Baroreflex

The regulation of the total peripheral resistance also involves the complex interactions of several mechanisms. These include baroreflexes and sympathetic nervous system activity response to neurohumoral substances and endothelial factors myogenic adjustments at the cellular level, some mediated by ion channels and events at the cellular membrane and intercellular events mediated by receptors and mechanisms for signal transduction. As examples of some of these mechanisms, there are two major neural reflex arcs (Fig. 1). Baroreflexes are derived from high-pressure barorecep-tors in the aortic arch and carotid sinus and low-pressure cardiopulmonary baroreceptors in ventricles and atria. These receptors respond to stretch (high pressure) or... 

When the temporal sequence of adjustments of blood pressure is analysed it seems, that CNS mechanisms (e.g., baroreflexes) will provide regulation of the circulation within seconds to minutes. Other mechanisms, such as the renin-angiotensin-aldosterone system and fluid shifts, occur over minutes to hours. Only the... 

The decrease in the ability of the aging body to respond to baroreflexive stimuli can result in very serious consequences for elderly patients [115-117]. Because of this decrease in sensitivity and the decreased cardiac output witnessed in elderly patients, they are predisposed to the effects of orthostatic hypotension that can occur when one is taking antihypertensive medication (e.g., prazosin). Indeed, the fact that elderly persons are prone to accidental falls may be due to this change in sensitivity [115-117]. 

Decrease baroreflex sensitivity Decrease -receptor response Decrease 2 -receptor response Increase sensitivity to barbiturates Decrease glucose tolerance... 

If persistent, these molecules (coding for inflammation, oxidative stress, remodeling, and thrombosis) can cause endothelial dysfunction and acceleration of arthrosclero-sis progression [117]. SWNTs were shown also to alter the cardiac activity by affecting the arterial baroreflex function (BRF) of sinus mode in rats exposed by intratracheal instillation [118]. 

Many other changes make older adults more vulnerable regarding cardiovascular drugs. There is a decrease in baroreceptor reflex response. This may explain the increased sensitivity to nitrates (Marchionni et al. 1990). With age there is a loss of blood vessel distensibility and enhanced intimal thickness. This can partly explain the increase of systolic blood pressure. Aging is also associated with a reduction in baroreflex-mediated heart rate response to hypotensive stimuli (Verhaeverbeke and Mets 1997, Lakatta and Levy 2003). 

Anesthesia induction with propofol causes a significant reduction in blood pressure that is proportional to the severity of cardiovascular disease or the volume status of the patient, or both. However, even in healthy patients a significant reduction in systolic and mean arterial blood pressure occurs. The reduction in pressure appears to be associated with vasodilation and myocardial depression. Although propofol decreases systemic vascular resistance, reflex tachycardia is not observed. This is in contrast to the actions of thiopental. The heart rate stabilization produced by propofol relative to other agents is likely the result of either resetting or inhibiting the baroreflex, thus reducing the tachy-cardic response to hypotension. 

General outlines of the cellular actions of sympathomimetics are presented in Tables 6-3 and 9-3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of a and 3 adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation. The net effect of a given sympathomimetic in the intact organism depends not only on its relative selectivity for cx or 3 adrenoceptors and its pharmacologic action at those receptors any effect these agents have on blood pressure is counteracted by compensatory baroreflex mechanisms aimed at restoring homeostasis. 

Effects of autonomic blockade on the response to phenylephrine (Phe) in a human subject. Left The cardiovascular effect of the selective K-agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal. In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. 

Table 9-4). Activation of 32 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine functions largely as a hormone after release from the adrenal medulla into the blood, it acts on distant cells. Norepinephrine (levarterenol, noradrenaline) is an agonist at both 0 and tx2 receptors. Norepinephrine also activates receptors with similar potency as epinephrine, but has relatively little effect on 32 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine however, the positive inotropic effects on the heart are maintained (Table 9-4). 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

Phenoxybenzamine Irreversibly blocks a and Lowers blood pressure (BP) but heart rate (HR) rises due to baroreflex activation Pheochromocytoma high catecholamine states Irreversible blocker half-life > 1 day Toxicity Orthostatic hypotension tachycardia myocardial ischemia... 

