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The HeartBlood VesselsCardiac Output and Blood Pressure Blood CellsHemostasis

Cardiac Output and Blood Pressure


Cardiac Output

Cardiac output is the volume of blood pumped by the heart per minute (mL blood/min). Cardiac output is a function of heart rate and stroke volume. The heart rate is simply the number of heart beats per minute. The stroke volume is the volume of blood, in milliliters (mL), pumped out of the heart with each beat. Increasing either heart rate or stroke volume increases cardiac output.

Cardiac Output in mL/min = heart rate (beats/min) X stroke volume (mL/beat)

An average person has a resting heart rate of 70 beats/minute and a resting stroke volume of 70 mL/beat. The cardiac output for this person at rest is:

Cardiac Output = 70 (beats/min) X 70 (mL/beat) = 4900 mL/minute.

The total volume of blood in the circulatory system of an average person is about 5 liters (5000 mL). According to our calculations, the entire volume of blood within the circulatory sytem is pumped by the heart each minute (at rest). During vigorous exercise, the cardiac output can increase up to 7 fold (35 liters/minute)


Control of Heart Rate

The SA node of the heart is enervated by both sympathetic and parasympathetic nerve fibers. Under conditions of rest the parasympathetic fibers release acetylcholine, which acts to slow the pacemaker potential of the SA node and thus reduce heart rate. Under conditions of physical or emotional activity sympathetic nerve fibers release norepinephrine, which acts to speed up the pacemaker potential of the SA node thus increasing heart rate. Sympathetic nervous system activity also causes the release of epinephrine from the adrenal medulla. Epinephrine enters the blood stream, and is delivered to the heart where it binds with SA node receptors. Binding of epinephrine leads to further increase in heart rate.


Control of Stroke Volume

Under conditions of rest, the heart does not fill to its maximum capacity. If the heart were to fill more per beat then it could pump out more blood per beat, thus increasing stroke volume. Also, the ventricles of the heart empty only about 50% of their volume during systole. If the heart were to contract more strongly then the heart could pump out more blood per beat. In other words, a stronger contraction would lead to a larger stroke volume. During periods of exercise, the stroke volume increases because of both these mechanisms; the heart fills up with more blood and the heart contracts more strongly.

Stroke volume is increased by 2 mechanisms:

  1. increase in end-diastolic volume
  2. increase in sympathetic system activity

End-diastolic Volume

An increase in venous return of blood to the heart will result in greater filling of the ventricles during diastole. Consequently the volume of blood in the ventricles at the end of diastole, called end-diastolic volume, will be increased. A larger end-diastolic volume will stretch the heart. Stretching the muscles of the heart optimizes the length-strength relationship of the cardiac muscle fibers, resulting in stronger contractility and greater stroke volume.

Starling's Law

Starling's Law describes the relationship between end-diastolic volume and stroke volume. It states that the heart will pump out whatever volume is delivered to it. If the end-diastolic volume doubles then stroke volume will double.



An Increase in Sympathetic Activity Increases Stroke Volume

The cardiac muscle cells of the ventricular myocardium are richly enervated by sympathetic nerve fibers. Release of norepinephrine by these fibers causes an increase in the strength of myocardiall contraction, thus increasing stroke volume. Norepinephrine is thought to increase the intracellular concentration of calcium in myocardial cells, thus facilitating faster actin/myosin cross bridging. Also, a general sympathetic response by the body will induce the release of epinephrine from the adrenal medulla. Epinephrine, like norepinephrine will stimulate an increase in the strength of myocardial contraction and thus increase stroke volume.



