Eur J Clin Pharmacol (1990) 38: S 82-S 88 EuropeanJournalof ~

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The pharmacology of carvedilol R. R. Ruffolo Jr, M. Gellai, J. R Hieble, R. N. Willette, and A. J. Nichols Department of Pharmacology, Smith Kline Beecham, p. 1.c., King of Prussia, Pennsylvania,USA

Summary. Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive [3-adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of [3-adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent "renal sparing" effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of [~1-and [32-adrenoceptors with a dissociation constant (KB) of 0.9 nM at both ~-adrenoceptor subtypes. Carvedilol is also a potent c~l-adrenoceptor antagonist (KB = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 gM, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the antihypertensive dose-response curve. Although the calciumchannel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a [3-adrenoceptor antagonist and a vasodilator. The vasodilating activity of carvedilol results largely from cq-adrenoceptor blockade, and its [~-adrenoceptor blocking activity prevents reflex tachycardia. In some regional vascular beds, such as the cutaneous circulation, the calcium-channel blocking activity of carvedilol may be responsible for increasing the blood flow.

Carvedilol (Fig. 1) is a potent antihypertensive agent in animals (Sponer et al. 1987) and in humans (Eggertsen et al. 1987; Sundberg et al. 1987). Studies on its mechanism of action indicate that the compound is a [3-adrenoceptor antagonist and a vasodilator, and both of these activities contribute to the antihypertensive response produced by the compound. The reduction in blood pressure produced by carvedilol is associated with a decrease in peripheral vascular resistance, indicative of arterial vasodilation (Eggertsen et al. 1987; Strein et al. 1987; Sundberg et al. 1987), and the lack of reflex tachycardia is a consequence of the [3-adrenoceptor blocking properties of the compound (Eggertsen et al. 1987). OH

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Fig.& Effects of carvedilol on renal blood flow (RBF) and renal vascular resistance (RVR) throughout the antihypertensive doseresponse curve in conscious, spontaneously hypertensive rats

The mechanism(s) of action responsible for the vasodilator activity of carvedilol has not been completely established, inasmuch as this compound has a variety of pharmacologic actions over a wide range of concentrations (Sponer et al. 1987; Strein et al. 1987). It has been proposed that the vasodilation produced by carvedilol results from nonspecific relaxation of vascular smooth muscle, selective cq-adrenoceptor blockade, calcium channel blockade, and/or some combination of these actions. In this manuscript we review the pharmacologic activities of carvedilol in a variety of in vivo and in vitro test systems, with emphasis on the mechanism of action of carvedilol as an antihypertensive agent.

gonists that decrease the heart rate and cardiac output and increase total peripheral vascular resistance (Ruffolo 1988). The effects of carvedilol on renal hemodynamics in conscious, spontaneously hypertensive rats are presented in Fig. 4. Throughout the antihypertensive dose range for carvedilol, renal blood flow remains relatively stable, indicating that renal autoregulatol 7 integrity is unaffected by carvedilol. As shown in Fig. 5, sodium excretion does not change during sustained i. v. infusion of carvedilol, indicating an important "renal sparing" effect. This is in marked contrast to another [3- and C~l-adrenoceptor antagonist, labetalol, which significantly decreases sodium excretion, 1.2

A n t i h y p e r t e n s i v e activity o f carvedilol

The antihypertensive activity of carvedilol in conscious, spontaneously hypertensive rats is shown in Fig.2. The dose-dependent reduction in mean arterial blood pressure produced by carvedilol is not associated with reflex activation of sympathetic outflow to the myocardium that leads to tachycardia. In fact, throughout the entire doseresponse curve for the antihypertensive effect of carvedi1ol, the heart rate remains relatively stable. The systemic hemodynamic effects of carvedilol are depicted in Fig. 3 and are consistent with two mechanisms of action, namely, [3-adrenoceptor blockade and vasodilation. The reduction in mean arterial blood pressure produced by carvedilol results largely from a vascular effect, since cardiac output, like the heart rate, remains relatively constant and total peripheral vascular resistance declines in parallel with blood pressure. This hemodynamic profile of carvedilol is distinct from that of ~3-adrenoceptor anta-

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R. R. Ruffolo et al.: The pharmacology of carvedilol

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of Arunlakshana and Schild (1959) gives a Schild regression with a slope of 1.1, which is not significantly different from the theoretical value of unity, indicating that blockade is competitive in nature (Ruffolo 1982). The pA2 value obtained from the Schild regression is 9.03 + 0.17, which corresponds to a dissociation constant (KB) of 0.9 nM. In pithed, normotensive rats, carvedilol (0.3 mg/kg i.v.) produces a parallel rightward displacement of the 131adrenoceptor-mediated, positive chronotropic response to isoproterenol (data not shown). This dose of carvedilol, which is associated with a significant reduction in mean arterial blood pressure in spontaneously hypertensive rats, results in a dose ratio of approximately 100-fold, demonstrating pronounced 131-adrenoceptor blockade.

