Introduction to the Regulation of Cardiovascular Function

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*

* 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.

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).

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.

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