Blood Volume

Fluid Exchange Betweem Capillaries and Tissues

Capillaries are composed of a single layer of squamos epithelium surrounded by a thin basement membrane. Most capillaries (except those servicing the nervous system) have pores (spaces) between the individual cells that make up the capillary wall. Plasma fluid and small nutrient molecules leave the capillary and enter the interstitial fluid through these pores, in a process called bulk flow. Bulk flow facilitates the efficient transfer of nutrient out of the blood and into the tissues. However, blood cells and plasma proteins, which are too large to fit through the pores, do not filter out of the capillaries by bulk flow.
Together, blood plasma and interstitial fluid make up the extracellular fluid (ECF). Plamsa constitutes 20%, while interstitial fluid constitutes 80% of the ECF. The distribution of extracellular fluid between these two compartments is determined by the balance between two opposing forces: hydrostatic pressure and osmotic pressure.
The beating of the heart generates hydrostatic pressure, which, in turn, causes bulk flow of fluid from plasma to interstitial fluid through walls of the capillaries. In other words, the pressure in the system forces plasma to filter out into the interstitial compartment. The composition of the interstitial fluid and the plasma is essentially the same except that plasma also contains plasma proteins not found in the interstitial fluid. Because of the presence of plasma proteins, the plasma has a higher solute concentration than does the interstitial fluid. Consequently, osmotic pressure causes interstitial fluid to be absorbed into the plasma compartment. In other words, the plasma proteins drive the reabsorption of water back into the capillaries via osmosis.
The magnitudes of filtration and absorption are not equal. The net filtration of fluid out of the capillaries into the interstitial compartment is greater than the net absorption of fluid back into the capillaries. The excess filtered fluid is returned to the blood stream via the lymphatic system. In addition to its roles in digestion and immunity, the lymphatic system functions to return filtered plasma back to the circulatory system. The smallest vessels of the lymphatic system are the lymphatic capillaries (shown in yellow). These porous, blind-ended ducts form a large network of vessels that infiltrate the capillary beds of most organs. Excess interstitial fluid enters the lymphatic capillaries to become lymph fluid.

Lymphatic capillaries converge to form lymph vessels that ultimately return lymph fluid back to the circulatory system via the subclavian vein. The presence of one-way valves in the lymph vessels ensures unidirectional flow of lymph fluid toward the subclavian vein.

If excess fluid cannot be returned to the blood stream then interstitial fluid builds up, leading to swelling of the tissues with fluid, this is called edema.


Causes of Edema

1. Reduced concentration of plasma proteins. When the concentration of plasma proteins drops, the osmotic potential of plasma drops, thus less interstitial fluid is absorbed into the capillaries. The rate of filtration, however, remain unchanged. Therefore, the ratio of filtration to absorption increases, leading to a build up of interstitial fluid. Any condition that would lead to a reduction in plasma proteins could potentially cause edema. Examples of conditions that reduce plasma proteins include:

  • Kidney disease can result in the loss of plasma proteins in the urine.
  • Liver disease can decrease the synthesis of plasma proteins.
  • A protein-deficient diet will decrease plasma proteins.
  • Severe burns result in a loss of plasma proteins (albumin) at the burn site

2. Increased capillary permeability. During an inflammatory response, tissue damage leads to the release of histamine from immune cells. Histamine causes an increase in the size of capillary pores. As capillaries become more permeable, the rate of filtration increases.

3. Increase in venous pressure. If venous pressure is increased then blood dams up in the upstream capillary bed, resulting in excess filtration. Examples of this condition include:

  • Left heart failure. The left half of the heart drains blood from the lungs. When the left ventricle fails to adequately pump blood, venous pressure in the lungs increases. This increase in hydrostatic pressure causes an increase in the rate of filtration of fluid out of the capillaries and into the interstitial compartment. As a result, the lungs fill with fluid, a condition called, pulmonary edema.
  • Standing still. If one stands still for long period of time, then blood will pool in the veins of the legs. This will increase venous pressure and lead to weeping of fluid into the tissues. You can actually feel your feet swell if you stand motionless for a long time.

4. Blocked Lymphatics. If lymph vessels become blocked, then lymph fluid will not be drained from the effected area and the area will swell. Any condition that causes blockage or removal of lymph vessels can lead to edema. Examples of this condition include:

  • Filaria round worms are transmitted to humans by some species of mosquitos. The worms migrate to the lymph vessels and block them. This causes dramatic swelling of the effected area, a condition called elaphantiasis.
  • Treatment for breast cancer may include removal of lymph vessels from breast and arms. This is done to limit the metastasis (spread) of cancerous cells to other parts of the body through the lymph. Removal of lymph vessels results in swelling of the effected area.


