Alpha2 adrenoceptors are present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when α2 agonists are given locally, by rapid intravenous injection or in very high oral doses. When given systemically, these vascular effects are obscured by the central effects of α2 receptors, which lead to inhibition of sympathetic tone and reduced blood pressure. Hence, α2 agonists can be used as sympatholytics in the treatment of hypertension (see Chapter 11). In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact.
C. Effects of Beta-Receptor Activation
The cardiovascular effects of β-adrenoceptor activation are exemplified by the response to the nonselective β agonist isoproterenol, which activates both β1 and β2 receptors. Stimulation of β receptors in the heart increases cardiac output by increasing contractility and by direct activation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating β2 receptors, leading to vasodilation in certain vascular beds (Table 9–4). The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased (Figure 9–6).
The cardiac effects of β agonists are determined largely by β1 receptors (although β2 and α receptors may also be involved, especially in heart failure). Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Beta-activation in the sinoatrial node increases pacemaker activity and heart rate (positive chronotropic effect). Excessive stimulation of ventricular muscle and Purkinje cells can result in ventricular arrhythmias. Beta
TABLE 9–4 Cardiovascular responses to sympathomimetic amines.
FIGURE 9–6 Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate.
0 100 0 80 BP mm Hg HR bpm 0 100 0 100 Phe 75 µg Phe 7.5 µg
FIGURE 9–7 Effects of ganglionic blockade on the response to phenylephrine (Phe) in a human subject. Left: The cardiovascular effect of the selective α 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 (HR scale is different). In the absence of baroreflex buffering, approximately a 10-fold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate.