Info

'Detectable only at doses much greater than required for b blockade.

'Detectable only at doses much greater than required for b blockade.

CARDIOVASCULAR SYSTEM The major therapeutic effects of ß receptor antagonists are on the cardiovascular system. It is important to distinguish these effects in normal subjects from those in subjects with cardiovascular disease such as hypertension or myocardial ischemia.

Since catecholamines have positive chronotropic and inotropic actions, ß antagonists slow the heart rate and decrease myocardial contractility. When tonic stimulation of ß receptors is low, this effect is correspondingly modest. However, when the sympathetic nervous system is activated, as during exercise or stress, ß receptor antagonists attenuate the expected rise in heart rate. Short-term administration of ß receptor antagonists decreases cardiac output; peripheral resistance increases in proportion to maintain blood pressure as a result of blockade of vascular ß2 receptors and compensatory reflexes, such as increased sympathetic nervous system activity, leading to activation of vascular ß receptors. With long-term use of ß receptor antagonists, total peripheral resistance returns to initial values or decreases in patients with hypertension. With ß antagonists that also are ß1 receptor antagonists (e.g., labetalol, carvedilol, bucindolol) or direct vasodilators (celiprolol, nebivolol, nipradilol, carteolol, betaxolol, bopindolol, bevantolol), cardiac output is maintained with a greater fall in peripheral resistance.

ß Receptor antagonists have significant effects on cardiac rhythm and automaticity, to which blockade of both ß1 and ß2 receptors likely contributes. ß3 receptors occur in normal myocardial tissue, where they can couple to Gi and inhibit cardiac contraction and relaxation. The physiological role of cardiac ß3 receptors remains to be established. ß antagonists reduce sinus rate, decrease the spontaneous rate of depolarization of ectopic pacemakers, slow conduction in the atria and in the AV node, and increase the functional refractory period of the AV node.

ACTIVITY AS ANTIHYPERTENSIVE AGENTS ß Receptor antagonists generally do not reduce blood pressure in patients with normal blood pressure but will lower blood pressure in patients with hypertension. Reduction of ßj-stimulated renin release from the juxtaglomerular cells is a putative contributing mechanism (see Chapter 30).

Since presynaptic ß receptors enhance the release of NE from sympathetic neurons, diminished release of NE resulting from ß blockade is a possible response, but its relationship to the antihy-pertensive effects of ß antagonists is unclear. Although ß blockade would not be expected to decrease the contractility of vascular smooth muscle, long-term administration of these drugs to hypertensive patients ultimately decreases peripheral vascular resistance. The mechanism of this effect is unknown, but the delayed fall in peripheral vascular resistance in the face of a persistently reduced cardiac output appears to account for much of the antihypertensive effect of these drugs. There is relatively little evidence to support a postulated CNS effect of ß blockers that contributes to their antihypertensive effects. Indeed, drugs that poorly penetrate the blood-brain barrier are effective antihypertensive agents.

Some ß receptor antagonists produce peripheral vasodilation; at least six properties may contribute to this effect, including production of nitric oxide, activation of ß2 receptors, blockade of a receptors, blockade of Ca2+ entry, opening of K+ channels, and antioxidant activity (see Table 10-5 and Figure 10-4). These mechanisms appear to contribute to the antihypertensive effects by enhancing hypotension, increasing peripheral blood flow, and decreasing afterload. Two of these agents (e.g., celiprolol and nebivolol) may produce vasodilation and thereby reduce preload. Nebivolol reportedly activates endothelial ß3 receptors, leading to NO production and dilation of human coronary microvessels.

Table 10-5

Third-Generation B Receptor Antagonists with Additional Cardiovascular Actions: Proposed Mechanisms Contributing to Vasodilation

Table 10-5

Nitric Oxide

b2 Receptor

al Receptor

Ca2+ Entry

K+ Channel

Antioxidant

Production

Agonism

Antagonism

Blockade

Opening

Activity

Celiprolol*

Celiprolol*

Carvedilol

Carvedilol

Tilisolol*

Carvedilol

Nebivolol*

Carteolol

Bucindolol*

Betaxolol

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