Regulation of Blood Volume by the Kidneys

The kidneys filter the blood and eliminate excess water and metabolic wastes by producing and excreting urine. The daily volume of urine produced by the kidneys affects the amount of ECF in the body and thus has a direct influence on blood volume. If the kidneys retain water then blood volume rises. However, if the kidneys excrete large amounts of water then the blood volume will decrease.

The regulation of water excretion by the kidneys is controlled, in large part, by antidiuretic hormone (ADH). In the presence of ADH, the kidneys retain water. In the absence of ADH the kidneys excrete more water. ADH is produced by the hypothalamus and secreted by the posterior pituitary gland. The hypothalamus contains osmoreceptors that directly monitor the osmolality of plasma. Plasma osmolality is high when plasma volume is low. Osmoreceptors detect this condition and signal for the secretion of ADH. Retention of water by the kidney restores blood volume to normal. ADH has the added effect of stimulating thirst. Thus when your body needs water you are driven to seek water.


Regulation of Blood Flow

Blood Flow through Vessels is effected by Pressure and Resistance

The flow of blood through the vessels of the circulatory system is a function of the pressure in the system and the resistance to flow caused by the blood vessels. Blood flow is directly proportional to pressure and inversely proportional to resistance.

If the pressure in a vessel increases then the blood flow will increase. However, if the resistance in a vessel increases then the blood flow will decrease.

Resistance in the blood vessels is effected by three parameters:

  1. Length of the vessel. The longer the vessel the greater the resistance.
  2. Viscosity of the blood. The greater the viscosity the greater the resistance.
  3. Radius of the vessel. The smaller the radius the greater the resistance.

The relationships between factors that effect blood flow are described by Poiseuille's Law, which states:

Of all of the factors that effect blood flow, the radius of the blood vessel is the most potent. Blood flow is proportional to the 4th power of vessel radius. This means that if the radius of a blood vessel doubles (by vasodilation) then the flow will increase 16 fold (2 to the 4th power is 16). On the other hand, if the radius of a vessel is reduce in half (by vasoconstriction), then the blood flow will be reduced 16 fold. Because small changes in vessel radius make very large changes in blood flow, it is no surprise that the body controls blood flow to specific areas of the body by controlling the radius of arterioles servicing those areas.


Extrinsic Regulation of Blood Flow

Extrinsic regulation refers to a form of control that comes from an outside source. The extrinsic regulation of blood flow refers to the control of arteriolar radius by both the autonomic nervous system and the endocrine system.

Sympathetic Control of Arteriolar Radius
Arterioles are enervated by the sympathetic nervous system only. (Parasympathetic enervation of arterioles only occurs in the male penis, where it results in erection.) Sympathetic nerve fibers secrete norepinephrine. Binding of norepinephrine to receptors on the smooth muscles of arterioles causes contraction and thus leads to vasoconstriction. Arterioles servicing tissues at rest receive a baseline amount of sympathetic stimulation and thus are slightly constricted (vessel b in the figure). This baseline level of constriction is called Vascular Tone. Vasodilation is accomplished by decreasing sympathetic stimulation below baseline (vessel a). Vasoconstriction is accomplished by increasing sympathetic stimulation above baseline (vessel c).


Endocrine Control of Arteriolar Radius.

The endocrine system is composed of a variety of glands that produce and secrete hormones. Hormones are signalling molecules that enter the blood stream and travel throughout the body. Although all body cells are exposed to the hormone, the only cells that respond to it are the cells that have specific receptors that bind the hormone. Epinephrine is a hormone that has a significant effect on the radius of blood vessels. Epinephrine is secreted by the adrenal medulla (an endocrine gland atop the kidneys) in response to sympathetic stimulation. Epinephrine enters the blood stream and travels to all part the body interacting with those cells having epinephrine receptors on their cell surface.


There are two types of epinephrine receptors found in blood vessels, alpha receptors (a) and beta-2 receptors (b-2). Epinephrine can cause either vasoconstiction or vasodilation of blood vessels depending on the type of receptor found in the smooth muscle of a particular vessel. The binding of epinephrine to a receptors leads to vasoconstriction. a receptors are found in all arterioles. Conversely, the binding of epinephrine to b-2 receptors leads to vasodilation. b-2 receptors are found predominantly in arterioles servicing skeletal muscle and heart muscle. During a full-blown sympathetic response (fight or flight), blood is directed to the skeletal muscle and heart, and away from the internal organs. This is possible because b-2 receptors mediate vasodilation in the skeletal muscle and heart, while the rest of the circulatory system (which has a receptors) experiences vasoconstriction.


