 28 mmHg
● In the arterial end net outward pressure exceeds
inward pressure by 10 mmHg allowing bulk
filtration to occur
● In the venous end on the other hand hydrostatic
pressure has decreased to approximately 15
mmHg due to resistance encountered as blood
flowed along the capillary wall
● Other three forces virtually the same as arterial
end
● Net inward pressure therefore is 10 mmHg
greater than outward pressure and bulk
absorption of fluid into the capillaries will occur
● Net movement of fluid from the plasma into the
interstitial space at the arterial end of capillaries
tends to be balanced by fluid flow in the opposite
direction at the venous end of the capillaries
● In actuality net outward for normally slightly
larger than the inward
● Dilating the arterioles in a particular tissue raises
capillary hydrostatic pressure in that region
○ Less pressure is lost overcoming
resistance between the arteries and the
capillaries
● Increased capillary hydrostatic pressure
increases filtration and more protein-free fluid is
transferred to the interstitial
● Constricting the arterioles decreases capillary
hydrostatic pressure
● Favors the net movement of interstitial fluid into
the vascular compartments
● Remember that the capillary filtration and
absorption only has a small function in exchange
of nutrients and metabolic end products between
capillaries and tissues
○ Greater quantities are moving by net
diffusion
● Previously mentioned Starling forces only
applicable in systemic circulation
● In terms of pulmonary circulation (low-
resistance, low-pressure circuit):
○ Normal pulmonary capillary hydrostatic
pressure averages at 7 mmHg
○ Offset by greater accumulation of
proteins in lung interstitial fluid than is
found in other tissues
43
 ○ Starling forces in the lung slightly favor
filtration as in other tissues
○ But extensive and active lymphatic
drainage prevents accumulation of
extracellular fluid in the interstitial space
and airways
Edema
● Abnormal accumulation of fluid in the interstitial
spaces
● Heart failure
○ Condition wherein increased venous
pressure reduces blood flow out of the
capillaries, and the increased capillary
hydrostatic pressure (Pc) causes excess
filtration and accumulation of interstitial
fluid
● Resulting edema can occur in either systemic or
pulmonary tissues
● A more common experience is the swelling that
occur during an injury (e.g. ankle sprain)
● Histamine and other chemical factors released
locally respond to dilate arteries and therefore
increase capillary pressure and filtration
● Chemicals released also distort endothelial cells,
increasing the size of intercellular clefts and
allowing plasma proteins to escape from the
bloodstream more readily
● Increase in protein osmotic force in the
interstitial fluid adds to the tendency for filtration
and edema
● An abnormal decrease in plasma protein
concentration also can result in edema
● Reduces the main absorptive force at capillaries,
thereby allowing an increase in net filtration
● Can be caused by liver or kidney disease as well
as protein malnutrition (kwashiorkor)
● This type of edema produces the swollen-belly
appearance commonly observed in people with
insufficient protein
Venues and Veins
● Blood flows from capillaries into venules and
then into veins
● Some exchange of materials occurs between
the interstitial and the venules
● Venules have a large capacity for blood
○ They are called capacitance vessels
● They are also a site of migration of leukocytes
into tissues during inflammation and infection
● Veins are the last set of tubes through which
blood flows on its way back to the heart
● For systemic circulation, driving force of venous
return is the pressure difference between the
peripheral and veins and right atrium
○ Pressure in the first portion of the veins
at 15 mmHg
○ Right atrial pressure is normally close to
0 mmHg
○ Total driving pressure for flow from
peripheral veins to the right atrium is 10-
15 mmHg on average
○ Peripheral veins include all veins not
contained within the chest cavity
● Major function of veins is to act as low-
resistance conduits for blood flow from the
tissues to the heart
● Peripheral veins of the arms and legs contain
valves that permit flow only toward the heart
● Diameter of veins are reflexively altered in
response to changes in blood volume
○ Maintains peripheral venous pressure
and venous return to the heart
● Explanation why peripheral venous pressure is
an important determinant of stroke volume
Determinants of Venous Pressure
● Total blood volume is one important determinant
of venous pressure
● Most blood is within the veins
○ Have thinner and more compliant walls
(compared to arteries)
○ Able to accommodate large volumes of
blood with small increase in internal
pressure
○ Also capacitance vessels
● 60% of the total blood volume is present in
systemic venules and veins
44
● Walls of veins contain smooth muscles
innervated by sympathetic neurons
● Stimulation of these neurons releases NE
causing contraction ● For the respiratory pump, during inspiration of
○ Decreases diameter and compliance of air, diaphragm descends
vessels ● This pushes on the abdominal contrast and
○ Increasing pressure within them increases abdominal pressure
● Increase venous pressure drives more blood out ● Pressure increase transmitted passively to the
of the veins into the right side of the heart intra-abdominal veins
● In contrast with arterioles wherein constriction ● Pressure in the thorax, on the other hand,
reduces forward flow through the systemic decreases
circuit ● Causes a decrease in pressure in the
● Venous smooth muscle also responds to intrathoracic veins and right atrium
hormonal and paracrine vasodilators and ● Net effect of these changes is increase of
vasoconstrictors pressure difference between peripheral veins
● Two other mechanism that can increase venous and the heart enhancing venous return
pressure and facilitate venous return: ● Summary:
○ Skeletal muscle pump
○ Respiratory pump
● During skeletal muscle contraction, veins
running through the muscle are partially
compressed
● This reduces their diameter and forces blood
back to the heart
● When the skeletal muscle pump increases local
venous pressure, the valves permit blood flow
only toward the heart and prevent flow back
towards the capillaries

45
 ■ Also known as systemic
vascular resistance (SVR)
○ MAP = CO x TPR
● CO and TPR set the mean systemic arterial
pressure because they determine the average
volume of blood in the systemic arteries over
time
● All changes in mean arterial pressure must be
the result of changes in cardiac output and/or
total peripheral resistance
