Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 19 Introduction to the Regulation of Cardiovascular Function

Dysfunction of the cardiovascular system is the principal cause of death and disability in middle-aged and elderly men and women in the industrialized world. In the United States in 2004, there were nearly 1 million deaths from cardiovascular disease, representing approximately 36% of all deaths. In addition, estimates of the prevalence of cardiovascular disease in 2005 indicated that more than 70 million individuals had hypertension, 16 million had coronary heart disease, and more than 5 million had congestive heart failure (Table 19-1). To best understand pharmacological approaches to the management of these disorders, an overview of the regulation of cardiovascular function is warranted.

TABLE 19–1 Prevalence of Cardiovascular Disease in the United States in 2005*

Hypertension

73

Coronary heart disease

16

Myocardial infarction

8.1

Angina pectoris

9.1

Stroke

5.8

Congestive heart failure

5.3

* Data from the American Heart Association; numbers represent millions of persons.

The function of the cardiovascular system involves the autonomic nervous system (ANS), the kidneys, the heart, the vasculature, and the blood.

The ANS innervates the heart, blood vessels, kidney, and adrenal medulla and has the potential to modify cardiovascular function in a number of different ways (see Chapter 9).

The kidneys adjust the excretion of Na+, other ions and H2O to maintain extracellular fluid and volume; fluid retention by the kidney is a modifiable physiological parameter that can result in changes in blood pressure.

The heart, including the rhythmic nature of its electrical signals, force of contraction, and magnitude of the discharge pressure, is responsible for pumping the blood through the pulmonary system for oxygenation and delivering it through the vasculature to organs throughout the body.

The circulation (both blood volume and composition), including H2O, electrolyte and iron balances, cholesterol, lipid composition and capabilities for clot formation and lysis, delivers O2 and nutrients to and carries away CO2 and waste from all tissues.

Because these systems represent an integrated network, cardiovascular function can be affected by alterations at any point.

Cardiac performance and vascular caliber are controlled by several intrinsic regulatory mechanisms. The firing of pacemaker cells in the sinoatrial node determines heart rate, and several homeostatic mechanisms modulate cardiac pumping efficiency. Local regulation of the caliber of most resistance-producing blood vessels is influenced by the intrinsic contractile state of vascular smooth muscle, balanced by the production of vasodilator and vasoconstrictor substances originating from the endothelial cell monolayer lining the vessel lumen.

Abbreviations

ACh

Acetylcholine

ANS

Autonomic nervous system

CNS

Central nervous system

Epi

Epinephrine

NE

Norepinephrine

NPY

Neuropeptide Y

Superimposed on these control processes intrinsic to the heart and blood vessels are extrinsic factors that affect cardiovascular function. These include the metabolic status of the tissues in which blood vessels are embedded and locally produced and blood-borne vasoactive chemicals (autocrine/paracrine/endocrine regulation). It is critical to remember that arterial blood pressure is the product of cardiac output and total peripheral resistance to blood flow through the vascular system, with cardiac output determined by the rate and efficiency of the pumping of the heart. Vascular resistance increases as the viscosity of the blood and the length of blood vessels increases, and resistance to blood flow increases as blood vessel luminal diameter (caliber) decreases, particularly in precapillary arterioles, which represent the major structural determinant of vascular resistance.

The overall coordination and integration of organismal cardiovascular function is accomplished primarily by the ANS. Through its sympathetic and parasympathetic limbs, the ANS has powerful effects on both cardiac performance and blood vessel caliber (see Chapter 9).

The sympathetic and parasympathetic nerves innervating cardiovascular end organs are tonically active, which means that activity can be modulated by either increasing or decreasing the firing rate of these nerves. Effects of autonomic nerve activity on the mechanisms that control blood pressure are summarized in Figure 19-1. Parasympathetic effects are mediated by acetylcholine (ACh) released from postganglionic parasympathetic nerve endings, whereas sympathetic effects are mediated by norepinephrine (NE) released from postganglionic sympathetic nerve endings. Although there is no circulating ACh because of high cholinesterase activity in both tissue and blood, NE released from postganglionic sympathetic nerve endings escapes into the circulation because its degradation or reuptake is incomplete. This source of NE, in concert with the epinephrine (Epi) and NE released into the blood from the adrenal medulla, influence cardiovascular function as circulating neurohormones (see Chapter 9).

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FIGURE 19–1 Effects of the autonomic nervous system on blood pressure control. Vascular resistance is affected almost exclusively by the sympathetic nervous system, whereas cardiac output is regulated by both sympathetic and parasympathetic influences.