Intrinsic Regulation of Blood Flow

Intrinsic regulation refers to local control of arteriolar radius. Intrinsic regulation allows some organs to regulate their own blood flow regardless of what may be happening elsewhere in the body. Intrinsic regulation take the form of metabolic control or myogenic control.

Metabolic Control

As a result of metabolic activity, cells produce by-products called metabolites. When a tissue increases its activity the production of metabolites will also increase. If blood flow to the area remains constant in the face of this change, then the metabolites will build up in the tissues. The major metabolites that build up include CO2, ADP, extracellular K+ and organic acids. These metabolites directly stimulate the vasodilation of local arterioles, thus increasing blood flow. This mechanism, in which an increase in the activity of a tissue induces an increase in blood flow to the area, is called active hyperemia. This increase in blood flow eventually lowers the levels of metabolites thus removing the original stimulus for vasodilation. In the absence of excess metabolites the arteriole returns to its original diameter.


Myogenic Control

The smooth muscles in blood vessels are directly affected by pressure. If blood pressure and flow of blood to an organ are low then the smooth muscles of adjacent arterioles relax. The resulting vasodilation restores adequate blood flow. Conversely, if blood flow to an organ is excessive then smooth muscles of the arterioles will vasoconstrict, thus reducing flow to appropriate levels. Through myogenic control, arterioles are somewhat self-regulating.


Exercise and Blood Flow

The changes in blood flow that occur during exercise provide an excellent illustration of intrinsic and extrinsic control of arteriolar radius. The vascular tone of arterioles found in skeletal muscle is relatively high, consequently blood flow to resting muscles is low (20-25% of total blood flow). However, during heavy exercise, blood flow to the skeletal muscles increases significantly (up to 80-85% of total blood flow). The increase in blood flow to skeletal muscles during exercise is mediated by three factors: (1) an increase in cardiac output, (2) vasodilation of skeletal muscle arterioles, (3) vasoconstriction of arterioles in the viscera and skin.

  1. An increase in cardiac output. Exercise activates the sympathetic nervous system. Increased sympathetic output to the heart causes an increase in heart rate and stroke volume. Heavy exercise increases venous return of blood to the heart via the skeletal muscle pump and the respiratory pump. An increase in venous return leads to an increase in end-diastolic volume (EDV), which in turn, causes an increase in stroke volume.
  2. Vasodilation of skeletal muscle arterioles. The most important factor governing flow of blood to exercising muscles is local metabolic control (active hyperemia). As muscular activity increases, metabolites build up and directly induce the vasodilation of local arterioles. Additionally, beta-adrenergic stimulation by epinephrine causes vasodilation of arterioles in skeletal muscle.
  3. Vasoconstriction of arterioles in the viscera and skin. As a result of alpha-adrenergic sympathetic stimulation, arterioles in the viscera and skin vasoconstrict during exercise. However, as exercise progresses and body temperature rises, cutaneous arterioles dilate in order to radiate heat and reduce body temperature.
Summary of Factors that Effect Blood Flow during Exercise


Regulation of Blood Pressure

Constant and adequate pressure in the arterial system is required to drive blood into all of the organs. Abnormally low blood pressure results in inadequate perfusion of organs, while abnormally high blood pressure can cause heart disease, vascular disease and stroke. Therefore, it is essential that blood pressure be maintained within a narrow range of values that is consistent with the needs of the tissues.

Pressure in the arterial system fluctuates with the cardiac cycle. Blood pressure reaches a peak in systole and is lowest in diastole. Rather than focusing on these extremes of blood pressure we will discuss blood pressure in terms of the mean arterial pressure (MAP). Mean arterial pressure represents the average pressure in the arterial system. This value is important because it is the difference between MAP and the venous pressure that drives blood through the capillaries of the organs. Because more time is spent in diastole than in systole, MAP is not simply the average of the systolic and diastolic pressures.