● If cardiac output doubles and total peripheral
resistance decreases by half, mean arterial
pressure will not change
● Cardiac output
○ The volume of blood pumped into the
arteries per unit time
● Total peripheral resistance
○ Its contribution to mean arterial pressure
is less obvious

● Refer to figure
SKIPPED LYMPHATIC SYSTEM INSERT HERE IF
NEEDED
Integration of Cardiovascular Function: Regulation
of Systemic Arterial Pressure
● The major cardiovascular variable being
regulated is the mean arterial pressure in the
systemic circulation
● Arterial pressure is the driving force for blood
flow through all the organs except the lungs
● Importance of maintaining blood pressure within
a normal range: homeostasis
● Without a homeostatic control system operating
to maintain blood pressure, the tissues of the
body would quickly die if pressure decreases
significantly
● Mean systemic arterial pressure is the arithmetic
product of two factors
○ Cardiac output
○ Total peripheral resistance (TPR)
○ A pump pushes fluid into a container at
1 L/min
○ At a steady state, fluid also leaves
through the overflow tubes at 1 L/min
○ Height of the fluid (delta P, aka driving
pressure for outflow) remains stable
○ Disturbing the steady state through
dilating outflow of tube 1
■ Increases the radius
■ Reducing its resistance
■ Increasing its flow
○ Total outflow for the system immediately
becomes greater than 1L/min
○ More fluid leaves the reservoir than
enters from the pump
○ Volume and height of the fluid column
begin to decrease until a new steady
state between inflow and outflow is
reached
46
 ○ In any given pump input, a change in
total outflow resistance must produce
changes in the volume and height
(pressure) in the reservoir
● In the circulatory system
○ Equating the pump with the heart, the
reservoir with the arteries, and the
outflow tubes with various arteriolar
beds
● Major sites of resistance in the systemic circuit
are the arterioles
● Changes in total resistance are normally due to
changes in the resistance of arterioles
● Total peripheral resistance is determined by total
arteriolar resistance
● Physiological analogy
○ During exercise, the skeletal muscle
arterioles dilate
○ Decreases resistance
○ If cardiac output and the arteriolar
diameters of all other vascular beds
remain unchanged, the increase runoff
through the skeletal muscle arterioles
would decrease systemic arterial
pressure
● Total arteriolar resistance influences systemic
arterial blood pressure
● Refer to figure
○ Right side: outflow tube 1 has been
opened while tubes 2 to 4 have been
simultaneously constricted
○ Increased resistance in tubes 2 to 4
compensates for the decreased
resistance resistance in tube 1
○ Total resistance remains unchanged
and the reservoir pressure is unchanged
○ Total outflow remains 1L/min, though
distribution of flows is such that flow
through tube 1 increases and tubes 2 to
4 decreases, and tube 5 is unchanged
● When the skeletal arterioles dilate, total
resistance of systemic circulation can still be
maintained if arterioles constrict in other organs
○ E.g. kidneys, stomach, intestine
● Brain arterioles remain unchanged, ensuring
constant brain blood supply
● This resistance juggling can maintain total
resistance only within limits
● If tube 1 opens too wide, even complete closure
of the other tubes potentially might not prevent
total outflow resistance from decreasing
○ Cardiac output must increase to
maintain pressure in the arteries
● Because the systemic vascular system is a
continuous series of tubes, this equation holds
for the entire system (arteries to R. atrium)
○ Delta Pressure = Flow x Resistance
● From this, delta P can be termed as the mean
systemic arterial pressure (MAP) minus right
atrial pressure, F is CO, and R is TPR
○ MAP - Right atrial pressure = CO x
TPR
● Because right atrium is close to zero, we drop
the term
○ MAP = CO x TPR
● This equation is the fundamental equation if
cardiovascular physiology
● For pulmonary circulation:
○ Mean pulmonary arterial pressure =
CO x Total pulmonary vascular
resistance
● Blood flow (cardiac output) through the
pulmonary and systemic arteries are the same
● Therefore, pressures can differ only if the
resistance differs.
● Pulmonary vessels offer much less resistance to
flow than do the systemic vessels
● Total pulmonary vascular resistance is lower
than the total peripheral resistance
● Refer to p. 413 for the grand scheme of factors
that determine mean systemic arterial pressure
● Hemorrhage
○ Leads to a decrease in mean arterial
pressure
● Any deviation in mean arterial pressure will elicit
homeostatic reflexes so that cardiac output
and/or TPR will change in the direction required
to minimize the initial change in arterial pressure
47
 ● Baroreceptors Reflexes
○ Makes the homeostatic adjustments to
mean arterial pressure
○ The effectors are mainly alterations in
■ The activity of the autonomic
neurons supplying the heart and
blood vessels
■ Secretion of the hormones that
influence these structures
● E.g. epinephrine,
angiotensin II,
vasopressin
○ Become less important and factors
controlling blood volume figure
dominantly in determining blood
pressure
Baroreceptor Reflexes
Arterial Baroreceptors
● Arterial receptors that respond to changes in
pressure
● Where reflexes that homeostatically regulate
arterial pressure originate from
● Two of these receptors are found where the left
and right common carotid arteries divide into two
● Carotid sinus
○ Portion where wall of the artery is
thinner than usual and contain a large
number of branching, sensory neuronal
processes
○ Sensory neurons highly sensitive to
stretch or distortion
○ Degree of wall stretching directly related
to the pressure within the artery
○ A baroreceptor
● Aortic arch baroreceptor
○ Found in the arch of the aorta
○ Functionally similar to carotid sinus
● Arterial baroreceptors
○ Made up of the two carotid sinuses and
the aortic arch baroreceptor
○ Afferent neurons of baroreceptors —>
brainstem —> neurons of cardiovascular
control centers
● Rate of discharged of the carotid sinus is directly
proportional to mean arterial pressure
● At any given mean pressure, the large the pulse
pressure, the faster the rate of firing by the
carotid sinus
Medullary Cardiovascular Center
● Primary integrating center for baroreceptor
reflexes
● A diffuse network of highly interconnected
neurons
● Located in the medulla oblongata
● Increase in arterial baroreceptors’ rate of
discharge results in:
○ Decrease in sympathetic neuron activity
○ Increase in parasympathetic neuron
activity
● Decrease in discharge results in opposite
pattern
● Angiotensin II generation and vasopressin
secretions also altered by baroreceptors