Overall cardiac performance is influenced by both parasympathetic and sympathetic actions at different sites within the heart.

Heart rate is decreased by parasympathetic activity and increased by sympathetic activity at the sinoatrial node, but the parasympathetic effect is usually dominant.

Ventricular contractile force is little influenced by parasympathetic activity but can be greatly increased by sympathetic activity, including the actions of circulating Epi and NE. Increased sympathetic activity reduces vascular caliber by contracting vascular smooth muscle. Although there are parasympathetic influences on a few vascular beds, their contribution to overall vascular resistance is insignificant. Constriction of veins in response to sympathetic activity reduces venous capacitance, thereby increasing venous return to the heart, which augments atrial and ventricular filling, resulting in increased cardiac output. Sympathetically mediated constriction of arterioles can reduce cardiac output by increasing the resistance against which the heart must pump blood. In addition, elevated sympathetic activity to the kidney increases renin release and subsequent angiotensin II formation and causes causing Na+ and H2O retention. All of these effects act in concert to elevate arterial blood pressure. Conversely, a reduction of sympathetic activity reduces blood pressure by removing the sympathetic stimulus. The receptors and signaling pathways involved are discussed in Chapter 9.

CENTRAL CONTROL OF AUTONOMIC NERVE ACTIVITY

The organization of autonomic cardiovascular control systems within the central nervous system (CNS) is summarized in Figure 19-2. The final common (preganglionic) output neurons for cardiovascular control by the parasympathetic nervous system are located principally in the nucleus ambiguus of the brainstem. The preganglionic neurons of the sympathetic nervous system are located in the intermediolateral columns of the thoracolumbar region of the spinal cord. Antecedent to these final output neurons, much of the integration of neural signals contributing to autonomic regulation of cardiovascular function occurs at other sites in the brainstem. These neurons, in turn, receive input from all levels of the CNS, some of the more important of which are diagrammed in Figure 19-2.

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FIGURE 19–2 Organization of autonomic cardiovascular control systems. Major inputs are in boxes. Many reciprocal connections are not illustrated. AP, Area postrema; CPA, caudal pressor area; CVLM, caudal ventrolateral medulla; CVO, circumventricular organs;DRG, dorsal root ganglia; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; VMM, ventromedial medulla.

Origin and Regulation of Autonomic Activity

One of the principal roles of the ANS is to provide adaptive regulation and coordination of blood pressure and flow to various organs of the body in the face of an ever-changing internal environment. This is accomplished by neural circuits intrinsic to the CNS and as a response to mechanical and humoral signals originating in the periphery. Integration of these signals by the CNS produces patterns of autonomic activity that ensure adequate organ perfusion appropriate to such diverse demands as changes in posture, hemorrhage, digestion, and exercise.

Parasympathetic preganglionic neurons that project to the heart via the vagus nerves have low levels of spontaneous firing, and their discharge rate is driven mostly by inputs from various afferents, particularly arterial baroreceptors. Inputs to spinal sympathetic preganglionic neurons originate in the brainstem, pons, and hypothalamus and can be either excitatory or inhibitory. However, the activity of spinal sympathetic preganglionic neurons regulating cardiovascular function is driven primarily by excitatory neurons located in the rostral ventrolateral medulla.

In addition to intrinsic CNS control, the efferent activity of autonomic nerves is powerfully regulated by neural signals arising from the periphery. Activation of visceral sensory afferents projecting to the brain via the vagus nerves generally reduces sympathetic activity and increases parasympathetic activity. These afferents include stretch receptors located in the cardiovascular system, which provide information about arterial pressure (arterial baroreceptors) and cardiac filling (cardiac baroreceptors) as well as stretch receptors and chemosensory receptors in the lungs, which provide information about respiratory mechanics and lung irritants, respectively. Afferents with chemosensory terminals located in the carotid sinus encode blood gas O2 concentration, send projections to the brain via the glossopharyngeal nerve, and when activated by hypoxia, hypercapnia, or acidic pH, increase efferent sympathetic nerve activity. All of these afferents make their first central synapse within the nucleus of the tractus solitarius located in the dorsomedial brainstem. Vagal afferents producing sympathoinhibition project primarily to the lateral aspects of the solitary tract nucleus, whereas glossopharyngeal afferents that produce sympathoexcitation project to more medial aspects of this nucleus.

