Physiology 5th Ed.


The cardiovascular system always operates in an integrated manner. Thus, it is impossible to discuss a change only in cardiac function (e.g., a change in contractility) without then considering the effect such a change would have on arterial pressure, on hemodynamics, on the reflexes involving the sympathetic and parasympathetic nervous systems, on the renin–angiotensin II–aldosterone system, on filtration from capillaries and lymph flow, and on the distribution of blood flow among the organ systems.

The best and most enduring way to understand the integrative functions of the cardiovascular system is by describing its responses to exercise, to hemorrhage, and to changes in posture.

Responses to Exercise

The cardiovascular responses to exercise involve a combination of central nervous system (CNS) and local mechanisms. The CNS responses include a central command from the cerebral motor cortex, which directs changes in the autonomic nervous system. The local responses include effects of metabolites to increase blood flow and O2 delivery to the exercising skeletal muscle. Changes in arterial PO2, PCO2, and pH apparently play little role in directing these responses because none of these parameters changes significantly during moderate exercise.

Central Command

The central command refers to a series of responses, directed by the cerebral motor cortex, which are initiated by the anticipation of exercise. These reflexes are triggered by muscle mechanoreceptors, and possibly muscle chemoreceptors, when exercise is anticipated or initiated. Details concerning the afferent limb of this reflex (i.e., information traveling from the muscles to the CNS) are lacking. It is clear, however, that the efferent limb of the reflex produces increased sympathetic outflow to the heart and blood vessels and decreased parasympathetic outflow to the heart.

One consequence of the central command is an increase in cardiac output. This increase is the result of two simultaneous effects on the heart. (1) The increase in sympathetic activity (β1 receptors) and the decrease in parasympathetic activity cooperate to produce an increase in heart rate. (2) The increase in sympathetic activity (β1 receptors) produces an increase in contractility and a resulting increase in stroke volume.

Together, the increases in heart rate and stroke volume produce an increase in cardiac output. The increase in cardiac output is essential in the cardiovascular response to exercise. It ensures that more O2 and nutrients are delivered to the exercising skeletal muscle. (If cardiac output did not increase, for example, the only way to increase blood flow to the skeletal muscle would be through redistribution of blood flow from other organs.)

Recall that cardiac output cannot increase without a concomitant increase in venous return (Frank-Starling relationship). In exercise, this concomitant increase in venous return is accomplished by two effects on the veins: The contraction of skeletal muscle around the veins has a mechanical (squeezing) action, and activation of the sympathetic nervous system produces venoconstriction. Together, these effects on the veins decrease the unstressed volume and increase venous return to the heart. Again, the increase in venous return makes the increase in cardiac output possible.

Another consequence of the increased sympathetic outflow in the central command is selective arteriolar vasoconstriction. (1) In the circulation of the skin, splanchnic regions, kidney, and inactive muscles, vasoconstriction occurs via α1 receptors, which results in increased resistance and decreased blood flow to those organs. (2) In the exercising skeletal muscle, however, local metabolic effects override any sympathetic vasoconstricting effects, and arteriolar vasodilation occurs. (3) Other locations where vasoconstriction does not occur are in the coronary circulation (where blood flow increases to meet the increased level of myocardial O2 consumption) and the cerebral circulation. (4) In the cutaneous circulation, there is a biphasic response. Initially, vasoconstriction occurs (due to increased sympathetic outflow); later, however, as body temperature increases, there is selective inhibition of sympathetic cutaneous vasoconstriction (see Temperature Regulation, pages 173–174), resulting in vasodilation and dissipation of heat through the skin.

In summary, there is vasoconstriction in some vascular beds so that blood flow can be redistributed to the exercising skeletal muscle and the heart, with blood flow being maintained in essential organs such as the brain.

Local Responses in Muscle

Local control of blood flow in the exercising skeletal muscle is orchestrated by active hyperemia. As the metabolic rate of the skeletal muscle increases, production of vasodilator metabolites such as lactate, potassium, and adenosine also increases. These metabolites act directly on the arterioles of the exercising muscle to produce local vasodilation. Vasodilation of the arterioles results in increased blood flow to meet the increased metabolic demand of the muscle. This vasodilation in the exercising muscle also produces an overall decrease in TPR. (If these local metabolic effects in the exercising muscle did not occur, TPR would increase because the central command directs an increase in sympathetic outflow to the blood vessels, which produces vasoconstriction.)