● Decreased arterial pressure elicits increased
plasma concentration of these hormones
● Increases arterial pressure by constricting
arterioles
Operation of the Arterial Baroreceptor Reflex
48
 ● Arterial pressure decreases, as during
hemorrhage, the discharge of arterial
baroreceptors also decreases
● Fewer action potentials traveling to the
medullary cardiovascular center induces:
○ Increased heart rate because of
increased sympathetic activity and
decreases parasympathetic activity
○ Increased ventricular contractility
because of increased sympathetic
activity to the ventricular myocardium
○ Arteriolar constriction because of
increased sympathetic activity to the
arterioles (and increased plasma
concentrations of angiotensin II and
vasopressin)
○ Increased venous constriction because
of increased sympathetic activity to the
veins
● Net result is:
○ Increased cardiac output (increased
heart rate and stroke volume)
○ Increased total peripheral resistance
(arteriolar constriction)
○ Return of blood pressure to normal
● Conversely, increase of arterial blood pressure
causes:
○ Increased firing of arterial baroreceptors
○ Reflexively induces compensatory
decreases in cardiac output and total
peripheral resistance
● Baroreceptor reflex functions primarily as a
short-term regulator of arterial blood pressure
● Activated instantly by any blood pressure
change and functions to restore it to normal
● If arterial pressure remains increased from
normal set point for more than a few days,
baroreceptors decrease their action potential
firing at any given pressure Blood Volume and Long-Term Regulation of Arterial
Pressure
Other Baroreceptors ● Major mechanism for long-term regulation
● Large systemic veins, pulmonary vessels, and occurs through blood volume
walls of the heart also have baroreceptors ● Increased blood volume increases arterial
● Function analogous to arterial baroreceptors pressure
● However opposite causal chain exists—
increased arterial pressure reduces blood
volume (specifically plasma component of blood
volume)
● These mechanisms are described by the
diagrams below:

49
 the long run, only at a value at which blood
volume is also stable
● Changes in steady-state blood volume blood
volume are the single most important long-term
determinant of blood pressure

Other Cardiovascular Reflexes and Responses

● Following stimuli can cause an increase in blood
pressure:
○ Decreased arterial oxygen concentration
○ Increased arterial carbon dioxide
concentration
○ Decreased blood flow to the brain
○ Pain originating from the skin
● In contrast pain from viscera or joints can
decrease arterial pressure
● Physiological states can also affect blood
pressure
○ Attending a stressful meeting may
● An increase in arterial pressure due to, for increase blood pressure
example, an increased cardiac output induces a ○ Walking increases blood pressure
decrease in blood volume by promoting fluid ○ Sleep decreases blood pressure
secretion in kidneys ○ Eating and sexual activity also
● Tends to restore arterial pressure to it original associated with changes in blood
value pressure
● Mood also has a significant effect in blood
pressure
○ Blood pressure lower when happy
compared to when they are angry or
anxious
● Changes triggered by input from receptors or
higher brain centers to the medullary
cardiovascular center or to pathways distinct
from this centers
● Cushing’s phenomenon
○ Increased intracranial pressure causes
a dramatic increase in mean arterial
pressure
○ Numerous causes of increase of
pressure in brain such as a tumor or
traumatic head injury causing edema
○ Pressure is directed inward which
causes a collapsing force on intracranial
● An increase in blood volume due, for example, vasculature and reduction in radius
to increased fluid ingestion induces an increase greatly increasing resistance to blood
in arterial pressure flow
● Tends to restore blood volume to its original ○ Blood flow is reduced below the level
value by promoting fluid excretion by the kidneys needed to satisfy metabolic
● Because arterial blood pressure influences requirements, brain oxygen
blood volume but blood volume also influences concentration decreases, and carbon
arterial pressure, blood pressure can stabilize, in dioxide and other metabolic wastes
increase
50
 ○ Accumulating metabolites stimulate ○ Result in decrease in skin blood flow
sympathetic neurons of systemic due to arteriolar constriction
arterioles resulting in a large increase of ○ Cause paleness and coldness of skin
TPR and mean arterial pressure after significant hemorrhage
● Renal and intestinal blood flow also decrease
Hemorrhage and Other Causes of Hypotension
● Hypotension
○ General term for low blood pressure,
regardless of cause
● One cause of hypotension is significant loss of
blood volume (e.g. hemorrhage)
● Most serious consequence of hypotension is
reduced blood flow to the brain and cardiac
muscle
● Immediate counteracting response is arterial
baroreceptors

● Another compensatory mechanism is

autotransfusion
○ Movement of interstitial fluid to
capillaries
○ Occurs due to decrease in blood
pressure and increase in arteriolar
constriction which decrease capillary
hydrostatic pressure favoring absorption
of interstitial fluid
○ Can restore blood volume in normal
levels within 12-24 hours
○ Restoration within this time is due to
expansion of plasma volume which
● Factors directly affected by hemorrhage:
decreases hematocrit
○ Stroke volume
● Absorption of interstitial only redistributes
○ Cardiac output
extracellular fluid
○ Mean arterial pressure
● Ultimate restoration of blood volume involves:
● Factors not altered directly by hemorrhage but
○ Increasing fluid ingestion
by reflex response
○ Minimizing water loss via kidneys
○ Heart rate
● These slow-acting compensations include:
○ Total peripheral resistance
○ Increase in thirst
● Increased peripheral resistance results from
○ Reduction of excretion of salt and water
increased sympathetic outflow to the arterioles
in urine
in vascular beds (except brain and heart)
● Mediated by hormones including:
○ Renin
51
 ○ Angiostatin
○ Aldosterone
● Replacement of erythrocytes by erythropoietin
● Replacement processes requires days to weeks
● Hypotension due to decrease in fluid can occur
through:
○ The skin as in severe sweating or burns
○ The GI tract as in diarrhea or vomiting
○ The kidneys as with unusually large
urinary losses
● Loss of water and ions (Na+, Cl-, K+, H+, HCO3-)
● Loss of fluid causes decrease in blood volume
resulting in compensatory mechanisms similar to
hemorrhage
● Other events that may cause hypotension:
○ Decrease in cardiac contractility (i.e.
