Other things being unchanged, an increased cardiac output raises mean arterial pressure. Therefore, it is not surprising that, as we have just seen, the heart is an important effector organ in the feedback loops that regulate mean arterial pressure. Cardiac output is the product of the heart rate and stroke volume (see Equation 17-6), and both factors are under the dual control of (1) regulatory mechanisms intrinsic to the heart, and (2) neural and hormonal pathways that are extrinsic to the heart.
Mechanisms intrinsic to the heart modulate both heart rate and stroke volume
Intrinsic Control of Heart Rate
As the length of diastole increases, the heart rate necessarily decreases. The diastolic interval is determined by the nature of the action potential fired off by the SA node. Such factors as the maximum diastolic potential, the slope of the diastolic depolarization (phase 4), and the threshold potential all influence the period between one SA node action potential and the next (see Fig. 21-6). Intrinsic modifiers of the SA node pacemaker, such as [K+]o and [Ca2+]o, greatly influence the ionic currents responsible for SA node pacemaker activity but are not part of any cardiovascular feedback loops.
Intrinsic Control of Stroke Volume
Stroke volume is the difference between end-diastolic volume and end-systolic volume (see Equation 22-2). Various processes intrinsic to the heart affect both of these variables.
The end-diastolic volume (EDV) depends on the following:
1. Filling pressure. Ventricular filling pressure depends to a large degree on atrial filling pressure. When increased venous return causes atrial filling pressure to rise, EDV rises as well.
2. Filling time. The longer the filling time, the greater the EDV. As heart rate rises, diastole shortens to a greater extent than does systole, thereby decreasing EDV.
3. Ventricular compliance (reciprocal of the slope of the diastole curve in Fig. 22-12B). As ventricular compliance increases, a given filling pressure will produce a greater increase in ventricular volume, thus resulting in a greater EDV.
The end-systolic volume (ESV) depends on the following:
1. Preload (i.e., end-diastolic volume). According to Starling's law of the heart, increase of the EDV increases the stretch on the cardiac muscle and the force of the contraction (see the systole curve in Fig. 22-12B), and thus the stroke volume. Only at a very large EDV does contraction begin to weaken as the muscle fibers are too stretched to generate maximal power (see Fig. 22-12A).
2. Afterload (force against which the ventricle ejects its contents). The afterload of the left ventricle is the mean systemic arterial pressure; the afterload of the right ventricle is the mean pulmonary arterial pressure. Increased afterload impedes the heart's ability to empty and thereby increases ESV.
3. Heart rate. An increased heart rate leads to greater Ca2+ entry into myocardial cells, thereby increasing contractility and reducing ESV (see p. 530).
4. Contractility. Positive inotropic agents act by increasing [Ca2+]i within the myocardial cells (see p. 530), thereby enhancing the force of contraction and decreasing ESV.
Note that a particular variable may affect both EDV and ESV. For example, an increased heart rate decreases EDV and decreases ESV. Therefore, its effect on stroke volume—the difference between these two volumes—may be difficult to predict.
Mechanisms extrinsic to the heart also modulate heart rate and stroke volume
We have already seen that the sympathetic and parasympathetic pathways are the efferent limbs of the feedback loops that control mean arterial pressure (see Fig. 23-5). These efferent limbs also control cardiac output via heart rate and stroke volume. Because we have already described the anatomy, neurotransmitters, and transduction mechanisms involved in these pathways, we focus here on how these pathways specifically affect the heart rate and stroke volume.
Baroreceptor responses affect both heart rate and stroke volume, the product of which is cardiac output. However, baroreceptors do not monitor cardiac output per se but rather arterial pressure. Thus, the baroreceptor response does not correct spontaneous alterations in cardiac output unless they happen to change mean arterial pressure. For example, when an increase in the cardiac output matches a commensurate decrease in the peripheral resistance, leaving the mean arterial pressure unchanged, the baroreceptors do not respond. On the other hand, even if cardiac output is unchanged, it will be the target of the baroreceptor response if other factors (e.g., changes in peripheral resistance) alter arterial pressure.
In Figure 23-6B, we saw that the integrated response to hypoxia and respiratory acidosis is tachycardia. This tachycardia response turns out to be a very helpful feedback mechanism for maintaining cardiac output. For example, a reduced cardiac output lowers arterial , raises , and lowers pH. These changes stimulate the peripheral chemoreceptors, indirectly producing tachycardia and thereby increasing cardiac output. Thus, the chemoreceptor response corrects changes in blood chemistry that are likely to result from reduced cardiac output. Once again, the detector (i.e., the peripheral chemoreceptor) does not sense changes in the cardiac output per se but rather in the metabolic consequences of altered cardiac output. Changes in cardiac output go unnoticed by the chemoreceptors if they do not affect arterial , , or pH.