Overall Responses to Exercise

The two components of the cardiovascular response to exercise, the central command and the effects of local metabolites, now can be viewed together (Table 4-8 and Fig. 4-35). The central command directs an increase in sympathetic outflow and a decrease in parasympathetic outflow. This produces an increase in cardiac output and vasoconstriction in several vascular beds (excluding exercising skeletal muscle, coronary, and cerebral circulations). The increase in cardiac output has two components: increased heart rate and increased contractility. The increase in contractility results in increased stroke volume and is represented by an increased pulse pressure (increased volume is pumped into the low-compliance arteries). Increased cardiac output is possible because venous return increases (Frank-Starling relationship). Venous return increases because there is sympathetic constriction of the veins (which reduces unstressed volume) and because of the squeezing action of the exercising skeletal muscle on the veins.

Table 4–8 Summary of Cardiovascular Responses to Exercise


Response to Exercise

Heart rate


Stroke volume

Pulse pressure

↑ (increased stroke volume)

Cardiac output


Venous return

Mean arterial pressure

↑ (slight)

Total peripheral resistance (TPR)

↓↓ (vasodilation in skeletal muscle)

Arteriovenous O2 difference

↑↑ (increased O2 consumption by tissues)


Figure 4–35 Cardiovascular responses to exercise. TPR, Total peripheral resistance.

A higher-than-normal percentage of this increased cardiac output will perfuse the exercising skeletal muscle because of local metabolic responses: Local metabolites produce vasodilation. Overall, TPR decreases because of this vasodilation in skeletal muscle, even though other vascular beds are vasoconstricted. There is an increase in systolic arterial pressure and pulse pressure because of the increase in stroke volume. However, diastolic arterial pressure remains the same or may even decrease secondary to the decrease in TPR.

Responses to Hemorrhage

When a person loses a large quantity of blood, arterial pressure decreases rapidly, followed by a series of compensatory cardiovascular responses that attempt to restore arterial pressure back to normal and to sustain life (Fig. 4-36and Box 4-3).


Figure 4–36 Effect of hemorrhage on mean arterial pressure (Pa). In some persons, compensatory responses to blood loss return Pa to normal within a few hours; in other persons, the compensatory response fails and irreversible shock and death occur.

BOX 4–3 Clinical Physiology: Hypovolemic Shock

DESCRIPTION OF CASE. Two teenagers, Adam and Ben, are involved in an automobile accident, and both suffer significant blood loss. They are taken to the nearest trauma center. Adam has a Pa of 55 mm Hg, a pulse pressure of 20 mm Hg, and a heart rate of 120 beats/min. He is anxious but alert, has a slightly decreased urine output, and has cool, pale skin. Ben has a Pa of 40 mm Hg, a barely measurable pulse pressure, and a heart rate of 160 beats/min. He is comatose, has no urine output, and is cold and cyanotic.

Adam is treated by stopping the bleeding and administering lactated Ringer solution intravenously and a blood transfusion. The physicians are prepared to administer a positive inotropic agent but find it unnecessary because Adam shows signs of improvement. During the next 5 hours, Adam’s Pa increases back to normal and his heart rate simultaneously decreases to a normal value of 75 beats/min. His skin gradually warms, and the normal pink color returns.

Ben is treated in the same way as Adam, but despite the efforts of the medical team, he dies.

EXPLANATION OF CASE. These teenagers illustrate two different responses to significant blood loss. In the first patient, Adam, the blood loss led to decreased Pa (decreased blood volume → decreased mean systemic pressure → decreased venous return → decreased cardiac output → decreased Pa). The decreased Pa triggered the baroreceptor reflex, resulting in increased sympathetic outflow to the heart and blood vessels. As a result of the reflex, the patient’s heart rate increased in an attempt to increase cardiac output. There was vasoconstriction of several vascular beds (excluding the heart and brain) and increased total peripheral resistance (TPR). Vasoconstriction of cutaneous blood vessels caused the skin to become cool and pale. Supportive therapy included intravenous infusion of buffered saline solution and transfusion, allowing the patient to fully recover. A positive inotropic agent might have been used to increase cardiac output; because the patient’s own reflex mechanisms increased myocardial contractility, it was unnecessary.

