Interplay of Central and Peripheral Factors That Control the Circulation

Mild to Moderate Exercise

In humans and in trained animals, anticipation of physical activity inhibits vagus nerve impulses to the heart; this withdrawal of vagal nerve activity underlies the initial increase in heart rate. Eventually, sympathetic nerve discharge also increases. The concerted inhibition of parasympathetic areas and activation of sympathetic areas of the medulla increase the heart rate and myocardial contractility. The tachycardia and the enhanced contractility increase the cardiac output, in turn raising the arterial pressure.

Exercise can be understood with the help of cardiac function and vascular function curves described in Chapter 10 . An example is shown in Fig. 13.1 . From the interactions described in Chapter 10 , Fig. 13.1 can be seen as a composite that illustrates the effects of two changes. First, along with tachycardia, there is increased contractility caused by norepinephrine released from cardiac sympathetic nerves (see also Figs. 5.23 and 10.15 ). Second, there is a change in the vascular function curve that results from vasodilation (see Fig. 13.1 ; see also Fig. 10.13 ). In this closed circulatory system, TPR is reduced as a result of vasodilation in the skeletal muscle vascular bed. The vascular function curve is shifted upward, as is the contractility curve, because cardiac output and venous return are two measures of the same parameter.

Peripheral Resistance Declines During Exercise

At the same time that the heart is stimulated, the sympathetic nervous system elicits vascular resistance changes in the periphery. In skin, kidneys, splanchnic regions, and inactive muscle, sympathetically mediated vasoconstriction increases vascular resistance, diverting blood away from these areas ( Fig. 13.2 ). This greater resistance in vascular beds of inactive tissues persists throughout the period of exercise.

The increase in blood flow in the active muscles at the onset of exercise cannot be attributed to a neural mechanism, because a chemical block of the autonomic nervous system does not alter this blood flow response. This increase in muscle blood flow may be caused by the modest elevation of blood pressure or by some unknown mechanism.

As cardiac output and blood flow to active muscles increase with progressive increments in the intensity of exercise, visceral blood flow ( splanchnic and renal vasculatures ) decreases. Blood flow to the myocardium increases, whereas that to the brain is unchanged (see Fig. 13.2 ). Skin blood flow initially decreases during exercise. It then increases, as body temperature rises with increments in duration and intensity of the exercise. Skin blood flow finally decreases when the skin vessels constrict, as the total body O ₂ consumption ( $\dot{\text{V}}{\text{O}}_2$ _max ) nears maximum.

The major circulatory adjustment to prolonged exercise involves the vasculature of the active muscles. Local formation of vasoactive metabolites induces marked dilation of the resistance vessels, which progresses as the intensity level of exercise increases. Potassium is one of the substances released by contracting muscle, and it may be in part responsible for the initial decrease in vascular resistance in the active muscles. Elevated interstitial K ⁺ can cause vasodilation by stimulation of the Na-K pump and by activation of the conductance of inwardly rectifying K ⁺ channels. Either action causes hyperpolarization of vascular smooth muscle membrane, thereby reducing Ca ⁺⁺ entry. Other contributing factors are the release of adrenocorticotropic hormone (ACTH) , the activation of adenosine triphosphate–sensitive potassium channels ( K _ATP channels ), and a decrease in pH during sustained exercise. All of these factors can act locally to dilate arterioles in contracting muscle. Adenosine release and K _ATP channel activation are thought to act at more distal arterioles to increase blood flow. The mechanism for the transmission of the dilating effect to distal arterioles is not understood.

The local accumulation of metabolites relaxes the terminal arterioles. Blood flow through the muscle may rise 15 to 20 times above the resting level (see Fig. 13.2 ). This metabolic vasodilation of the precapillary vessels in active muscles occurs very soon after the onset of exercise. Furthermore, the decrease in TPR enables the heart to pump more blood at a lesser load and more efficiently ( less pressure work ; see Chapter 4 ) than if TPR were unchanged. Only a small percentage of the capillaries is perfused at rest, whereas in actively contracting muscle, nearly all of the capillaries contain flowing blood ( capillary recruitment ).

The surface available for exchange of gases, water, and solutes is increased manyfold. Furthermore, the hydrostatic pressure in the capillaries increases because of the relaxation of the resistance vessels. Hence there is a net movement of water and solutes into the muscle tissue. Interstitial pressure rises, and it remains elevated during exercise, as fluid continues to move out of the capillaries and is carried away by the lymphatics. Lymph flow is increased as a result of both the rise in capillary hydrostatic pressure and the massaging effect of the contracting muscles on the valve-containing lymphatic vessels (see Chapter 8 ).

