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Circulation Part 3
Veins

Veins are very thin, have very little elasticity and little tone. This is low-pressure system and
has very little resistance.

Veins are capacitance vessels because they can function as a blood reservoir. This is
because the smooth muscles around the veins do not myogenically contract to the degree
that they do around arteries.

Under resting conditions, veins have 60% of the total blood volume.

Venous capacity - the total volume of blood contained in the veins at a given time.

Venous Return - volume of blood entering each atrium per minute.

Sympathetic input - influences the venous return

Vasoconstriction - lowers venous capacity, increases venous return, therefore increases

CO (Frank-Starling). Remember that the sympathetic system also increases the force
of contraction and heart rate.

Remember that sympathetic stimulation will increase blood flow to the skeletal muscle of
the extremities so there is a shift in blood distribution during the fight or flight
response.

Veins of the extremities are valved. As skeletal muscles contract, they act as pumps. They
also shorten the column length of venous blood, which reduces venous pressure in the
extremities.
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Respiratory pump - you have standard atmospheric pressure on the vessel walls in most of
your body. But the pressure on venous vessel walls of the thorax can be as much as 5
mmHg less that atmospheric pressure during inhalation. This pressure gradient helps
drive blood into the chest wall.

When a person is lying down, gravity is uniform on blood vessels. When a person stands up,
venous capacity increases temporarily causing a drop on venous return. This leads to a
reduction in CO and MAP. The sympathetic constriction of the venous system insures
adequate blood flow to the brain.

This decrease in MAP effects an increase in the sympathetic nervous system activity, causing
venous vasoconstriction, re-establishing MAP.
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Blood Pressure

MAP needs to be high enough to ensure sufficient blood flow but not so high that it creates
extra work for the heart and increases vascular damage.

Remember MAP = CO x total peripheral resistance.

At a given CO, if arterioles constrict in one part of the body, then arterioles must dilate in
another part of the body to compensate if MAP is to remain constant.
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Baroreceptors (pressure sensors or mechanoreceptors)

These monitor MAP and pulse pressure.

Short term regulation - Baroreceptor Reflex

Two major locations for baroreceptors:

Carotid sinus

Aortic arch

An increase in MAP or Pulse Pressure results in an increase in the firing rate of sensory
neurons.

A decrease in MAP or Pulse Pressure results in a decrease in firing rate of sensory

neurons.

Information from the baroreceptors is conveyed to the cardiovascular control center in the
medulla.

Neurons in this control center send efferent fibers to the parasympathetic and sympathetic
nervous system.
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What happens when you eat a bag of potato chips?

Large salt ingestion results in an increase in blood volume because of the increase
osmotic pressure. This increase is temporary because normal kidney will eliminate
the positive Na+ balance. The stretch receptors sense this and start to inhibit the
sympathetic system. This keeps MAP from going up. A decreased sympathetic input
to the kidney results in a decrease in sodium retention.

Chemoreceptors

These receptors are called Carotid bodies and Aortic bodies and are located in the carotid
and aortic arteries (near the baroreceptors). They are sensitive to low O2 (< 60 mmHg
PO2) and carotid bodies are sensitive to low pH. In addition to effecting an increased
respiration, they increase MAP by stimulating the medullary cardiovascular center.

During exercise, there is a substantial increase in skeletal muscle blood flow, CO2 increases
and total peripheral resistance decreases. The result is only a slight increase of MAP.
(See table 10-4 text)

Hypothalamus
Hypothalamic control over cutaneous (skin) arterioles for temperature regulation takes
precedence over control that the cardiovascular center has over these same vessels for
the purpose of blood pressure regulation. Therefore, blood pressure can fall when
skin vessels are widely dilated.

Long Term Control over Blood Pressure

Atrial volume receptors (pressure receptors), are primarily important in water and salt
balance. These receptors stimulate the release of atrial natriuretic peptide (ANP) if
blood volume is too high.

ANP acts on the kidney to reduce water retention. It is a diuretic.

Hypothalamic osmotic receptors cause release of ADH (vasopressin) when osmolarity is

too high as in the case of dehydration.

Hypertension

Normal blood pressure is 120/80 mmHg

Hypertension - above 140/90 mmHg
Hypotension - below 100/60 mmHg

Know how a Sphygmomanometer works, read Chap 10. Know relevant terms.
With 90% of patients with hypertension, the etiology is unknown. This is called idiopathic
hypertension or essential hypertension or primary hypertension.
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Read possible causes of idiopathic hypertension, Chap 10. Know relevant terms.

With 10% of hypertension cases, the etiology is known. This is called secondary
hypertension.