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Carvedilol produces a concentration-dependent inhibition of the 132-adrenoceptor-mediated relaxation induced by isoproterenol in guinea pig trachea precontracted with i gM carbachol (Fig. 7). The antagonism of isoproterenol by carvedilol is competitive, as evidenced by the concentration-dependent, parallel rightward shifts in the isoproterenol concentration-response curves, with no significant reduction in the maximal response. A Schild regression based on these data provides a slope of 0.9, which is not significantly different from unity, and a pA2 value of 9.03 + 0.12, which corresponds to a KB of 0.9 nM. This value is identical to that obtained at [31-adrenoceptors and indicates that carvedilol is a relatively nonselective 13-adrenoceptor antagonist. In the pithed rat, carvedilol (0.3 mg/kg i. v.) significantly inhibits the [32-adrenoceptor-mediated vasodilator response of salbutamol, confirming in vivo the 132-adrenoceptor blocking activity observed in vitro. The dose ratio obtained at the half-maximal response of salbutamol is similar to that observed for 131-adrenoceptors in the pithed rat, indicating that carvedilol does not discriminate between 131-and 132-adrenoceptors in vivo.

(z-Adrenoceptor blockade oq-Adrenoceptor blockade

thereby leading to sodium retention, which is a common phenomenon among antihypertensive agents.

[3-Adrenoceptor blocking activity 131-Adrenoceptor blockade Carvedilol is a potent antagonist of the 131-adrenoceptormediated, positive chronotropic response to isoproterenol in the guinea pig atrium. As shown in Fig. 6, carvedilol produces concentration-dependent, parallel rightward displacements of the concentration-response curve to isoproterenol, with no significant effect on the maximal chronotropic response. Analysis of these data by the technique

Carvedilol is a potent, competitive antagonist of ~ladrenoceptors in vivo and in vitro. In isolated rabbit aorta, the ~l-adrenoceptor-mediated vasoconstrictor response to norepinephrine is antagonized in a concentration-dependent manner by carvedilol, resulting in parallel rightward displacements in the norepinephrine concentrationresponse curves, with no change in the maximal response (Fig. 8). Schild analysis of these data yield a straight line with a slope of 0.9 and a pA2 of 7.97 + 0.11, which corresponds to a KB of 11 nM. These results indicate that carvedilol is approximately 1 order of magnitude less potent as an (zl-adrenoceptor antagonist than as a 13-adrenoceptor antagonist. At an established antihypertensive dose, carvedilol (0.3 mg/kg i.v.) significantly antagonizes the (zl-adreno-

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ceptor-mediated vasopressor response to cirazoline in the pithed rat (data not shown). These results establish that significant oq-adrenoceptor blockade occurs at antihypertensive doses of carvedilol in vivo, in spite of the fact that the C~l-adrenoceptor blocking activity of the drug is > 10fold weaker than the corresponding ~3~-and 132-adrenoceptor blockade.

{~2-Adrenoceptorblockade Carvedilol inhibits the ~x2-adrenoceptor-mediated vasoconstrictor response of B - H T 920 in the isolated canine saphenous vein. This effect is noncompetitive, with high doses of carvedilol depressing the maximal response to BH T 920, suggesting that the former has a complex action at the ~2-adrenoceptor and/or its effector system (see below). Electrophysiologic studies suggest only a weak interaction of carvedilol with cza-adrenoceptors (Seki et al. 1988).

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sponse that results from the opening of calcium channels associated with the cell membrane. Carvedilol produces a concentration-dependent relaxation of the potassiumdepolarized rat uterus, with an EDs0 of 7.65 +_0.62 g M (Fig. 9). Similar results are also obtained in potassiumdepolarized rabbit aorta (data not shown). Furthermore, in rabbit aorta incubated in calcium-free buffer and depolarized with potassium (70 nM), a response to calcium chloride can be observed that is sensitive to inhibition by calcium channel blockers. At concentrations > 1 ~tM carvedilol significantly inhibits the calcium-induced contractile response in this tissue, with a 10-fold parallel rightward displacement of the calcium concentration-response curve being observed at a 10 ~tM concentration of the drug (Fig. 10). The calcium-channel blocking activity of carvedilol has also been demonstrated in vivo. In the pithed rat, the direct calcium channel activator, Bay-K-8644, produces a

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At concentrations of ~>1 gM, carvedilol inhibits the {z2adrenoceptor-mediated vasoconstrictor response to BH T 920 in canine saphenous vein in a noncompetitive manner. Because c~2-adrenoceptor-mediated vasoconstriction in this tissue is invariably dependent on the translocation of extracellular calcium (Nichols and Ruffolo 1988) and because no compelling evidence exists to suggest that carvedilol interacts directly with (z2-adrenoceptors, it was hypothesized that carvedilol may be a calcium channel blocker at these higher concentrations. A series of experiments were performed to confirm the hypothesis that carvedilol is a calcium channel antagonist. Depolarization of the rat uterus by potassium (70 nM) produces a nifedipine-sensitive, contractile re-

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dose-dependent vasoconstrictor response that is inhibited by calcium channel blockers. At a carvedilol dose of i mg/kg i.v., which represents the higher portion of the antihypertensive dose-response curve, the drug significantly inhibits the vasoconstrictor response of Bay-K8644, thereby confirming in vivo that carvedilol is a calcium channel blocker. Although carvedilol can indeed block calcium channels, our studies do not suggest a prominent role for this activity in the antihypertensive response of the compound. Thus, in spontaneously hypertensive rats pretreated with propranolol and prazosin to block [3- and oqadrenoceptors, carvedilol does not produce an additional reduction in blood pressure, whereas the potent calcium channel antagonist nifedipine does (data not shown). Although the calcium-channel blocking activity of carvedilol may not play an important role in the antihypertensive response of the compound, it may be of importance in increasing the blood flow in specific regional vascular beds that do not contribute greatly to total peripheral vascular resistance, such as the cutaneous circulation.