during a heart attack)
○ Strong emotion
● Vasovagal syncope
○ Brain centers involved in emotion inhibit
sympathetic activity to the circulatory
system and enhanced parasympathetic
activity to the heart
○ Result in markedly decreased arterial
pressure and brain blood flow
● Massive release of endogenous substances that
relax arteriolar smooth muscle may also cause
hypotension through reducing total peripheral
resistance
Shock
● Any situation which a decrease in blood flow to
the organs and tissues damages them
● Arterial pressure is usually decreased in shock
● Hypovolemic shock
○ Caused by a decrease in blood volume
secondary to hemorrhage or loss of fluid
other than blood
● Low-resistance shock
○ Due to a decrease in total peripheral
resistance secondary to excessive
release of vasodilator as in allergy and
infection
● Cardiogenic shock
○ Due to an extreme decrease in cardiac
output from a any of a variety of factors
(i.e. during a heart attack)
The Upright Posture
● A decrease in effective circulation blood volume
occurs when moving from a lying, horizontal
position to a standing vertical one
● The weight of the blood produces a negligible
pressure in a horizontal position
○ Pressures described in previous
sections only applicable in horizontal
position
● In an upright position, the intravascular pressure
everywhere becomes equal to the pressure
generation by cardiac contraction
● An additional pressure equal to the weight of a
column of blood from the heart to the point of
measurement is also considered
○ In an adult, average weight of a column
form the heart to the feet would be 80
mmHg
○ In a foot capillary, pressure can move
from 25 mmHg to 105 mmHg due to this
● Increase in pressure due to gravity can influence
effective blood volume in several ways
● First, increased hydrostatic pressure in the legs
(as well as in the buttocks and pelvic area)
pushes outward on the highly distensible vein
walls, causing marked distension
● Results in pooling of blood in the veins
○ Some blood emerging in the capillaries
goes to expanding the veins rather than
returning to the heart
● Simultaneously, increased capillary pressure
produces increased filtration of fluid out of the
capillaries into the interstitial space
○ Reason why feet can swell during
prolonged standing
● Combined effects of venous pooling and
increased capillary filtration reduce effective
circulating blood volume
● Venous pooling explains why a person
sometimes feels faint when standing up
suddenly
○ Reduced venous return causes a
transient decrease in end-diastolic
volume and therefore decreased stretch
of the ventricles
○ Reduces stroke volume, which in turn
reduces cardiac output and blood
pressure
● Decrease in arterial pressure from this cause
baroreceptor-reflex-mediated compensatory
adjustments similar to hemorrhage
● Effects of gravity can be offset by contraction of
skeletal muscles in the legs
● Contractions produce intermittent, complete
emptying of deep leg veins so that
52
 uninterruptible columns of venous blood the
heart to the the feet no longer exist
● Result in a decrease in both venous distention
and pooling
● Also a significant reduction in capillary
hydrostatic pressure and fluid filtration out of the
capillaries
● When standing for to long one may feel faint due
to minimal leg contractions
● Fainting considered adaptive in this situation as
it allows the person to be in a horizontal position
● When in a horizontal position, pooled venous
blood is mobilized and fluid is absorbed back
into the capillaries from the interstitial fluid of the
legs and feet
● The wrong thing to do for a person who has
fainted is to hold them upright
Exercise
● Cardiac output may increase from a resting
value of about 5 L/min to a maximal of 35L/min
in a trained athlete
● Increase in cardiac output goes to:
○ Majority in exercising muscles
○ To the heart, to provide for the increase
metabolism and workload
○ To the skin, if it becomes necessary to
dissipate heat generated by metabolism
● Increase of flow in these areas caused by
arteriolar vasodilation
● In skeletal and cardiac muscle metabolic factors
mediate vasodilation
● In the skin, it is achieved by a decrease in firing
of sympathetic neurons
● At the same time, arteriolar vosconstic is
occuring in the kidney and GI organs
○ Caused by increased activity of
sympathetic neurons
○ Manifest a decreased blood flow
● Vasodilation in mentioned sites causes a
decrease in total peripheral resistance to blood
○ Offset by vasoconstriction of arterioles
in other organs
● Compensatory mechanism not enough causing
a net result in a decrease in total peripheral
resistance
● Mean arterial pressure usually increases in a
small amount
○ Due to cardiac output somewhat
increasing more than peripheral
resistance
● Pulse pressure significantly increases because
of an increase in stroke volume and the speed at
which it is ejected significantly increase systolic
pressure
● Measurements only considered for exercises
that are cyclic contraction and relaxation of
muscles occuring over a period of time (e.g.
jogging)
○ Intense isometric contractions have a
different effect
● Increased cardiac output = large increase in
heart rate and small increase in stroke volume
53
● Increase in heart rate because of decreased
parasympathetic activity to the SA node and
increased sympathetic activity
● Increase in stroke volume because of increased
ventricular contractility (increased ejection
fraction mediated by sympathetic neurons to the
ventricular myocardium)
● Cardiac output can be increased in high levels
only if the peripheral processes favoring venous
return to the heart are simultaneously activated
● Factors promoting venous return:
○ Increased activity of the skeletal muscle
pump
○ Increased depth and frequency of
inspiration (respiratory pump)
○ Sympathetically mediated increase in
venous tone
○ Greater ease of blood flow from arteries
to veins through the dilated skeletal
muscle arterioles
● Summary of control mechanisms that elicit
cardiovascular changes in exercise:
Maximal Oxygen Consumption and Training
● Primary outflows to the sympathetic and
parasympathetic neurons is via pathways from
“exercise centers” in the brain
● Afferent input from mechanoreceptors and
chemoreceptors in the exercising muscles and
from reset arterial baroreceptors also influences
the autonomic neurons by way of the medullary
cardiovascular center
● Enhanced sympathetic outflow due a
preprogrammed pattern, modified by continuous
afferent input
● Activation of centers during exercise by output
from the cerebral cortex
● Descending pathways from these centers to the
appropriate autonomic preganglionic neurons
elicit the firing pattern typical of exercise
● During exercise blood flow and metabolic
demands do not match causing local chemical
changes in the muscle
● Chemoreceptors (muscle)—> medullary
cardiovascular center—> autonomic neurons
from higher brain centers
● Results in further increase in heart rate,
myocardial contractility, and vascular resistance
in the non-active organs
● Mechanoreceptors also stimulated to send input
to medullary cardiovascular center
● Arterial baroreceptors involved in increasing
arterial baroreceptors over that existing at rest
○ Opposite to its usual job of countering
increase in arterial pressure
● This is due to one neural component of the
central command output travels to the arterial
baroreceptors and “resets” them upward as
exercise begins
● Causes baroreceptors to respond as though