A simple formula for calculation of MAP is:

MAP = diastolic pressure + 1/3 pulse pressure

Pulse pressure = systolic pressure - diastolic pressure


Major Factors that Effect Mean Arterial Pressure

The three most important variables effecting MAP are:

  1. total peripheral resistance (TPA)
  2. cardiac output
  3. blood volume.


MAP = Cardiac Output X Total Peripheral Resistance


Total Peripheral Resistance (TPA)

Blood vessels provide resistance to the flow of blood because of friction between moving blood and the wall of the vessel. The TPA refers to the sum total of vascular resistance to the flow of blood in the systemic circulation. Because of their small radii, arterioles provide the greatest resistance to blood flow in the arterial system. Adjustments in the radii of arterioles has a significant effect on TPA, which in turn has a significant effect on MAP. Resistance and pressure are directly proportional to each other. If resistance increases, then pressure increases. When the radii of arterioles decrease with vasoconstriction, TPA increases, which causes MAP to increase.


Cardiac Output

Cardiac output refers to the volume of blood pumped by the heart each minute. Put another way, the cardiac output is a measure of blood flow into the arterial system. Blood flow is directly proportional to pressure (Flow = pressure/resistance), therefore an increase in flow (cardiac output) will cause an increase in pressure (MAP).


Blood Volume

Blood volume is directly related to blood pressure. If the blood volume is increased, then venous return of blood to the heart will increase. An increase in venous return will, by Starling's Law, cause stroke volume to increase. As stroke volume goes up the cardiac output goes up and the blood pressure rises. Thus one way to control blood pressure over the long term is to control blood volume.


Baroreceptor Reflexes in Short-term Regulation of MAP

Blood pressure is contolled on a minute-to-minute basis by baroreceptor reflexes. Baroreceptors are specialized stretch receptors that detect changes in blood pressure. Baroreceptors are located in the walls of arteries, veins and the heart. The most important baroreceptors being those found in the carotid sinus and the aorta. Baroreceptors, which constantly monitor blood pressure, communicate with the Cardiovascular Control Center (CCC) found in the brain stem. Changes in blood pressure effect the frequency of action potentials sent to the CCC from the baroreceptors. The CCC responds to changes in baroreceptor input by initiating compensatory mechanisms that restore blood pressure back to normal.

The diagram to the right illustrates the efffect of blood pressure on the production of action potentials by the baroreceptors. 80 mmHg is a baseline MAP for a typical person (given a measured blood pressure of 120/60). At a baseline of 80 mmHg a baroreceptor will produce a constant baseline frequency of action potentials (seen as small, vertical, blue lines in the diagram). If blood pressure rises above baseline, the baroreceptor increases its frequency of action potential output. On the other hand, if blood pressure drops below baseline, then the baroreceptor decreases its frequency of action potential output.


Baroreceptor Response to Increased Blood Pressure

An increase in blood pressure causes an increase in action potentials sent to the cardiovascular control center. The CCC responds by decreasing sympathetic input and increasing parasympathetic input to the heart. This causes a drop in heart rate and stroke volume, which lowers cardiac output, which in turn lowers MAP. The CCC also decreases sympathetic input to the blood vessels. This causes vasodilation, which lowers resistance (TPA) which causes blood pressure to drop. Overall, the compensatory mechanisms of the baroreceptor reflex act to restore blood pressure back to normal.

Conversely, a decrease in blood pressure causes a decrease in action potentials sent to the cardiovascular control center, which causes an increase in sympathetic input, which causes vasoconstriction and increased cardiac output, which causes a rise in blood pressure, thus restoring blood pressure back to normal.


Blood Volume in Long Term Regulation of MAP

Blood volume is directly related to blood pressure. If the blood volume is increased then venous return of blood to the heart will increase, thus stroke volume will increase, thus cardiac output will increase and the blood pressure will rise. Therefore, blood pressure can be controlled by controlling blood volume.

Plasma, the liquid portion of blood, is part of the extracellular fluid (ECF). If the kidneys retain water, then the volume of the ECF rises and blood volume rises. If the kidneys retain salt (NaCl), then the ECF becomes saltier and thus capable of retaining more water (water follows solute). Higher ECF volume leads to higher blood volume and thus higher blood pressure.



Summary of Factors that Effect Mean Arterial Pressure


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(Revised September 17 1999)
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