Medical Physiology, 3rd Edition

Response to Exercise

Adaptation to exercise probably places the greatest demands on circulatory function. The main feature of the cardiovascular response to exercise is an increased cardiac output, up to four or five times the resting cardiac output. The increase in cardiac output during exercise is more the result of increased heart rate (~3 times the control value) than of increased stroke volume (~1.5 times control). The cardiovascular response to exercise has both early and late components and originates from higher centers in the CNS (early), from mechanical and chemical changes triggered by contracting skeletal muscle (delayed), and from various reflexes (delayed).

Early physiologists suggested that muscle contraction leads to mechanical and chemical changes that trigger an increase in cardiac output

Contracting skeletal muscle produces cardiovascular changes that mimic many of those that occur during exercise. In fact, early physiologists believed that these skeletal muscle effects triggered all of the cardiovascular changes associated with exercise. We now know that these skeletal muscle effects are important only for the delayed cardiovascular responses in exercise. Muscle contraction directly affects the cardiovascular system in two ways (Fig. 25-6)—through a mechanical response that increases venous return and through a chemical response that dilates blood vessels in active muscle.


FIGURE 25-6 Early model of how exercise affects cardiovascular function. EDV, end-diastolic volume.

Mechanical Response: Increased Venous Return

The pumping action of contracting skeletal muscle improves venous return (see pp. 516 and 565). As a result, RAP, ventricular end-diastolic pressure, and end-diastolic volume should all increase. According to the Starling mechanism (see pp. 524–526), the result should be an increase in stroke volume.

Chemical Response: Local Vasodilation in Active Muscle

Enhanced skeletal muscle metabolism produces multiple changes in the chemistry of the interstitial fluid. The image and pH fall, whereas other metabolites (CO2, lactic acid, K+, and adenosine) accumulate. Moreover, the accumulation of metabolites causes interstitial osmolarity to increase. After a small delay that follows the onset of muscle contraction, the developing chemical changes cause the arterioles to dilate (see pp. 477–478 and 563–564), which may lead to an initial fall in arterial pressure. However, this fall is transient because of the intervening baroreceptor response (see p. 534), which increases heart rate and stroke volume, both of which enhance cardiac output. At the same time, the baroreceptor reflex vasoconstricts inactive muscle regions as well as the splanchnic, renal, and cutaneous circulations.

Cardiovascular physiologists believed for a long time that the mechanical and chemical limbs in Figure 25-6, both of which originate in active muscle, are responsible for the increased cardiac output during exercise. However, Figure 25-6 is not only incomplete, some of its predictions are incorrect or do not occur in the predicted order. As far as the mechanical effect on venous return is concerned, the model predicts a rise in ventricular end-diastolic pressure and thus end-diastolic volume. As far as the chemical effect is concerned, the model predicts that it should take time for chemical changes in active skeletal muscle to produce local vasodilation. Therefore, there ought to be a time lag between the initiation of exercise and the fall in mean arterial pressure that triggers the baroreceptor response (e.g., increased heart rate).

In the 1950s, Rushmer tested these predictions on trained unanesthetized dogs. Recording the mechanical limb of Figure 25-6, he found that at the onset of exercise, left ventricular end-diastolic pressure does not rise and that left ventricular end-diastolic volume diminishes rather than increases. These findings cast doubt on the primary role of the Starling mechanism in raising stroke volume during exercise. Recording the chemical limb of Figure 25-6, Rushmer found no transient fall in mean arterial pressure, thus casting doubt on the importance of the baroreceptor reflex. Furthermore, he saw no delay between the onset of exercise and the increase of heart rate, thus calling into question the idea that the chemically induced vasodilation is at the root of the tachycardia.

The explanation for the discrepancies between the predicted and actual findings is the presence of a central command that rapidly activates the sympathetic division of the ANS.