arterial pressure decreased
● Output (decreased action potential frequency)
signals for decreased parasympathetic and
increased sympathetic outflow
● See table 12.10 on page 423 for summary of
cardiovascular changes during exercise
● Lol i skipped the last paragraph for this
check na lang if its important
● Maximal oxygen consumption (Vo2 max)
○ As the intensity of any endurance
exercise increases, oxygen
consumption also increases
proportionally until reaching a point
when it fails to increase despite a further
increment in workload
● Theoretically Vo2 can be limited by:
○ Cardiac output
○ Exercising muscle’s ability to deliver
oxygen to the blood
○ The exercising muscles’ ability to use
oxygen
● In healthy people (except athletes), cardiac out
is the factor that determines Vo2 max
● With increasing workload, heart rate increases
progressively until it reaches a maximum
● Stroke volume increases much less and levels
off at 75% Vo2 max
● Factors limiting increase in stroke volume and
therefore cardiac output:
54
 ○ Very rapid heart rate which decreases
diastolic filling time
○ Inability of the peripheral factors
favoring venous return (skeletal muscle
pump, respiratory pump, venous
vasoconstriction, arterioles vasodilation)
to increase ventricular filling further
during the very short time available
● Comparison of trained and untrained individuals:
Hypertension
● A chronically increased systemic arterial
pressure (above 140/90 mmHg)
● Left ventricular hypertrophy
○ Development of an adaptive increase in
muscle mass
○ Occurs in an hypertensive person
○ Due to the left ventricle needing to
chronically pump against an increased
arterial pressure (afterload)
● Overtime (left ventricular hypertrophy) causes
changes in the organization and properties of
myocardial cells
● Result in diminished contractile function and
heart failure
● Hypertension enhances development of:
○ Arteriosclerosis
○ Heart attacks
○ Kidney damage
○ Stroke— blockage or rupture of a
cerebral blood vessel causing localized
brain damage
● Primary hypertension (formerly essential
hypertension)
○ Hypertension of uncertain cause
○ Theorized to involve a number of
genetic and environmental factors
○ A number of genes implicated including
some coding for enzymes involved in
renin-angiotensin-aldosterone system
○ Some genes involved in regulation of
endothelial cell function and arteriolar
smooth muscle
○ Increased total peripheral resistance
caused by reduced arteriolar radius is
the most significant factor
● Secondary hypertension
○ Hypertension with identified causes
● Environmental risk factors (Primary
hypertension):
○ Obesity and associated insulin
resistance
■ Weight loss significantly reduce
blood pressure in most
○ Chronic, high salt intake
■ Even slight elevations in Na+
levels lead to chronic
overstimulation of sympathetic
nervous system, constriction of
arterioles and narrowing of
lumen of arteries
○ Smoking
○ Excess alcohol consumption
○ Diets low in fruits, vegetables and low
grains
○ Diets low in vitamin D and calcium
○ Lack of exercise
○ Chronic stress
○ Excess caffeine consumption
○ Maternal smoking
○ Low birth weight
○ Not being breast-fed as an infant
● Renal hypertension
○ Caused by damage to kidneys or their
blood supply
○ Increase renin release leads to
excessive concentrations of angiotensin
55
 II (vasoconstrictor) and inappropriately
decreased urine production
○ Results in excessive extracellular fluid
volume
● Syndromes involving hypersecretion of cortisol,
aldosterone and thyroid hormone may cause
hypertension
● A link has also been established between
hypertension and sleep apnea (abnormal
nighttime breathing pattern)
● To see drugs used to treat hypertension go to
Table 12.11 in page 425
Heart Failure
● Also called congestive heart failure
● Collection of signs and symptoms that occur
when the heart does not pump an adequate
cardiac output
● 2 categories (but many exhibit elements of both
categories)
○ Diastolic dysfunction
○ Systolic dysfunction
● Diastolic dysfunction
○ Wall of the ventricle has reduced
compliance
○ Its abnormal stiffness results in a
reduced ability to fill adequately at
normal diastolic filling pressures
○ Results in reduced end-diastolic volume
○ Consequently results in a reduced
stroke volume by the Frank-Starling
mechanism
○ Pure diastolic dysfunction
■ Ventricular compliance is
decreased
■ Ventricular contractility is normal
○ Systemic hypertension
■ Most common condition that
lead to decreased ventricular
compliance
○ Hypertrophy
■ Make the ventricle stiff and less
able to expand
● Systolic dysfunction
○ Results from myocardial damage
resulting from a heart attack
○ Characterized by a decreased in cardiac
contractility
■ Lower stroke volume at any
given end-diastolic volume
■ Manifested as a decrease in
ejection fraction and downward
shift of the ventricular-function
curve
● End diastolic volume
increases
● Reduced cardiac output of heart failure triggers
the arterial baroreceptor reflexes
● These reflexes are elicited more than usual
because afferent baroreceptors are less
sensitive
○ Discharge less rapidly than normal at
any given mean or pulsatile arterial
pressure
○ Brain interprets this as a larger-than-
usual decrease in pressure
● Results of the reflexes
○ Heart rate is increased through
increased sympathetic and decreased
parasympathetic activation of the heart
○ Total peripheral resistance is increased
by increased sympathetic activation of
■ Systemic arterioles
■ Plasma concentrations of
angiotensin II and vasopressin
○ Reflex increases in heart rate and TPR
■ Beneficial in restoring cardiac
output and arterial pressure
● Baroreceptor reflexes bring about fluid retention
and an expansion of extracellular volume
56
 ○ Neuroendocrine efferent components of
the reflexes cause the kidneys to reduce
their excretion of sodium and water
● Retained fluid causes expansion of the
expansion of extracellular volume
○ Plasma volume increases → increase
venous pressure → increases venous
return → increases end-diastolic
ventricular volume
■ Restore stroke volume toward
normal by the Frank-Starling
mechanism
● Problem as fluid retention progresses
○ When a ventricle with systolic
dysfunction becomes distended with
blood
■ Force of contraction decreases
○ Causes edema (fluid retention + inc.
venous pressure)
■ Accumulation of interstitial fluid
● Capillaries drain via
venules into the veins
● When venous pressure
increases, capillary
pressure also increases
● This causes increase
filtration of fluid out of
the capillaries and into
the interstitial fluid
■ Swelling of the legs and feet
● Pulmonary edema
○ Failure of left ventricle
○ Can be due to either systolic or diastolic
dysfunction
○ Accumulation of fluid in the interstitial
spaces of the lung or air spaces
○ Impairs pulmonary gas exchange
○ Left ventricle fails to pump blood to the
same extent as the right ventricle
■ Volume of blood in pulmonary
vessels increase
■ Increases capillary pressure
● Filtration is faster than
removal of fluid by
lymphatics
○ Daytime: person is in upright position,
so swelling is in the legs
○ Night time: fluid is absorbed into the
capillaries when person lies down
■ Expansion of plasma volume
■ Development of pulmonary
edema
● Heart failure increases in TPR, mediated by
sympathetic neurons to arterioles and by
angiotensin II and vasopressin
● Increased resistance makes the failing heart
work harder
● Treatment for heart failure
○ Correct the precipitating cause (e.g.