Other visceral mechanosensitive and chemosensitive nerve terminals are located throughout the body. Some of these bipolar neurons, with cell bodies in the dorsal root ganglia, may initially commingle their axons within various sympathetic nerve trunks (sympathetic afferents) before synapsing on cells located in the dorsal horns of the spinal cord. Other sensory afferents do not travel with the sympathetic nerves and, instead, associate with various sensory-motor nerve trunks (somatic afferents) before synapsing in the spinal dorsal horns. All of these afferents typically encode noxious or painful chemical or mechanical stimuli, such as those associated with cardiac or visceral ischemia, visceral organ distension, or injury, and detect the metabolic products produced by exercising skeletal muscle. Activation of these afferents typically produces sympathoexcitation.

In addition to neural signals from the periphery, the brain also detects chemical signals (including drugs, such as digitalis) that circulate in the blood. A wide variety of circulating humoral substances, including catecholamines, indoleamines, and peptides, directly contact neurons within the CNS by diffusing through the fenestrated capillaries of circumventricular organs that lack a blood-brain barrier (seeFig. 19-2). Activation of circumventricular organ neurons produces integrated autonomic, endocrine, and behavioral responses that can regulate salt and H2O balance and nutrient homeostasis, in addition to cardiovascular function. The most important of the circumventricular organs for central autonomic control are the area postrema, subfornical organ, and organum vasculosum of the lamina terminalis.

Baroreceptor Reflex

The most rapidly acting autonomic control system for regulating blood pressure is the baroreceptor reflex. The principal role of this reflex is to ensure adequate organ perfusion, particularly to the brain and heart, and to promote return of blood to the heart in the face of conditions that lower arterial blood pressure. These might include gravitational pooling of blood, when assuming an upright posture, and instances where blood volume is lost, such as during severe dehydration or hemorrhage. The baroreceptor reflex is also activated when drugs are used to lower blood pressure in patients with cardiovascular disease, and this reflex may profoundly affect both the therapeutic effects and potential side effects that accompany drug therapy.

Minute-to-minute control of arterial blood pressure is achieved when small pressure changes are linked to reflex alterations in autonomic nerve activity. Sensory nerve endings embedded in the wall of the carotid sinus and aortic arch (baroreceptors) are activated by wall stretch when arterial pressure increases. This leads within a few seconds to an increase in vagal (parasympathetic) activity and a reduction in sympathetic activity. Parasympathetic activation slows heart rate, and sympathetic inhibition results in passive vasodilation, thus tending to return arterial pressure toward the original level. Conversely, a decrease in arterial pressure is rapidly countered by increased sympathetic and decreased parasympathetic activity. This results in vasoconstriction and an elevated cardiac rate and force of cardiac contraction. Organization of the baroreceptor reflex is illustrated in Figure 19-3.

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FIGURE 19–3 Brainstem organization of the baroreceptor reflex and associated neurotransmitters. Primary pathways only are shown. Other afferents and interneurons are omitted. CVLM, caudal ventrolateral medulla; GABA, γ-aminobutyric acid; GLU, 1-glutamate; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla; +, excitatory pathway; –, inhibitory pathway.

The baroreceptor reflex is important primarily in short-term control of blood pressure. When changes in blood pressure persist beyond a few minutes, reflex autonomic responses diminish. This is calledbaroreflex adaptation and involves both peripheral and CNS components. Varying degrees of baroreflex impairment occur with normal aging and in patients with heart failure or hypertension. This impairment may help to explain why some antihypertensive drugs are more effective in hypertensive than in normotensive patients, because lowering of blood pressure by antihypertensive drugs may be less effectively counteracted by baroreflex-mediated sympathetic vasoconstriction in these individuals.

The influence of baroreceptors on sympathetic nerve activity can vary greatly in different vascular beds. Some beds, such as the cutaneous vasculature, are largely independent of arterial baroreceptor influence and contribute little to total peripheral vascular resistance. In contrast, the baroreceptor reflex predominates in controlling sympathetic regulation of vascular caliber in many organs that receive a significant fraction of the cardiac output, such as skeletal muscle and kidney. For this reason baroreflex regulation of sympathetic vasoconstriction plays an important role in determining total peripheral resistance. In fact, except under some special circumstances (exercise, sleep, and certain behavioral states), baroreceptors are able to override all other inputs affecting autonomic regulation of arterial blood pressure. This may reflect the importance of maintaining a stable systemic blood pressure to ensure adequate organ perfusion under diverse environmental conditions.