In the second patient, Ben, the compensatory mechanisms failed. When compared with Adam, Ben’s Pa is lower, his stroke volume is much lower (he had no pulse pressure), his heart rate is much higher, and the vasoconstriction is more pronounced (his skin was cold). His kidneys are not producing urine, which may explain his deteriorating condition. Clearly, the baroreceptor reflex is strongly activated because his heart rate is high and there is intense peripheral vasoconstriction. Vasoconstriction reduces blood flow to nonvital organs, such as skin, in order to preserve blood flow to vital organs such as the brain, heart, and kidneys. In this patient, vasoconstriction unfortunately extended to the vital organs, and the ischemic damage in them proved fatal. In this patient, myocardial ischemia and renal ischemia were particularly devastating: Without oxygen, his heart could not adequately function as a pump; without blood flow, his kidney could not produce urine.

TREATMENT. Despite treatment, one patient dies. The other patient responds well to treatment, which includes stopping the bleeding and administering lactated Ringer solution and a blood transfusion.

Decreased Arterial Pressure—Initiating Event

The initiating event in hemorrhage is loss of blood and decreased blood volume. Recall, by referring to Figure 4-29B, how a decrease in blood volume leads to a decrease in arterial pressure. When blood volume decreases, mean systemic pressure decreases and the vascular function curve shifts to the left. In the new steady state, the cardiac and vascular function curves intersect at a new equilibrium point, where both cardiac output and right atrial pressure are decreased.

These events also can be understood without referring to the graphs. Consider that when hemorrhaging occurs, there is a decrease in total blood volume. The decrease in blood volume produces a decrease in venous return to the heart and a decrease in right atrial pressure. When venous return decreases, there is a corresponding decrease in cardiac output (Frank-Starling mechanism). The decrease in cardiac output then leads to a decrease in Pa because Pa is the product of cardiac output and TPR (Pa = cardiac output × TPR). Hence, cardiac output and Pa decrease almost immediately, but thus far there has been no change in TPR (although TPR will change as a later compensatory response).

Within the few hours immediately following hemorrhage, arterial pressure gradually begins to increase back toward the normal (prehemorrhagic) value. This increase in arterial pressure is the result ofcompensatory responses in the cardiovascular system (Fig. 4-37 and Table 4-9; see Fig. 4-36).


Figure 4–37 Cardiovascular responses to hemorrhage. Pa, Mean arterial pressure; Pc, capillary hydrostatic pressure; TPR, total peripheral resistance.

Table 4–9 Summary of Cardiovascular Responses to Hemorrhage


Compensatory Response to Hemorrhage*

Carotid sinus nerve firing rate

Heart rate


Cardiac output

Unstressed volume

↓ (produces an increase in venous return)

Total peripheral resistance (TPR)


Angiotensin II


Circulating epinephrine

↑ (secreted from adrenal medulla)

Antidiuretic hormone (ADH)

↑ (stimulated by decreased blood volume)

*These compensatory responses should be compared with values immediately after the hemorrhage occurs, not with the prehemorrhagic values. For example, the compensatory increase in cardiac output does not mean that cardiac output is higher than it is in a normal person: It means that cardiac output is higher than just after the hemorrhage occurred.

In some persons the compensatory responses fail, and after a brief upswing, mean arterial pressure falls irreversibly and death ensues (i.e., irreversible shock). There are multiple reasons for this irreversible process including severe vasoconstriction of essential vascular beds and cardiac failure.

Responses of the Baroreceptor Reflex

Among the compensatory responses to a decrease in mean arterial pressure are those involved in the baroreceptor reflex. Baroreceptors in the carotid sinus detect the decrease in Pa and relay the information to the medulla via the carotid sinus nerve. The medulla coordinates an output that is intended to increase Pa back toward normal: Sympathetic outflow to the heart and blood vessels increases, and parasympathetic outflow to the heart decreases. The four consequences of these autonomic reflexes are (1) increased heart rate, (2) increased contractility, (3) increased TPR (due to arteriolar vasoconstriction in many vascular beds, but sparing of the coronary and cerebral vascular beds), and (4) constriction of the veins, which reduces unstressed volume, increases venous return, and increases stressed volume.