hypertension)
○ Cardiac transplantation
● Refer to table 12.12 on p. 427 for the types of
drugs most often used for treatment
Hypertrophic Cardiomyopathy
● Frequently leads to heart failure
● One of the most common inherited cardiac
diseases
● Increase in thickness of the interventricular
septum and wall of left ventricle
● Disruption of the orderly array of myocytes and
conducting cells within the walls
● Thickening of septum interferes with the ejection
of blood through the aortic valve
○ Prevents cardiac output from increasing
to meet metabolic requirements
● Early warning sign: chest pain (angina pectoris)
● Can lead to dangerous, sometimes fatal,
arrhythmias
● Many have no symptoms until it has progressed
to an advanced stage
● Most often the cause when a young athlete
suffers sudden, unexpected cardiac death
● If it progresses with no treatment → heart failure
● Genetic mutations found to cause the disease
○ Proteins of the contractile system
(myosin, troponin, tropomyosin)
● Treatment
○ Drugs that prevent arrhythmias
○ Surgical repair of septum and valve
○ Heart transplantation
Coronary Artery Disease and Heart Attacks
● Coronary artery disease
○ Changes in one or more of the coronary
arteries causes insufficient blood flow
(ischemia)
○ Result
■ Myocardial damage in the
affected region
■ Myocardial infarction or heart
attack
○ Many patients with this disease
experience recurrent transient episodes
57
 of inadequate coronary blood flow and
angina before suffering a heart attack
● Symptoms of myocardial infarction
○ Prolonged chest pain (often to left arm)
○ Nausea
○ Vomiting
○ Sweating
○ Weakness
○ Shortness of breath
● Diagnosis of myocardial infarction
○ Made by ECG changes
○ Detection of specific cardiac muscle
proteins in plasma
■ These proteins leak out into the
blood when muscle is damaged
■ Commonly detected:
myocardial-specific isoform of
the enzyme creatine kinase, and
cardiac troponin
● Ventricular fibrillation
○ Sudden cardiac deaths during
myocardial infarctions are due to this
○ Abnormality in impulse conduction
triggered by the damaged myocardial
cells
○ Conduction pattern results in completely
uncoordinated ventricular contractions
○ Only a few individuals with this can be
saved if CPR (cardiopulmonary
resuscitation) was applied
■ Series of chest compressions
sometimes accompanied by
mouth-to-mouth respirations
■ Circulate a small amount of
oxygenated blood to brain,
heart, and other vital organs
when heart stops
○ CPR is followed by definitive treatment
like defibrillation
■ Electrical current is passed
through the heart to try to halt
the abnormal electrical activity
causing the fibrillation
● Automatic electronic defibrillators (AEDs)
○ Make it relatively simple to render timely
aid to victims of ventricular fibrillation
Causes and Prevention
● Atherosclerosis
○ Major cause of coronary artery disease
○ Disease of arteries
○ Thickening of the portion of the arterial
vessel wall closet to the lumen with
plaques made up of
■ Large numbers of cells (smooth
muscle cells, macrophages, and
lymphocytes)
■ Deposits of cholesterol and
other fatty substances (inter and
extracellular)
■ Dense layer of connective tissue
matrix
○ Reduces coronary blood flow
■ Extra muscle cells and deposits
in the wall bulge into the lumen
of the vessel and increase
resistance to flow
○ Dysfunctional endothelial cells in the
atheroscleortic area release
■ Excess vasoconstrictors (e.g.
endothelin-1)
■ Lower-than-normal amounts of
vasodilators (nitric oxide and
prostacyclin)
○ The processes are progressive and
could sometimes lead to complete
occlusion
○ Total occlusion is usually caused by
formulation of blood clot (coronary
thrombosis) in the narrowed
atherosclerotic artery
■ Triggers heart attack
● Processes that lead to atherosclerosis
58
 ○ Likely that the damage is initiated by
agents that injure the endothelium and
underlying smooth muscle
○ Leads to an inflammatory and
proliferative response that ultimately
becomes excessive
● Risk factors that increase incidence and severity
of atherosclerosis and coronary artery disease
○ Cigarette smoking
○ High blood concentrations of certain
types of cholesterol and homocysteine
○ Hypertension
○ Diabetes
○ Obesity
○ Sedentary lifestyle
○ Stress
○ Menopause
■ Incidence of heart attacks on
women is very low until after
menopause
● Prevention efforts
○ Eliminate or minimize the risk factors
through lifestyle change and/or
medication
○ Exercise
■ Perform regular activity and not
sudden burst of strenuous
physical activity (can trigger
heart attack)
■ The more you exercise, the
better the protective effect
■ Overall risk of heart attack is
reduced as much as 35% to
55%
■ Regular exercise induces
● Decreased myocardial
oxygen demand
● Increased diameter of
coronary arteries
● Decreased severity of
hypertension and
diabetes
● Decreased total plasma
cholesterol
concentration
● Increase in plasma of
good cholesterol-
carrying lipoprotein
(HDL)
● Decreased tendency of
blood to clot
● Better control of blood
glucose (increased
sensitivity in insulin)
○ Nutrition
■ Reduction in the intake of
saturated fat (abundant in red
meat)
■ Regular consumption of fruits,
vegetables, whole grains, and
fish reduces bad cholesterol
(LDL)
■ Supplements like folic acid (B
vitamin)
● Reduces blood
concentration of
homocysteine
■ Folic acid
● Involved in metabolic
reaction that lowers the
plasma concentration of
homocysteine
■ Moderate alcohol intake (red
wine) reduce risk of dying from
a heart attack
● Alcohol in higher doses
increases chance of
early death from other
diseases
● For health purposes,
one standard drink per
day (12 oz beer, 5 oz
wine or 1.5 oz 80-proof
liquor)
Drug Therapy
● Vasodilator drugs
○ E.g. nitroglycerin
○ Converted in the body to nitric oxide
○ Dilates coronary arteries and systemic
arterioles and veins
○ Arteriolar effect lowers total peripheral
resistance, which lowers arterial blood
pressure and the work the heart must do
to eject blood
○ Venous dilation decreases venous
pressure and reduces venous return,
stretch of the ventricle, and its oxygen
requirement during contraction
● Drugs that block beta-adrenergic receptors
○ Reduce the arterial pressure in people
with hypertension
59
 ○ Reduce myocardial work and cardiac
output
■ Inhibiting the effect of
sympathetic neurons on heart
rate and contractility
● Drugs that prevent or reverse clotting within
hours of occurrence
○ Treatment and prevention of heart
attacks
● Other drugs decrease plasma cholesterol
○ Influencing one or more metabolic
pathways for cholesterol
○ E.g. statins interfere with a critical
enzyme involved in the liver’s synthesis
of cholesterol
Interventions
● Coronary balloon angioplasty
○ Threading a catheter with a balloon at
its tip into the occluded artery
○ Expand balloon
○ Enlarges the lumen by stretching the
vessel and breaking up abnormal tissue
deposits
○ Usually accompanied by the placement
of coronary stents in the narrowed or
occluded coronary vessel
○ Coronary stents
■ Tubes made of stainless steel
lattice
■ Provide a scaffold within a
vessel to open it and keep it
open
● Coronary artery bypass grafting
○ Surgical treatment
○ New vessel is attached across an area
of occluded coronary artery
○ New vessel is often a vein taken from
elsewhere in the patient’s body
Stroke and TIA
● Transient ischemic attacks (TIAs)
○ People with atherosclerotic cerebral
vessels may also suffer this
○ Reversible neurological deficits