Tank J et al Yohimbine attenuates baroreflex-mediated bradycardia in humans. Hypertension 2007 50 899. 

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11-1) arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 (see Chapter 17) constricts and nitric oxide (see Chapter 19) dilates blood vessels. 

Considerable evidence indicates that the hypotensive effect of clonidine is exerted at a adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of a antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain stem vasomotor centers to inhibition by baroreflexes. 

TankJ, Diedrich A, Szczech E, et al. Alpha-2 adrenergic transmission and human baroreflex regulation. Hypertension. 2004 43 1035-1041. 

Fluid depletion may also be a serious problem during diuretic therapy. A decrease in blood volume may cause a reflex increase in cardiac output and peripheral vascular resistance because of activation of the baroreflex (see Chapter 18). This occurrence may produce an excessive demand on the myocardium, especially in patients with cardiac disease. Decreased blood volume may also activate the renin-angiotensin system, thereby causing further peripheral vasoconstriction and increased cardiac workload. Again, the effects of fluid depletion may be especially serious in patients with certain types of heart failure. 

Although vasodilators are effective in lowering blood pressure, these drugs are associated with a number of adverse effects. Reflex tachycardia often occurs because baroreflex responses attempt to compensate for the fall in vascular resistance that these drugs produce. This side effect is analogous to the increased heart rate occurring when alpha blockers are used to decrease peripheral vascular resistance. Other common reactions include dizziness, postural hypotension, weakness, nausea, fluid retention, and headache. Minoxidil also increases hair growth on the face, ears, forehead,... 

Grassi G. Sympathetic and baroreflex function in hypertension implications for current and new drugs. Curr Pharrn Des. 2004 10 3579-3589. 

Lohmeier TE, Hildebrandt DA, Warren S, et al. Recent insights into the interactions between the baroreflex and the kidneys in hypertension. Am J Physiol Regul Integr Comp Physiol. 2005 288 R828-R836. 

Lohmeier TE, Hildebrandt DA, Dwyer TM, Barrett AM, Irwin ED, Rossing MA, Kieval RS. Renal denervation does not abolish sustained baroreflex-mediated reductions in arterial pressure. Hypertension. 2007 49 373-379. 

Gonzalez, A. A., Kumar, R., Mulligan, J. D., Davis, A. J., Weindruch, R., and Saupe, K. W. 2004. Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am. J. Physiol. Endocrinol. Metab. 287 E1032-E1037. Grassi, G. 2004. Leptin, sympathetic nervous system, and baroreflex function. Curr. Hypertens. Rep. 6 236-240. 

The baroreflex system consists of mechanosensitive receptors in the aorta and carotid sinus that detect changes in blood pressure. The receptors give rise to afferent nerve fibers that relay impulses to the CNS. Within the CNS, the afferent signals are processed and ultimately transmitted to efferent sympathetic and parasympathetic fibers to the vasculature and heart. Increases in blood pressure will increase baro-receptors activity leading to an inhibition of sympathetic impulses to the blood vessels (thereby relaxing them) and to the heart (decreasing heart rate and contractility). In addition, parasympathetic activity to the heart is increased leading to a reduction in heart rate and possibly contractility. 

Direct vasodilators frequently produce baroreflex-induced tachycardia, but rarely orthostatic hypotension. They are usually prescribed with a beta blocker or a centrally acting antihypertensive to minimize the reflex increase in heart rate and cardiac output. It should be noted that another member of the directly acting class of antihypertensives is minoxidil. This potent, long-acting drug has gained considerable notoriety for its use as a topical hair-restorer. Oral use can result in hirsutism (unwanted hair growth over the face as well as other parts of the body). 

Baroreflexes involving the sympathetic nervous system are responsible for the rapid moment-to-moment regulation of blood pressure. A fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the aortic arch and carotid sinuses) to send fewer impulses to cardiovascular centers in the spinal cord. This prompts a reflex response of increased sympathetic and decreased parasympathetic output to the heart and vasculature, resulting in vasoconstriction and increased cardiac output. These changes result in a compensatory rise in blood pressure (Figure 19.3, and Figure 3.5, see p. 31). 

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