Notice that each of these four cardiovascular responses occurs in the direction of increasing Pa. Constriction of the veins (which decreases their compliance or capacitance) returns more blood to the heart, increases venous return and cardiac output, and shifts blood from the venous to the arterial side of the circulation. Increased heart rate and increased contractility result in increased cardiac output, which is possible because of the increased venous return. Finally, constriction of arterioles and increased TPR result in more blood being “held” on the arterial side (increased stressed volume and increased Pa).

Responses of the Renin–Angiotensin II–Aldosterone System

Another set of compensatory responses to the decrease in mean arterial pressure are those of the renin–angiotensin II–aldosterone system. When Pa decreases, renal perfusion pressure decreases, which stimulates the secretion of renin from the renal juxtaglomerular cells. Renin, in turn, increases the production of angiotensin I, which is then converted to angiotensin II. Angiotensin II has two major actions: (1) It causes arteriolar vasoconstriction, reinforcing and adding to the increase in TPR from the increased sympathetic outflow to the blood vessels. (2) It stimulates the secretion of aldosterone, which circulates to the kidney and causes increased reabsorption of Na+. By increasing total body Na+ content, aldosterone increases ECF volume, thereby raising blood volume and reinforcing the increase in stressed volume, which resulted from a shift of blood from the veins to the arteries.

Responses in the Capillaries

The compensatory responses to hemorrhage include changes in the Starling forces across capillary walls. These compensatory changes favor absorption of fluid into capillaries as follows: Increased sympathetic outflow to blood vessels and increased angiotensin II both produce arteriolar vasoconstriction. As a result of this vasoconstriction, there is a decrease in capillary hydrostatic pressure (Pc), which opposes filtration out of the capillary and favors absorption.

Responses of Antidiuretic Hormone

Antidiuretic hormone (ADH) is secreted in response to decreases in blood volume, mediated by volume receptors in the atria. ADH has two actions: (1) It increases water reabsorption by the renal collecting ducts (V2 receptors), which helps to restore blood volume. (2) It causes arteriolar vasoconstriction (V1 receptors), which reinforces the vasoconstricting effects of sympathetic activity and angiotensin II.

Other Responses in Hemorrhage

If a person becomes hypoxemic (has decreased arterial PO2) following a hemorrhage, chemoreceptors in the carotid and aortic bodies sense the decrease in PO2 and respond by increasing sympathetic outflow to the blood vessels. As a result, there is vasoconstriction, increased TPR, and increased Pa. This mechanism augments the baroreceptor reflex (which senses the decreased Pa rather than the decreased PO2).

If cerebral ischemia occurs following a hemorrhage, there will be a local increase in PCO2 and a decrease in pH. These changes activate chemoreceptors in the medullary vasomotor center to increase sympathetic outflow to blood vessels, resulting in peripheral vasoconstriction, increased TPR, and increased Pa.

Responses to Changes in Posture

The cardiovascular responses to a change in posture (or gravity) are illustrated in a person who changes from a supine (lying) position to a standing position. A person who stands up too quickly may briefly experience orthostatic hypotension (i.e., a decrease in arterial blood pressure upon standing), light-headedness, and possibly fainting. Normally, a series of fast compensatory cardiovascular responses involving the baroreceptor reflex occurs to offset this brief, initial decrease in Pa (Fig. 4-38 and Table 4-10).


Figure 4–38 Cardiovascular responses in a person moving from a supine to a standing position. TPR, Total peripheral resistance.

Table 4–10 Summary of Cardiovascular Responses to Standing


Pooling of Blood in the Extremities—Initiating Event

When a person moves from a supine to a standing position, blood pools in the veins of the lower extremities. The capacitance of the veins allows for large blood volumes to accumulate. When blood pools in the veins, venous return to the heart decreases and cardiac output decreases (Frank-Starling mechanism), which results in a decrease in mean arterial pressure.

Venous pooling also causes increased capillary hydrostatic pressure in the veins of the legs, which results in increased filtration of fluid into the interstitial fluid with a loss of intravascular volume. For example, if a person stands for an extended period of time (e.g., a soldier who is standing at attention), filtration from capillaries can exceed the ability of the lymphatics to return fluid to the circulation, which results in edema formation in the lower extremities. Increased filtration of fluid out of the capillaries contributes further to the decreased venous return and decreased Pa. If the decrease in Pa is dramatic, then cerebral blood pressure may decrease and cause fainting.