It is fortunate that a high increases the heart rate (see Fig. 23-6B) because a high has a direct effect on the heart, decreasing myocardial contractility. High leads to intracellular acidosis of the myocardial cells (see pp. 645–646). The low pHi shifts the [Ca2+]i-tension curve of cardiac muscle to higher [Ca2+]i values, which reflects a lower sensitivity of the cardiac form of troponin C (TNNC1) to [Ca2+]i. Thus, in the absence of reflex tachycardia, high would decrease myocardial force and thereby lower cardiac output.
Low-pressure baroreceptors in the atria respond to increased “fullness” of the vascular system, triggering tachycardia, renal vasodilation, and diuresis
The baroreceptors located at high-pressure sites (i.e., the carotid sinus and aortic arch) are not the only stretch receptors involved in feedback regulation of the circulation. Low-pressure baroreceptors—bare ends of myelinated nerve fibers—are located at strategic low-pressure sites, including the pulmonary artery, the junction of the atria with their corresponding veins, the atria themselves, and the ventricles (Fig. 23-7A). Distention of these receptors depends largely on venous return to the heart. Therefore, these mechanoreceptors detect the “fullness” of the circulation and are part of a larger system of volume sensors that control the effective circulating volume of blood (see p. 838). These low-pressure receptors also help control cardiac output. By regulating both effective circulating volume and cardiac output, these receptors also indirectly regulate mean arterial blood pressure.
FIGURE 23-7 Low-pressure receptors. In B, A-type receptors (orange) are located mainly in the body of the right atrium; B-type receptors (green) are located mainly in the superior and inferior vena cava. ECG, electrocardiogram.
The most extensively studied low-pressure receptors are the atrial receptors. These are located at the ends of afferent axons—either A or B fibers—that join the vagus nerve (CN X). The A fibers fire in synchrony with atrial systole and therefore monitor heart rate (see Fig. 23-7B). The B fibers fire in a burst during ventricular systole (see Fig. 23-7B) and gradually increase their firing rate as the atria fill, reaching maximum firing frequency at the peak of the v wave of the atrial (i.e., jugular) pulse (see Fig. 22-7A). Thus, the B fibers monitor the rising atrial volume. Because the central venous pressure (CVP)—the pressure inside large systemic veins leading to the right heart—is the main determinant of right atrial filling, the B fibers also detect changes in CVP. By inference, the atrial B-type stretch receptors primarily monitor effective circulating volume and venous return.
The afferent pathways for the low-pressure receptors are similar to those for high-pressure baroreceptors and peripheral chemoreceptors traveling along the vagus nerve and projecting to the NTS (see p. 537) and other nuclei of the medullary cardiovascular center. To some extent, the efferent pathways and effector organs (i.e., heart and blood vessels) also are similar. However, whereas increased stretch of the high-pressure receptors lowers heart rate, increased stretch of the atrial B-type receptors raises heart rate (the Bainbridge reflex, which we discuss in the next section). Moreover, whereas increased stretch of the high-pressure receptors causes generalized vasodilation, increased stretch of the atrial B-type receptors decreases sympathetic vasoconstrictor output only to the kidney. The net effect of increased atrial stretch (i.e., tachycardia and renal vasodilation) is an increase in renal blood flow and—as seen on page 768—an increase in urine output (i.e., diuresis). Decreased atrial stretch has little effect on heart rate but increases sympathetic output to the kidney. Therefore, as far as their direct cardiovascular effects are concerned, the high-pressure baroreceptors respond to stretch (i.e., increased blood pressure) by attempting to decrease blood pressure. The low-pressure baroreceptors respond to stretch (i.e., increased fullness) by attempting to eliminate fluid.
The afferent fibers of the atrial receptors that project to the NTS also synapse there with neurons that project to magnocellular neurons in the paraventricular nucleus of the hypothalamus (see Fig. 40-8). These hypothalamic neurons synthesize arginine vasopressin (AVP)—also known as antidiuretic hormone (see pp. 817–819)—and then transport it down their axons to the posterior pituitary for release into the blood (see pp. 979–981). Increased atrial stretch lowers AVP secretion, which produces a water diuresis and thus decreases total body water (see pp. 846–849).
In addition to stimulating bare nerve endings, atrial stretch causes a non-neural response by stretching the atrial myocytes themselves. When stretched, atrial myocytes release atrial natriuretic peptide (ANP) or factor (ANF). N3-18 ANP is a powerful vasodilator. It also causes diuresis (see p. 843) and thus enhances the renal excretion of Na+ (i.e., it causes natriuresis). In these ways, it lowers effective circulating volume blood pressure.
Thus, enhanced atrial filling with consequent stretching of the atrial mechanoreceptors promotes diuresis by at least three efferent mechanisms, the first two of which are neurally mediated: (1) Tachycardia in combination with a reduced sympathetic vasoconstrictor output to the kidney increases renal blood flow. (2) Atrial baroreceptors cause decreased secretion of AVP. (3) The stretch of the atrial myocytes themselves enhances the release of ANP.