○ Could last from minutes to hours without
experiencing a stroke at the time
● Myocardial infarcts and strokes due to occlusion
may result when
○ A fragment of blood clot or fatty deposit
(embolus) breaks off and then lodges
elsewhere
○ Blocks a smaller vessel
Hemostasis: The Prevention of Blood Loss
● Most effective in dealing with injuries in small
vessels
● Body usually cannot control bleeding from a
medium or large artery
● Venous bleeding
○ Leads to less rapid blood loss
○ Veins have low blood pressure
○ Decrease in hydrostatic pressure
induced by raising the bleeding part
above the level of the heart may stop
hemorrhage from a vein
○ If internal, accumulation of blood may
increase interstitial pressure enough to
eliminate the pressure gradient required
for continued blood loss
○ Hematoma
■ Accumulation of blood in the
tissues as a result of bleeding
from any vessel type
● Immediate inherent response of a severed blood
vessel is to constrict
● Most likely involves changes in local vasodilator
and constrictor substances released by
endothelial cells and blood cells
● Short-lived response slows the flow of blood in
the affected area
● Constriction presses the opposed endothelial
surfaces of the vessels together
● The contact induces a stickiness capable of
keeping them glued together
● Permanent closure of the vessel by constriction
and contact stickiness occurs only in the
smallest vessels
● Staunching of bleeding ultimately depends upon
two other interdependent processes that occur
in rapid succession
○ Formation of platelet plug
○ Blood coagulation
Formation of a Platelet Plug
● Involvement of platelets in hemostasis requires
their adhesion to a surface
● Injury to a vessel disrupts the endothelium and
exposes the underlying connective-tissue
collagen fibers
● Platelets adhere to collagen via the intermediary
von Willebrand factor (vWF)
○ Plasma protein secreted by endothelial
cells and platelets
○ Binds to exposed collagen molecules
60
 ○ Changes the molecules’ conformation ○ Decreases pressure within the damaged
○ Becomes able to bind platelets vessel
○ Forms a bridge between the damaged ● The vasoconstriction is the result of platelet
vessel wall and the platelets activity because it is mediated by thromboxane
● Binding of platelets to collagen triggers the A2 and other chemicals in the platelet secretory
platelets to release the content of their secretory vesicle
vesicles that contains a variety of chemical
agents
○ ADP and serotonin
● Platelet activation
○ Act locally to induce multiple changes in
the metabolism, shape, and surface
proteins of the platelets
● Platelet aggregation
○ New platelets adhere to the old ones
○ Positive feedback phenomenon
○ Creates the platelet plug inside the
vessel
● Adhesion of the platelets rapidly induces them to
synthesize thromboxane A2
○ Eicosanoid
○ From arachidonic acid in the platelet
plasma membrane
○ Released into the extracellular fluid
○ Acts locally to further stimulate platelet
aggregation and release of their
secretory vesicle contents
● Fibrinogen
○ Plasma protein
○ Has a crucial function in the platelet ● Why does the platelet plug not continuously
aggregation produced by clotting factors expand?
○ Forms the bridges between aggregating ○ Prostacyclin (aka prostaglandin I2 or
platelets PGI2)
○ Receptors (binding sites) for fibrinogen ■ Synthesized and released by
on the platelet plasma membrane adjacent undamaged
become exposed and activated during endothelial cells
platelet activation ■ Profound inhibitor of platelet
● Platelet plug can completely seal small breaks in aggregation
blood vessel walls ○ Nitric oxide
● Platelets contain a very high concentration of ■ Released by the adjacent
actin and myosin endothelial cells
○ Stimulated to interact in aggregated ■ Vasodilator
platelets ■ Inhibitor of platelet adhesion,
○ Causes compression and strengthening activation, and aggregation
of the platelet plug ● Platelet plug
○ Clot retraction ○ Built up very rapidly
■ Contraction and compression ○ Primary mechanism used to seal breaks
that occur in a test tube in vessel walls
● As the plug is being built up and compacted,
vascular smooth muscles in the damaged vessel
is simultaneously being stimulated to contract
○ Decreases blood flow to the area
61
Blood Coagulation: Clot Formation
● Transformation of blood into solid gel called clot
or thrombus
○ Consists of fibrin, a protein polymer
● Occurs locally around the original platelet plug
● Dominant hemostatic defense
● Functions
○ Support and reinforce the platelet plug
○ Solidify blood that remains in the wound
channel
● The events leading to clotting are initiated when
○ Injury to a vessel disrupts the
endothelium
○ Permits the blood to contact the
underlying tissue
● The contact initiates a locally occurring cascade
of chemical activations
● An inactive protein (aka factor) is converted
(activated) to a proteolytic enzyme
● The enzyme catalyzes the generation of the next
enzyme in the sequence
● Each of the activations results from the splitting
of a small peptide fragment from the inactive
plasma protein precursor
● This exposes the active site of the enzyme
● Several plasma protein factors functions only a
cofactors for enzymes
● Prothrombin is converted to the enzyme
thrombin
● Thrombin
○ Catalyzes a reaction in which several
polypeptides are split from molecules of
the large, rod-shaped plasma protein
fibrinogen
○ Exerts a profound positive feedback
effect on its own formation
● Fibrinogen remnants bind to each other to form
fibrin
● Fibrin
○ Initially a loose mesh of interlacing
strands
○ Rapidly stabilized and strengthened by
the enzymatically mediated formation of
covalent cross-linkages
○ Essential component of the clot
● Factor XIIIa
○ Chemical linking catalyzing enzyme
○ Formed from plasma protein factor XIII
that is catalyzed by thrombin
○ Stabilizes the fibrin network
● Once thrombin formation has begun, reactions
leading to much more thrombin generation are
activated by this initial thrombin
● In the process of clotting, many erythrocyte and
other cells are trapped in the fibrin meshwork
● Clotting can occur in the absence of all cellular
elements except platelets
● Activated platelets are essential because
several of the cascade reactions take place on
the surface of the platelets
● Platelet activation occurs early in the hemostatic
response as a result of platelet adhesion to
collagen
● Thrombin is also an important stimulator of
platelet activation
○ Causes the platelets to display specific
plasma membrane receptors that bind
several of the clotting factors
○ Permits the reactions to take place on
the surface of the platelets
● Platelet Factor (PF)
○ Phospholipid displayed in activated
platelets
○ Functions as a cofactor in the steps
mediated by the bound clotting factors
● Plasma Ca2+
○ Required at various steps in the clotting
cascade
○ Ca2+ concentration in the plasma can
never decrease enough to cause
clotting defects
■ Death would occur from muscle
paralysis or cardiac arrhythmias
before low concentrations were
reached
● Pathways of blood clotting
○ Intrinsic
○ Extrinsic
62

● Intrinsic Pathway
○ Factor XII
■ First plasma protein in the
intrinsic pathway
■ Can become activated to XIIa
when it contacts certain types of
surfaces, including the collagen
fibers underlying damaged
endothelium
○ Contact activation of factor XII to XIIa
■ A complex process that requires
the participation of several other
plasma proteins