Response of the Baroreceptor Reflex

The primary compensatory cardiovascular response to the decrease in mean arterial pressure involves the baroreceptor reflex. As blood pools in the veins of the lower extremities and is not returned to the heart, both cardiac output and Pa decrease. The baroreceptors in the carotid sinus detect this decrease in Pa and send this information to the medullary vasomotor center. The vasomotor center directs anincrease in sympathetic outflow to the heart and blood vessels and a decrease in parasympathetic outflow to the heart, attempting to increase Pa back to normal. The results of these autonomic changes now are familiar: increased heart rate, increased contractility, constriction of arterioles (increased TPR), and constriction of the veins (decreased unstressed volume and increased venous return). Collectively, these changes increase cardiac output and increase TPR, attempting to restore Pa back to normal.

Box 4-4 describes heart failure and further illustrates the integrative nature of the cardiovascular system.

BOX 4–4 Clinical Physiology: Heart Failure

DESCRIPTION OF CASE. A 60-year-old woman is admitted to the hospital after complaining of extreme fatigue and weakness, shortness of breath (dyspnea), and swelling of her ankles. Her clothes no longer fit around the waist, and she has gained 3 kg in the past month. She finds that breathing is particularly difficult when lying down (orthopnea). Sleeping propped on several pillows no longer brings her relief. She has a history of chest pain and shortness of breath upon exertion.

Her physical examination reveals cyanosis (blue skin tone), rapid respirations, rapid pulse, distended neck veins, ascites (fluid) in the abdomen, edema in the ankles, and cold clammy skin. Her ventricular ejection fraction is 0.30. Her systolic pressure is 100 mm Hg, with a reduced pulse pressure. She is treated with digoxin and a diuretic and placed on a low-sodium diet.

EXPLANATION OF CASE. The woman’s signs and symptoms are a classic presentation of heart failure. The history of angina (chest pain) suggests that blockage of the coronary arteries has resulted in insufficient blood flow to the heart. With insufficient coronary blood flow, there is inadequate oxygen delivery to the working myocardial cells and the ventricles are unable to develop normal pressures for ejection of blood during systole. A negative inotropic state develops in the ventricles, resulting in decreased contractility and decreased stroke volume for a given end-diastolic volume (downward shift of the Frank-Starling relationship; see Figure 4-21). The decreased stroke volume is reflected both in the reduced pulse pressure and in the reduced ejection fraction of 0.30 (normal value is 0.55): A smaller-than-normal fraction of the end-diastolic volume is ejected during systole. Although not stated explicitly, cardiac output is also reduced. Cyanosis and easy fatigability are signs of inadequate blood flow to the tissues and inadequate oxygenation of blood.

The woman has edema (accumulation of interstitial fluid) in the lungs, as evidenced by shortness of breath, and in the peripheral tissues. Edema fluid accumulates when filtration out of capillaries exceeds the capacity of the lymphatics. In her case, there is increased filtration from capillaries because of a rise in venous pressure (note the distended neck veins). Venous pressure increases because blood “backs up” on the venous side of the circulation, as the ventricles are unable to efficiently eject blood during systole. Both left and right ventricles apparently have failed because edema has formed in the lungs (left heart failure) and in the periphery (right heart failure).

The baroreceptor reflex is activated in response to the decrease in Pa. (Pa is decreased because blood has shifted from the arterial to the venous side of the circulation, as the ventricles failed to pump adequately.) The woman’s increased pulse rate and cold clammy skin result from the baroreceptor reflex: Decreased Pa activates the baroreceptors, causing an increased sympathetic outflow to the heart and blood vessels (increases heart rate and produces cutaneous vasoconstriction) and decreased parasympathetic outflow to the heart (also increases heart rate). TPR, if measured, would be increased as a result of sympathetic vasoconstriction of many vascular beds, in addition to that of the skin.

The renin–angiotensin II–aldosterone system also is activated by the low Pa, and the increased levels of angiotensin II contribute to peripheral vasoconstriction. The increased levels of aldosterone increase Na+ reabsorption, total body Na+ content, and ECF volume, perpetuating the cycle of edema formation.

TREATMENT. Treatment involves two strategies: (1) to increase contractility of the myocardial cells by administering a positive inotropic agent such as digoxin and (2) to reduce total body Na+ content and the cycle of edema formation by administering a diuretic and by restricting sodium intake.