The causes usually fall into four categories:

1) Cardiovascular hypertension
Increased total peripheral resistance caused by atherosclerosis (plaque buildup in
lumen of arteries). This is in distinction with arteriosclerosis which is when the
arteries loose elastic quality. Arteriosclerosis can also cause hypertension.

2) Renal hypertension (Kidney pathology)

Kidneys control blood volume by regulating the salt level (osmotic pressure). As we
have seen earlier, the kidneys can take care of a salt load. But if the kidneys are
not functioning correctly they have difficulty in not only processing abnormal salt
loads but normal as well. Kidneys contain both osmotic receptors
(chemoreceptors) and baroreceptors.

3) Endocrine hypertension
a) pheochromocytoma (adrenal medulla tumor) - abnormally high epinephrine and
norepinephrine release.

b) Conn's Syndrome - abnormally high aldosterone levels. This causes excess

water retention by the kidney. Aldosterone (secreted by the adrenal gland)
causes the retention of sodium in the kidney.

4) Neurogenic hypertension
A defect in the cardiovascular control center or in the baroreceptors/osmotic
receptors.

Chronic hypertension can be self-perpetuating because the baroreceptors are "reset" to the
higher blood pressure. This occurs after 1-2 days. The implication is that baroreceptors
play little role in long-term blood pressure control. In other words, baroreceptors think
it’s ok to have high BP.

Hypertension causes an increase in the heart workload because of the increase resistance. The
increase workload can lead to congestive heart failure. Blood vessels over time will
weaken increasing the likelihood of stroke or kidney failure or retinal damage.
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Hypotension

Orthostatic hypotension - caused by getting up after a prolonged period of lying down.

Baroreflexes are slow to adjust.

Transient hypotension - higher cortical emotional centers can cause depression of the
sympathetic activity. This results in vasodilation and concomitant drop in blood
pressure, reducing profusion to the brain.

Self study - Circulatory Shock, Chap 10 (Sherwood) text as well as Chapters 21 thru 24
from Guyton.

Aneurysms

Three layers of blood vessels, intima, media and adventitia.

True Aneurysm

Berry

Fusiform

Pseudo Aneurysm

Dissected blood vessel or Dissected Aneurysm

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Endothelins

Endothelins are the most powerful vasoconstrictors found in the body. There are three known
types, ET-1, ET-2 and ET-3. The best characterized and most important form body-wide is ET-1.
There are two known receptors for ET-1, ET-A and ET-B receptors, found on smooth muscle of
vasculature. The main response to ET-A binding is vasoconstriction. ET-B binding seem to have
a paradoxical response by producing both vasoconstriction and vasodilation. The latter effect
occurs by way of ET-B simulating endothelial NOS (eNOS) activity, thereby NO release.

NO is also known as endothelium-derived relaxing factor (EDRF). As you know NO is a

powerful vasodilator. In addition to the vasoconstriction activity of ET-1, it also exerts a potent
mitogenic action on smooth muscles associate with blood vessels. Physical factors such as shear
stress, or stimuli including thrombin, epinephrine, angiotensin II, growth factors, cytokines and
free radicals enhance secretion of ET-1. By contrast, mediators like nitric oxide (NO), cyclic
GMP, atrial natriuretic peptide, and prostacyclin (a prostaglandin, anticlotting factor) reduce the
release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully
regulated through inhibition or stimulation of ET-1 release from endothelium.

Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered

function of endothelium may result from absolute decrease in bioavailability of NO as well as
from relative augment in ET-1 synthesis, release or activity. Imbalance in the production of
vasodilator and vasoconstrictor agents may contribute to the onset of hemodynamic disorders.
Since dysregulation of the endothelin system is important in the pathogenesis of several
cardiovascular diseases, the ETA and ETB receptors are attractive therapeutic targets for
disorders associated with elevated ET-1 levels.

ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to

preserve endothelial integrity when the endothelin system is overactive. Disruption of this
balance of ET-1 and NO causes deleterious changes in vasculature such as thicken of blood
vessels, proliferation of smooth muscle, arteriosclerosis, atherosclerosis, hypertension, diabetes
mellitus, compromised blood flow.

In many of these pathologies, smooth muscled cells become hypersensitive to ET-1. In addition
to ET-1’s effect on blood vessels, it has been found that it can play a role in immune-response by
activating macrophages, resulting in pro-inflammatory chemotactic mediators including TNF-
alpha, IL-1, IL-6, IL 8. This inflammation process is thought to be involved in atherosclerosis.
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Pulmonary Hypertension

Pulmonary Hypertension (PH) is high blood pressure in the pulmonary circulation. It is defined
as any mean pulmonary arterial pressure of more than 25 mmHg at rest or 30 mmHg during
exercise. This elevated pressure can affect the right side of the heart, making it harder to pump
blood into the lung because of increased afterload, cor pulmonale (aka pulmonary heart disease).
If severe enough, this could cause right side heart failure. One could have mild pulmonary
hypertension and be asymptomatic. As the disease progresses the following symptoms may
emerge. PH could lead to pulmonary edema, but that depends on what type of PH is involved
and severity.