The contracting muscle avidly extracts O ₂ from the perfusing blood ( increased Ao ₂ –V.o ₂ difference ) ( Fig. 13.3 ), and the release of O ₂ from the blood is facilitated by the nature of oxyhemoglobin dissociation. The reduction in pH caused by the high concentration of CO ₂ and the formation of lactic acid and the increase in temperature in the contracting muscle all contribute to shifting the oxyhemoglobin dissociation curve to the right, an example of the Bohr effect (see Fig. 1.5 ). At any given partial pressure of O ₂ , less O ₂ is bound by the hemoglobin in the red blood cells; consequently, O ₂ removal from the blood is facilitated. Oxygen consumption may increase as much as sixtyfold, with only a fifteenfold increase in muscle blood flow. Muscle myoglobin serves as a limited O ₂ store in exercise; it can release attached O ₂ at very low partial pressures. Hence it facilitates O ₂ transport from capillaries to mitochondria by serving as an O ₂ carrier.

Cardiac Output Can Increase Substantially in Exercise

The enhanced sympathetic drive and the reduced parasympathetic inhibition of the sinoatrial node continue during exercise, and consequently tachycardia persists. If the workload is moderate and constant, the heart rate will reach a certain level and remain there throughout the period of exercise. However, if the workload increases, a concomitant rise in heart rate occurs until a plateau is reached during severe exercise at about 180 beats per minute (beats/min) (see Fig. 13.3 ). With moderate exercise, there is a substantial increase in stroke volume of about 10% to 35% (see Fig. 13.3 ), the larger values occurring in trained individuals. (In very well-trained distance runners, whose cardiac outputs can reach six to seven times the resting level, stroke volume reaches about twice the resting value.) The increase in stroke volume has been ascribed to the Frank-Starling mechanism because left ventricular end-diastolic pressure and end-diastolic volume increase (see Chapter 4 ). This is seen in the rightward shift of the equilibrium point B in Fig. 13.1 . (The importance of greater ventricular filling in the response of cardiac output during exercise is underscored by the observation that increasing the heart rate alone through pacing is associated with reduced stroke volume and a constant cardiac output.) Contractility also increases during moderate exercise, an indication of sympathetic activation (see Fig. 13.1 ; see also Chapter 5 ). When exercise is strenuous, cardiac output increases largely as a result of tachycardia. Stroke volume remains at a plateau or may even diminish slightly (see Fig. 13.3 ) while contractility remains elevated.

FLOAT NOT FOUND

Thus it is apparent that the increase in cardiac output observed with exercise is correlated with an increase in heart rate. If the baroreceptors are denervated, the cardiac output and heart rate responses to exercise are sluggish in comparison with the changes in animals with normally innervated baroreceptors. However, exercise still elicits an increment in cardiac output in the absence of autonomic innervation of the heart, as occurs when a donor heart is prepared for transplantation. Resting heart rate is elevated to about 100 beats/min because parasympathetic innervation is lacking. The increment in cardiac output is less than that observed in normal subjects, and it is achieved principally by means of a gradual increase in heart rate. The stroke volume also increases but is below the level seen in the normal heart. If a β -adrenergic receptor–blocking agent is given, exercise performance is impaired in subjects with transplanted hearts. The β-adrenergic receptor antagonist opposes the cardiac acceleration and enhanced contractility caused by increased amounts of circulating catecholamines. Hence the increase in cardiac output necessary for maximal exercise performance is limited.

Venous Return Is Enhanced in Exercise

In addition to the contribution made by sympathetically mediated constriction of the capacitance vessels in both exercising and nonexercising parts of the body, venous return is aided by the working skeletal muscles and the muscles of respiration (see Fig. 13.1 ). The intermittently contracting muscles compress the vessels that course through them (see Fig. 12.2 ). In the case of veins with their valves oriented toward the heart, blood is pumped back toward the right atrium. The flow of venous blood to the heart is also aided by the increase in the pressure gradient developed by the more negative intrathoracic pressure produced by deeper and more frequent respirations. In humans, there is little evidence that blood reservoirs such as skin, lungs, and liver contribute much to circulating blood volume. In fact, blood volume is usually reduced slightly during exercise, as evidenced by a rise in the hematocrit ratio, because of both water lost externally by sweating and enhanced ventilation, and movement of fluid into the contracting muscle.