Stretching of the ventricular low-pressure stretch receptors causes bradycardia and vasodilation, responses similar to those associated with stretching of the arterial high-pressure receptors. However, these ventricular receptors do not contribute appreciably to homeostasis of the cardiac output.
Cardiac output is roughly proportional to effective circulating blood volume
The Bainbridge reflex is the name given to the tachycardia caused by an increase in venous return. An increase in blood volume leads to increased firing of low-pressure B fibers (see Fig. 23-7B) during atrial filling. The efferent limb of this Bainbridge reflex is limited to instructions carried by both parasympathetic and sympathetic pathways to the SA node, which determines heart rate. Effects on cardiac contractility and stroke volume are insignificant. Because the Bainbridge reflex saturates, the increase in heart rate is greatest at low baseline heart rates.
The Bainbridge reflex acts as a counterbalance to the baroreceptor reflex in the control of heart rate. The orange curve on the right upper quadrant of Figure 23-8 illustrates the Bainbridge reflex: increase of the effective circulating volume (i.e., increase of venous return and stimulation of low-pressure receptors) increases heart rate. On the other hand, we have already noted that decreased atrial stretch has little effect on heart rate by the Bainbridge reflex. The orange curve in the left upper quadrant of Figure 23-8 illustrates the intervention of the high-pressure baroreceptors. That is, a decrease in blood volume does not cause heart rate to fall but rather causes it to rise. Indeed, a significant reduction in blood volume leads to a fall in mean arterial pressure, reduced baroreceptor firing, and—via the cardioinhibitory and cardioacceleratory areas in the medulla (see Fig. 23-4B)—stimulation of the SA node. Therefore, on examination of the full orange curve in Figure 23-8, we see that changes in blood volume or venous return have a biphasic effect on heart rate. By different mechanisms, volume loading and volume depletion both cause a graded increase in heart rate. In general, during volume loading, the Bainbridge reflex prevails, whereas during volume depletion, the high-pressure baroreceptor reflex dominates. Heart rate is at its minimum when effective circulating volume is normal.
FIGURE 23-8 Effect of blood volume on cardiac output. The investigators changed effective circulating volume (x-axis) by altering blood volume.
Like heart rate (see Fig. 23-8, orange curve), stroke volume also shows a peculiar, biphasic dependence on effective circulating volume (blue curve) that is the result of two competing effects. In the case of stroke volume, the competitors are Starling's law and the baroreceptor reflex. According to Starling's law, as venous blood volume increases, enhanced ventricular filling increases EDV, thereby improving cardiac performance and thus stroke volume (see pp. 524–526). The Starling relationship reflects the intrinsic properties of the heart muscle. However, in a real person, the baroreceptor reflex has a major influence on the dependence of stroke volume on blood volume. At low blood volumes, the baroreceptor reflex produces high sympathetic output, increasing contractility and steepening the Starling relationship (blue curve in the left lower quadrant of Fig. 23-8). At high blood volumes, the Starling relationship normally tends to be less steep. Moreover, the baroreceptor reflex reduces sympathetic output, thereby decreasing contractility and further flattening the blue curve in the right half of Figure 23-8.
In contrast to the biphasic response of heart rate and stroke volume to changes in effective circulating volume, cardiac output rises monotonically (see Fig. 23-8, red curve). The reason for this smooth increase is that cardiac output is the product of heart rate and stroke volume. Starting from very low blood volumes (see the extreme left of Fig. 23-8), increase in the blood volume causes a gradual rise in stroke volume (blue curve), offset by a fall in heart rate (orange curve), resulting in an overall rise of cardiac output (red curve) until blood volume and stroke volume reach normal levels. Further increases in blood volume have no effect on stroke volume (blue curve) but increase heart rate (orange curve), further increasing cardiac output (red curve). Consequently, the dependence of cardiac output on effective circulating volume N23-10 is the result of the complex interplay among three responses: (1) the Bainbridge reflex, (2) the baroreceptor reflex, and (3) Starling's law.
Monotonic Dependence of Cardiac Output on Effective Circulating Volume
Contributed by Emile Boulpaep
The following is a summary and restatement of the discussion that began on pages 547–548.
Starting from a volume-contracted state (change in effective circulating volume = −30 mL/kg in Fig. 23-8), a gradual increase in effective circulating volume causes the cardiac output to increase monotonically (see Fig. 23-8, lower left portion of red curve) because the rising stroke volume (Starling's law, steepened by baroreceptor response, as indicated by the lower left portion of the blue curve) more than counterbalances the falling heart rate (baroreceptor reflex, as indicated by the falling phase of the orange curve).
Continuing now from a normal volume state (change in effective circulating volume = 0 mL/kg in Fig. 23-8), an additional increase in effective circulating volume causes a further monotonic increase in cardiac output because a rising heart rate (the Bainbridge reflex, as indicated by the rising phase of the orange curve) combines with the flat stroke-volume curve (the Starling relationship—normally flattening at high degrees of stretch—is further flattened by the baroreceptor reflex).