Dyspnea, fatigue, syncope, chest pressure or pain, lower extremity edema, cyanosis, palpitations.

The high pressures result in endothelial damage and capillary leakage of serum proteins into the
interstitium. This leads to decreased production of nitric oxide (vasodilator) and increased
production of endothelin (vasoconstrictor) by the dysfunctional epithelium, resulting in increased
vascular tone. Over time, remodeling of the pulmonary vasculature occurs with
increased smooth muscle cell proliferation (medial hypertrophy) and collagen and elastase
deposition (intimal thickening and fibrosis). Remodeling is less extensive than in (idiopathic)
pulmonary arterial hypertension; therefore, PH due to left heart disease is usually at least
partially reversible following correction of the underlying abnormality (eg, LV dysfunction,
mitral valve disease).

There are many types and causes of PH. One of the ways to confirm pulmonary hypertension is
by right side heart catherization to check right atrial pressure.
Pulmonary hypertension is typically divided into 5 groups, depending on etiology.

Group 1: idiopathic pulmonary arterial hypertension (PAH); a specific gene mutation

that can cause pulmonary hypertension to develop in families, also called heritable
pulmonary arterial hypertension, congenital heart disease; anything involving connective
tissue disorders such as sclerodema, lupus. HIV infection or cirrhosis*. Note:
Eisenmenger syndrome (septal defect between left/right heart chambers).

* How does liver disease relate to pulmonary hypertension?

Liver disease can cause what is known as “portal hypertension,” meaning increased
blood pressure in the veins that enter the liver. This increased pressure causes blood
to bypass the liver; as a result, the blood is not subject to the liver’s work, which
includes the removal or detoxification of chemicals and poisons in the body.

As a result, the blood vessels of the lung are exposed to possible toxic substances and
this can damage the small arteries of the lungs, causing pulmonary arterial
hypertension (PAH). The criteria for PAH is mean arterial pressure greater than 25
mmHg with a normal left atrial pressure (pulmonary wedge pressure). This indicate
the etiology of the pathology is within the lung tissue proper and not a cardiac issue.
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Group 2: Left side valvular heart disease such as mitral or aortic valve defect or disease;
left ventricular failure. In this case one would have high pulmonary pressure, > 25 mmHg
and have a pulmonary wedge pressure above 15 mmHg.

Group 3: COPD (very common cause of PH); Restrictive lung disease; long term
exposure to high altitude.

Group 4: Pulmonary emboli

Group 5: Pulmonary hypertension associated with other conditions that have unclear
reasons why the pulmonary hypertension occurs: blood disorders, metabolic disorders,
tumors.
Drugs used to treat PH are typically from a class of drugs called Endothelin Receptor
Antagonists (ERAs)
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Sepsis

Sepsis is the body’s extreme response to an infection. The immune response to a pathogen is out
of balance with the infection and the cytokines and other molecules released in the blood from
the immune system causes organ damage.
Severe sepsis can lead to septic shock, which is the leading cause of death in the non-cardiac
intensive care unit (ICU). Sepsis and its progression to severe sepsis, septic shock and multiple
organ dysfunction syndrome is a major cause of ICU admissions and mortality. Severe sepsis
and septic shock may be characterized by a derangement in global cardiac indices typically
leading to low peripheral resistance, which the body tries to compensate for by increasing the
cardiac output. However, despite this increase in cardiac output, the tissues are unable to utilize
oxygen as evidenced by the high lactate levels, deranged acid-base balance, and increased gastric
carbondioxide level. The presence of tissue hypoxia despite adequate systemic oxygen transport
has been blamed on altered microhaemodynamics as well as in mitochondrial dysfunction during
sepsis. Most commonly, sepsis is caused by bacteria, but may also be virial, fungal or protozoan.
The early phase of sepsis characterized by excessive inflammation (sometimes resulting in a
cytokine storm) may be followed by a prolonged period of decreased functioning of the immune
system. The immune dysfunction may be in part, caused by wide spread apoptosis of immune
cells.