Central command organizes an integrated cardiovascular response to exercise

During exercise, a central command controls the parallel activation of both the motor cortex (see pp. 402–403) and cardiovascular centers. The central command involves such brain areas as the medial prefrontal cortex (involved in the mental state of thinking and planning exercise) as well as the insula and anterior cingulate gyrus, which are cortical parts of the limbic system (see p. 349). Indeed, the medial prefrontal cortex receives multiple limbic inputs. Moreover, both cortical centers modulate stress-related sympathetic outflow, including the sympathetic outflow related to exercise. imageN25-7 Rushmer and his colleagues explored various sites in the diencephalon (see p. 270) of dogs to determine if stimulation of any of them might mimic the integrated sympathetic response to exercise. In the 1950s, Rushmer found that stimulation of the H2 fields of Forel in the ventral thalamus or neurons in the periventricular gray matter of the hypothalamus reproduced all the details of the cardiac response to exercise, even though the muscles of the dog were completely quiescent. The central command centers project to the lateral hypothalamus, rostral ventrolateral medulla, and NTS to make autonomic adaptations appropriate for exercise (Fig. 25-7):


FIGURE 25-7 Integrated cardiovascular response to exercise. The hypothalamus orchestrates an early response, which includes vasodilation of active muscle (the mechanism of which is controversial in humans), vasoconstriction of certain inactive tissues, and increased cardiac output. In addition to those responses shown in Figure 25-6, the delayed responses (highlighted in yellow) include release of histamine, kallikreins, and epinephrine, leading to delayed vasodilation. Delayed local chemical responses from contracting muscles sustain early cardiovascular responses. Cutaneous thermoreceptors trigger delayed vasodilation in the skin.


Central Commands for Exercise Originating Outside the Medulla

Contributed by Emile Boulpaep

An increase in sympathetic output from the medullary cardiovascular center, by itself, would explain the immediate ventricular response during exercise. Increased sympathetic output from medullary centers would also explain the immediate vasoconstriction in inactive muscles and in the splanchnic, renal, and cutaneous circulations. However, sympathetic signals originating in the medulla cannot account for yet another immediate exercise response that occurs in dogs (though not humans and other primates)—a rapid vasodilation that occurs only in active skeletal muscle. On the contrary, experimental stimulation of medullary centers would constrict all muscle beds.

1. Increased cardiac output. Increased sympathetic output to the heart causes early tachycardia and increased contractility, resulting in a rapid upsurge of cardiac output.

2. Vasoconstriction. Sympathetic output from the medulla causes vasoconstriction in inactive muscle regions as well as in the renal, splanchnic, and cutaneous circulations. The net effect is to make more blood available for diversion to the contracting muscles. Except during maximal exercise, the increase in splanchnic and renal resistance does not result in a fall in local blood flow to the abdominal viscera and kidneys. Rather, because the arterial pressure increases along with the renal and splanchnic vascular resistance, the absolute blood flow remains close to resting levels in these tissues, even as the flow to the skeletal muscle increases markedly. However, fractional blood flow (i.e., local blood flow normalized to cardiac output) does fall in these regions. In the early phase of exercise, skin blood flow also decreases. However, cutaneous blood flow eventually rises, which reflects the attempt of the temperature-regulatory system to prevent body temperature from rising too much (see pp. 1200–1201).

3. Early vasodilation in active muscle. In dogs—although not in humans or other primates—at the initiation of exercise, central command stimulates hypothalamic neurons whose axons bypass the medullary cardiovascular centers and synapse on preganglionic sympathetic neurons in the spinal cord (see p. 539). The postganglionic neurons synapse on cholinergic sympathetic vasodilator fibers that innervate the vascular smooth muscle of skeletal muscle and trigger early peripheral vasodilation in active skeletal muscle. As discussed in the next section, the delayed local “chemical” response later reinforces this vasodilation.