The fluid loss from the vascular compartment into contracting muscle reaches a plateau as interstitial fluid pressure rises and opposes the increased hydrostatic pressure in the capillaries of the active muscle. The fluid loss is partially offset by movement of fluid from the splanchnic regions and inactive muscle into the bloodstream. This influx of fluid occurs as a result of a decrease in hydrostatic pressure in the capillaries of these tissues and an increase in plasma osmolarity caused by movement of osmotically active particles into the blood from the contracting muscle. In addition, reduced urine formation by the kidneys helps to conserve body water.

Arterial Pressure Increases Slightly During Exercise

If the exercise involves a large proportion of the body musculature, as in running or swimming, the reduction in total vascular resistance can be considerable (see Fig. 13.3 ). Nevertheless, arterial pressure starts to rise with the onset of exercise, and the increase in blood pressure roughly parallels the intensity of the exercise performed (see Fig. 13.3 ). Therefore the increase in cardiac output is proportionally greater than the decrease in TPR. The vasoconstriction produced in the inactive tissues by the sympathetic nervous system (and to some extent by the release of catecholamines from the adrenal medulla) is important for maintaining normal or increased blood pressure because sympathectomy or drug-induced block of the sympathetic adrenergic nerve fibers results in a decrease in arterial pressure ( hypotension ) during exercise.

Some sympathetically mediated vasoconstriction occurs in active muscle and increases during strenuous exercise, when more than half of the total body musculature is contracting. In experiments in which one leg is working at maximal levels and then the other leg starts to work, blood flow decreases in the first working leg. Furthermore, blood levels of norepinephrine rise significantly in exercise, and most is derived from the sympathetic nerve endings in the active muscles.

As body temperature rises during exercise, the skin vessels dilate in response to thermal stimulation of the heat-regulating center in the hypothalamus, and TPR decreases further (see Fig. 13.3 ). This would result in a decline in blood pressure were it not for the increasing cardiac output and constriction of arterioles in the renal, splanchnic, and other tissues.

In general, mean arterial pressure rises during exercise, as a result of the increase in cardiac output (see Fig. 13.3 ). However, the effect of enhanced cardiac output is offset by the overall decrease in TPR. Hence the mean blood pressure rise is relatively small. Vasoconstriction in the inactive vascular beds contributes to the maintenance of a normal arterial blood pressure for adequate perfusion of the active tissues. The actual pressure attained represents a balance between cardiac output and TPR (see p. 128). Systolic pressure usually increases more than diastolic pressure, resulting in an increase in pulse pressure (see Fig. 13.3 ). The larger pulse pressure is primarily attributable to a greater stroke volume and, to a lesser degree, to a more rapid ejection of blood by the left ventricle. Peripheral runoff is less during the brief ventricular ejection period.

Severe Exercise

When severe exercise is taken to the point of exhaustion, the compensatory mechanisms begin to fail. Heart rate attains a maximal level of about 180 beats/min, and stroke volume reaches a plateau. The stroke volume often decreases, resulting in a fall in blood pressure. Dehydration occurs, and sympathetic vasoconstrictor activity supersedes the vasodilator influence on the cutaneous vessels. The neural activity has the hemodynamic effect of a slight increase in effective blood volume. However, cutaneous vasoconstriction also reduces the rate of heat loss. Body temperature is normally elevated in exercise, and reduction in heat loss through cutaneous vasoconstriction can, under these conditions, lead to very high body temperatures, with associated feelings of acute distress. The tissue and blood pH values decrease as a result of greater lactic acid and CO ₂ production. The reduced pH is probably the key factor that determines the maximal amount of exercise a given individual can tolerate because of muscle pain, subjective feelings of exhaustion, and inability or loss of the will to continue. A summary of the neural and local effects of exercise on the cardiovascular system is schematized in Fig. 13.4 .

Postexercise Recovery

When exercise stops, sympathetic activity to the heart declines, and the heart rate and cardiac output decrease. Peripheral sympathetic activity also decreases, and coupled with resistance vessel dilation ( caused by the accumulated vasodilator metabolites ), arterial pressure falls, often below the preexercise level. This hypotension is brief, and the baroreceptor reflexes restore the blood pressure to normal levels.