The inflammatory mediators that herald sepsis, and the changes they induce in the
macrohaemodynamics i.e., blood pressure, heart rate and oxygen extraction are well known. The
ensuing section highlights the changes induced in the microcirculation by sepsis.
“Five to fifteen minutes after its (endotoxin) intravenous administration, there were strong waves
of contraction along the small arteries, arterioles, and metaarterioles. These could arrest flow and
last for several minutes. There would afterwards be a phase of dilation, followed by a strong
contraction. As time went on, the phases of relaxation became more prominent until preagonally
(means right before death) there was a general and permanent vasodilation. The circulation
would slow progressively until death.”
This early description of response of microvessels to endotoxin in guinea pig and mouse
mesentery demonstrates the immediate arteriolar vasoconstriction response to endotoxin
followed by the subsequent phases of changing microvascular tone and ultimate cardiovascular
collapse.
The release of endotoxin or proinflammatory cytokines initiates a cascade of cellular and
mediator changes in sepsis. The corner stone of impaired homeostasis in sepsis is an
inflamed microcirculation. It is clogged with microthrombi and leaks extensively and the
central role in this microcirculatory dysfunction is in turn played by the endothelium. It is
damage to the endothelium that turns the usual water tight blood vessels into sieves allowing
large amounts of protein rich fluid to leak into the subcutaneous tissues, causing extensive tissue
edema and intravenous dehydration. Activation of the coagulation cascade leading to intra-
vascular thrombosis is also a result of the damaged endothelium that starts liberating
progoabulant factors. Besides these alterations, the endothelium also fails to perform its
regulatory functions, and its nitric oxide (NO) system is severely disturbed. There is a
heterogenous expression of inducible nitric oxide synthase (iNOS) in the endothelium of
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different areas of organ beds. Areas that lack iNOS have less NO induced vasodilation and
become underperfused resulting in pathological shunting of blood flow. Endothelin 1 levels have
been shown to elevate during sepsis and possibly plays a role in cytokine cascades.
The endothelium is not the only component of microcirculation to be altered. All other cellular
components of the microcirculation also undergo deterioration during sepsis. Smooth muscle
cells lining the arterioles lose their adrenergic sensitivity and tone. The red blood cells become
more rigid thus increasing the blood viscosity. The percentage of activated neutrophils with
decreased deformability and increased agreeability, due to upregulation of adhesion molecules
also increases.
Recently, endothelial glycocalyx has also been shown to be involved in sepsis induced
microcirculatory dysfunction. The glycocalyx is a layer covering the endothelium and consists of
endothelial cell derived proteoglycans, hyaluronan glycosaminoglycans, and selectively adsorbed
plasma proteins. It is the first interface between blood and tissue, and is involved in
physiological processes such as maintenance of vascular tone, mechanotransduction, and
transport along vessels. Its thickness regulates the organ blood flow and red blood cell velocity.
It has been suggested that glycocalyx destruction occurs during endotoxemia, and this may
participate in causing microvascular perfusion deficit.
The aforesaid cellular alterations in the microcirculation lead to impairment of all three
functional elements of the microvascular network. The arterioles are hyporesponsive to
vasoconstrictors and vasodilators despite the elevated levels of catecholamines, perfused
capillaries are reduced in number, and venules are obstructed by the sequestered neutrophils. In
the capillaries, besides a decreased density, there also occurs increased heterogeneity and an
increase in the proportion of stopped and intermittently perfused capillaries. This shut-down of
the vulnerable microcirculatory units in the organ beds promotes the shunting of blood and hence
oxygen, from arterial to venous compartment leaving the microcirculation hypoxic, along with a
decrease in oxygen extraction. The local microcirculatory partial pressure of oxygen drops below
the venous oxygen pressure. This difference has been termed the “pO2 gap” and is an indicator of
the severity of functional shunting. The systemic manifestation of this pathologic shunting is
seen as a deficit of oxygen extraction by tissues with an apparently normal delivery, and raised
venous pO2, lactate, and gastric CO2 levels. In addition, the blood flow regulation of
microcirculation is severely disrupted.
Studies have found that septic patients with organ dysfunction and poor outcomes had nitric
oxide overproduction, antioxident depletion, mitochondrial dysfunction, and decreased
adenosine triphosphate (ATP) production in biopsied muscles. Taken together, the idea emerged
that organ dysfunction in sepsis derived from tissues' inability to consume oxygen and
subsequent mitochodrial dysfunction. Oxidative phosphorylation is the major process to produce
cellular energy source ATP available to the body. It has been demonstrated that cytochrome c
(complex IV in the respiratory chain) is inhibited in sepsis. Cells may maintain their viability by
decreasing oxygen consumption and ceasing nonessential cellular functions. This likely plays a
role in organ failure.