The increased alertness that accompanies the anticipation of exercise can elicit all the components of the early response to exercise. The early response resembles the fight-or-flight reaction. In humans, the anticipatory cardiovascular adjustments prepare the body for the increased metabolism of the exercising skeletal muscle. For sprinters at the start of a 100-m dash, the anticipatory response prepares them to deliver an increased cardiac output and simultaneously to divert the increased blood flow away from tissues that do not require increased blood flow.

Muscle and baroreceptor reflexes, metabolites, venous return, histamine, epinephrine, and increased temperature reinforce the response to exercise

In addition to the events orchestrated by the command center, the integrated cardiovascular response to exercise includes the following:

1. Exercise pressor reflex. A neural drive called the exercise pressure reflex originates within the exercising muscle itself. Contraction activates stretch receptors that sense muscle tension and may also activate chemoreceptors that sense metabolites. Signals from these receptors travel through small thinly myelinated (Aδ or group III in Table 12-1) and unmyelinated (C or group IV) sensory fibers from skeletal muscle to the spinal cord and then on to the medullary cardiovascular control centers. This sensory input reinforces the central input to the cardiovascular control center and thus sustains the sympathetic outflow.

2. Arterial baroreflexes. Elevated mean arterial pressure resulting from high cardiac output and vasoconstriction outside active muscle would normally slow the heart. However, during exercise, central command resets the sensitivity of the arterial baroreflex so that the heart slows only at much higher arterial pressures. Conversely, if massive vasodilation in exercising skeletal muscle would reduce total peripheral resistance, the baroreceptor reflex maintains mean arterial pressure.

3. Vasodilation triggered by metabolites in skeletal muscle. Metabolites released locally (see Fig. 25-7) dilate the resistance vessels and recruit capillaries that had received no blood flow at rest (see pp. 563–564). As a result of this decrease in resistance, in concert with the increase in cardiac output, blood flow to active skeletal muscle can be as much as 20 times that to resting skeletal muscle. This vasodilator effect of metabolites thus more than overcomes any vasoconstrictive tendency produced by norepinephrine.

4. Increased venous return. The central command discussed in the preceding section explains the early increase in cardiac output during exercise. The mechanical and the chemical limbs described in Figure 25-6 further sustain the high cardiac output. Mechanically, the muscle pump increases venous return, and stroke volume rises by the Starling mechanism. Chemical mediators cause a vasodilation of active muscle beds that results in the rapid mobilization of blood from the central blood volume to exercising muscle.

5. Histamine release. Cells near the arterioles may release their intracellular stores of histamine, a potent vasodilator (see Table 20-8). Although these histamine-containing cells are quiescent when sympathetic nerves release norepinephrine, they release histamine when sympathetic tone wanes. Because of relaxation of the arterioles and precapillary sphincters, the pressure in the muscle capillaries rises, leading to increased extravasation of fluid and enhanced lymph flow.

6. Epinephrine release. During severe exercise, preganglionic sympathetic fibers to the adrenal medulla stimulate epinephrine release. The systemic effects of circulating epinephrine on cardiac β1 adrenoceptors enhance the neural effects on the heart, thus increasing cardiac output. Circulating epinephrine also acts on vascular β2 adrenoceptors, augmenting vasodilation mainly in skeletal muscle and heart.

7. Regulation of body core temperature. As exercise continues, increased metabolism causes body core temperature to rise, activating temperature-sensitive cells in the hypothalamus (see p. 1199). This activation has two effects, both of which promote heat loss through the skin as part of a temperature-regulatory response (see p. 1200). First, the hypothalamus signals the medulla to inhibit its sympathetic vasoconstrictor outflow to the skin, thereby increasing cutaneous blood flow. Recall that vasoconstriction is part of the early response to exercise (see above). Second, the hypothalamus activates sympathetic cholinergic fibers to sweat glands, causing an increase in sweat production as well as an indirect cutaneous vasodilation that may involve kinin formation. In addition, these neurons may co-release neurotransmitters that directly dilate cutaneous vessels (see p. 571).