REGULATION OF SYMPATHETIC ACTIVITY

One of the causes of hypertension is a relative increase in the balance between sympathetic and parasympathetic control over the heart and blood vessels. Increased sympathetic effects can be produced by increased neural firing rate, increased catecholamine concentration at the neuroeffector junction, and alterations at postjunctional receptors and signal transduction pathways. Although there is support for each of these mechanisms, the first two are probably most important, and drugs that inhibit sympathetically mediated cardiovascular effects are useful for treating hypertension.

Under physiological conditions, the amount of NE released is influenced by various chemicals, some of which are coreleased, such as neuropeptide Y and adenosine triphosphate, whereas others are released from postjunctional tissues, including angiotensin II, or are present in the circulation such as Epi (Table 19-2). Endogenous compounds that alter Ca++, Na+, or K+ channel activity lead to alterations in vesicular NE release. In addition, the released transmitter itself, acting at prejunctional autoreceptors, and other transmitters or hormones acting at prejunctional heteroreceptors can affect NE release. Activation of prejunctional receptors modulates the probability that individual vesicles will discharge their contents by exocytosis congruent with depolarization; it does not affect the amount of transmitter released by individual vesicles. Activation of inhibitory autoreceptors by NE may function as a physiological brake on transmitter secretion during periods of high-frequency nerve discharge, thus limiting postjunctional responses. Agonists at heteroreceptors facilitating transmitter release such as angiotensin II amplify the effects of sympathetic nerve depolarization. In contrast, activation of inhibitory heteroreceptors, such as occurs with adenosine, reduces the probability of vesicular exocytosis and transmitter release. Some of these mechanisms are illustrated in Figure 19-4. It is important to remember that because local mechanisms regulating NE release differ in different tissues, similar rates of sympathetic nerve firing may produce different effects in different tissues.

TABLE 19–2 Prejunctional Modulators of Sympathetic Neurotransmitter Release

image

image

FIGURE 19–4 Prejunctional regulation at the sympathetic neuroeffector junction. The left varicosity illustrates autoinhibition of neurotransmitter release, including possible “lateral” inhibition (i.e., transmitter from one varicosity inhibiting release from an adjacent varicosity). The right varicosity illustrates prejunctional regulation of transmitter release by tissue and blood-borne chemicals. See Table 19-2 for a list of involved substances. Postjunctional receptors are shown as circles, image; prejunctional inhibitory autoreceptors are shown as squares, image; prejunctional heteroreceptors are shown as triangles, image.

In addition to prejunctional regulation of release, the concentration of neurotransmitter at neuroeffector junctions can be influenced by alterations in transmitter synthesis, storage within the nerve terminal, and removal from the neuroeffector junction by diffusion, metabolism, and reuptake. These latter mechanisms are important targets for therapeutically active drugs.

Some of the factors proposed to play a causative role in hypertension as a consequence of increased sympathetic activity are listed in Box 19-1.

BOX 19–1 Some Factors Proposed to Cause Increased Sympathetic Nervous System Activation in Hypertension

Elevated sympathetic discharge

Physiological dysfunction

Sleep apnea

Stress

Obesity

Increased central sympathetic outflow

Impaired baroreceptor reflexes

Humoral

Increased plasma insulin

Increased plasma leptin

Increased plasma or tissue angiotensin II

Increased extracellular Na+

Enhanced NE release

Increased angiotensin II facilitation

Increased β2 adrenergic receptor facilitation

Decreased neuropeptide Y inhibition

FURTHER READING

Pang CC. Autonomic control of the venous system in health and disease: effects of drugs. Pharmacol Ther. 2001;90:179-230.

Robertson D, Biaggioni I, Burnstock G, Low PA. Primer on the autonomic nervous system. New York: Elsevier, 2004.

Sved AF, Ito S, Sved JC. Brainstem mechanisms of hypertension: Role of the rostral ventrolateral medulla. Curr Hypertens Rep. 2003;5:262-268.

For information specific to cardiovascular diseases, see http://www.Americanheart.org.

SELF-ASSESSMENT QUESTIONS

1. Increased activity of the sympathetic nervous system:

A. Increases heart rate.

B. Increases the force of cardiac contraction.

C. Decreases arteriolar caliber.

D. Increases venous return to the heart.

E. Produces all of the above effects.

2. Sympathetic activity to which of the following vascular beds is influenced the least by arterial baroreflexes?

A. Muscle

B. Skin

C. Kidney

D. Heart

E. Splanchnic viscera

3. Peripheral information from the lungs and heart are transmitted via sensory afferents to which nucleus in the brain?

A. Nucleus of the tractus solitarius

B. Paraventricular nucleus

C. Nucleus ambiguus

D. Caudal raphe nucleus