■ Explains why blood coagulates
when it is taken from the body
and put in a glass tube
● Glass surface acts like
collagen and induces
the same activation of
factor XII
● Aggregates platelets at
a damaged vessel
surface
○ XIIa catalyzes the activation of factor XI
to XIa
○ XIa activates factor IX to factor IXa
○ IXa activates factor X to Xa
■ Enzyme that converts
prothrombin to thrombin
○ Note that VIIIa serves as a cofactor in
the factor IXa-mediated activation of X
○ Factor VIII
■ Hemophilia (excessive bleeding)
is usually due to the genetic
absence of this factor
● Extrinsic Pathway
○ Considered the most important of the
two pathways
○ Begins with the protein tissue factor
■ Not a plasma protein
■ Located on the outer plasma
membrane of various tissue
cells, including fibroblasts and
other cells in the walls of the
blood vessels outside the
endothelium
○ Blood is exposed to these
subendothelial cells when vessel
damage disrupts the endothelial lining
○ Tissue factor on these cells then binds a
plasma protein (factor VII) and activates
into VIIa
○ Complex of tissue factor and VIIa on the
plasma membrane of the tissue cell
catalyzes the activation of X
○ Also catalyzes the activation of IX which
can help activate even more factor X by
the way of the intrinsic pathway
Summary
● Clotting can be theoretically initiated either by
○ The activation of factor XII
○ Or by generation of the tissue factor-
factor XIIa complex
● Two paths merge at factor Xa
○ Catalyzes the conversion of prothrombin
to thrombin
○ Then catalyzes the formation of fibrin
● Thrombin also contributes to the activation of XI
and VIII in the intrinsic pathway
● Thrombin also contributes to the activation with
Va and cofactor for factor Xa
● Thrombin activates platelets
● The extrinsic pathway is the usual way of
initiating clotting in the body
● Factor XII normally has little if any function in
extrinsic
● Thrombin is initially generated only by the
extrinsic pathway
● The amount of thrombin is too small to produce
adequate, sustained coagulation
● However, it is large enough to trigger thrombin’s
positive feedback effects on the intrinsic
pathway
○ Activation of V, VIII, and XI and of
platelets
63
 ■ Only things needed to trigger ○ The reason that the extrinsic pathway by
the intrinsic pathway itself can generate only small amounts
independently of factor XII of thrombin
● Extrinsic pathway generates the large amounts ● Second anticoagulant mechanism
of thrombin required for adequate coagulation ○ Triggered by thrombin
● Via its initial generation of small amounts of
thrombin, the extrinsic pathway provides the
means for recruiting the more potent intrinsic
pathway without the participation of XII
● Thrombin eliminates the need for factor XII
● It also facilitates the prothrombin-thrombin step
by activating factor V and platelets
● Liver
○ Contributes indirectly to clotting
○ Persons with liver disease often have
serious bleeding problems
○ Site of production for many of the
plasma clotting factors
○ Produces bile salts
■ Important for normal intestinal
absorption of the lipid-soluble ○ Thrombin can bind to thrombomodulin
substance vitamin K (endothelial cell receptor)
○ Requires vitamin K to produce ○ The binding eliminates all of thrombin’s
prothrombin and several other clotting clot-producing effects
factors ○ The binding also causes the bound
thrombin to bind a particular plasma
Anticlotting System protein called protein C
● Platelet aggregation is an essential precursor for ○ The binding to thrombin activates
clotting and reduce the magnitude and extent of protein C
clotting ○ Protein C + another plasma protein
● The body has mechanisms for limiting clot inactivates factors VIIIa and Va
formation and for dissolving a clot after it has ○ Thrombin indirectly inactivates them via
formed protein C in areas where the
endothelium is intact
Factors that Oppose Clot Formation
● Hypercoagulability
○ Defects in any of the natural
anticoagulant mechanisms are
associated with this
○ Abnormally high risk of clotting
● First anticoagulant mechanism
○ Acts during initiation phase of clotting
○ Utilizes the plasma protein called tissue ● Third naturally occurring anticoagulant
factor pathway inhibitor (TFPI) mechanism
■ Secreted mainly by endothelial ○ Antithrombin III
cells ■ Plasma protein
■ Binds to tissue factor-factor VIIa ■ Inactivates thrombin and several
complexes other factors
■ Inhibits the ability of the ■ Prevents the spread of a clot by
complexes to generate factor Xa rapidly inactivating clotting
factors that are carried away

64
 from the immediate site of the
clot by the flowing blood
○ Antithrombin III is greatly enhanced
when it binds to heparin
■ Substance present on the
surface of endothelial cells
The Fibrinolytic System
● TFPI, protein C, and antithrombin III function to
limit clot formation
● Fibrin clot does not last forever
○ Temporary fix until permanent repair of
the vessel occurs
● Fibrinolytic System
○ Principal effector of clot removal
○ Constitutes a plasma proenzyme called
plasminogen
■ Activate to the active enzyme
plasmin by protein plasminogen
activators
○ Plasmin digests fibrin and dissolves the
clot
● Tissue plasminogen activator (t-PA)
○ Secreted by the endothelial cells
● Plasminogen and t-PA bind to fibrin and become
incorporated throughout the clot
● The binding of t-PA to fibrin is crucial because t-
PA is a very weak enzyme in the absence of
fibrin
● Fibrin profoundly increases the ability of t-PA to
catalyze the generation of plasmin from
plasminogen
● Fibrin is an important initiator of the fibrinolytic
process that leads its own dissolution
● The secretion of t-PA is the last of the various
anti clotting functions
● Check Table 12.15 for summary
Anticlotting Drugs
● One of the most common uses of these drugs is
to prevent and treat myocardial infarction
● Damage to endothelial cells interferes with the
normal anticlotting functions of the endothelial
cells
● Aspirin
○ Inhibits the cyclooxygenase enzyme in
the eicosanoid pathways that generate
prostaglandins and thromboxanes
○ Aspirin reduces both platelet
aggregation and the ensuing
coagulation
○ Low doses of aspirin cause a steady-
state decrease in platelet
cyclooxygenase (COX) activity
○ Does not decrease endothelial-cell COX
○ Formation of prostacyclin is not impared
■ Prostacyclin is the prostaglandin
that opposes platelet
aggregation
○ When COX of platelets is irreversibly
blocked, thromboxane A2 synthesis is
gone for that platelet’s lifetime
○ Endothelial cells produce new COX
molecules to replace the ones blocked
by the drug
○ Aspirin appears to be effective at
preventing heart attacks
○ Administration of aspirin following a
heart attack significantly reduces the
incidence of sudden death and recurrent
heart attacks
● Oral anticoagulants
○ Interfere with clotting factors
○ One class interferes with the action of
vitamin K
○ Vitamin K reduces the synthesis of
clotting factors by the liver
○ Another class inactivates factor Xa
● Heparin can also be administered as a drug
○ Binds to endothelial cells and inhibits
clotting
● Plasminogen activators
○ Dissolves a clot after it is formed
○ Thrombolytic therapy
■ Dissolution of clot after its
formation
○ Recombinant t-PA
■ Intravenous administration of
this within a few hours after
65
 heart attack reduces myocardial
damage and mortality
■ Has also been effective in
reducing brain damage following
a stroke caused by blood vessel
occlusion

66