Cutaneous circulation

To determine whether its calcium-channel blocking activity (or some other as yet unidentified activity) is relevant to the response to carvedilol, we compared the drug with another compound known to possess combined [3- and o~ladrenoceptor antagonist properties, labetalol, in the cutaneous circulation. The effectiveness of calcium channel blockers such as nifedipine in the treatment of peripheral vascular disease in humans (Rodeheffer et al. 1983; Smith and McKendry 1982) suggests the strong involvement of extracellular calcium in the regulation of cutaneous blood

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Isoproterenol (molar) Fig. 12. a The effects of S ( - )-carvedilol and b R ( + )-carvedilol in antagonizing the [31-adrenoceptor-mediated,positive chronotropic response of isoproterenol in isolated guinea pig atrium, n = 3. a Q) Control; • S( - )-carvedilol (1 x 10 -9 M); [ ] S( - )-carvedilol (3 x 10-9 M); • S(-)-carvedilol (lx 10-8 M). b Q) Control; • R ( + )-carvedilol (1 x 10 8M); [ ] R ( + )-carvedilol (3 x 10-8 M); • R ( + )-carvedilol (1 x 10-7 M)

flow. At doses of carvedilol and labetalol that produce equivalent reductions in mean arterial blood pressure and heart rate, labetalol significantly reduces cutaneous blood flow by over 20%, with no change in cutaneous vascular resistance (Fig. 11). In marked contrast, carvedilol increases cutaneous blood flow by over 60%, and this effect results from a dramatic reduction in cutaneous vascular resistance. Because the cutaneous circulation is highly sensitive to calcium channel blockers, it is tempting to speculate that the decrease in cutaneous vascular resistance produced by carvedilol but not by labetalol results from calcium channel blockade.

Enantiomers of carvediloi

Carvedilol possesses one asymmetric carbon atom, giving rise to a single pair of enantiomers (Fig. 1). The racemic mixture of carvedilol is being studied clinically. Racemic

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R,S(+)-carvedilol is a competitive antagonist against 131-adrenoceptors (KB = 0.9 nM) and al-adrenoceptors (KB = 11 riM), as described above. The enantiomers of carvedilol have also been evaluated as [31- and ~l-adrenoceptor antagonists to investigate stereoselectivity. S (-)-Carvedilol is a potent 131-adrenoceptor antagonist in guinea pig atrium, with a KB of 0.4 nM (Fig. 12A), which is approximately 2-fold more potent than the racemic mixture. In contrast, as a 131-adrenoceptor antagonist R(+)-carvedilol is approximately 100-fold weaker than the S ( - )-enantiomer, having a KB of 45 nM (Fig. 12B). Accordingly, S ( - )-carvedilol (0.1 mg/kg i.v.) produced a 25-fold rightward shift in the dose-response curve for the 131-adrenoceptor-mediated, positive chronotropic effect of isoproterenol in pithed rats, whereas at a dose 10-fold that above (lmg/kg i.v.), the R ( + ) enantiomer had no [31-adrenoceptor blocking activity (data not shown). Taken together, these results indicate that the 131-adrenoceptor blocking activity of racemic

carvedilol results predominantly from the S ( - )-enantiomer. In contrast to the marked enantioselectivity observed at [~l-adrenoceptors, S ( - ) - and R ( + )-carvedilol are equipotent as (zl-adrenoceptor antagonists in rabbit aorta (Fig. 13 A, B), with KB values against norepinephrine of 16 and 14 nM, respectively. Consistent with this observation, the dose-response curve for the oq-adrenoceptor-mediated pressor effect of cirazoline in pithed rats was shifted 6-fold in parallel and to the right with both the S ( - )- and R ( + )-enantiomers of carvedilol (1 mg/kg i.v.). The results demonstrate that the enantiomers of carvedilol show marked stereoselective antagonism of ~1-but not oq-adrenoceptors. This represents an unusual instance in which enantiomers of an optically active drug differ not only quantitatively in terms of potency (Ruffolo 1984) but also qualitatively, in that they possess distinct pharmacologic profiles. As such, neither enantiomer alone has the same pharmacologic profile as the racemic mixture of carvedilol used clinically, since only the S ( - )-enantiomer of carvedilol provides potent [3~-adrenoceptor blocking activity, whereas both enantiomers contribute equally to the vasodilation resulting from oq-adrenoceptor blockade. As such, the most active enantiomer of carvedilol as a 131adrenoceptor antagonist [i.e., S(-)-carvedilol] is not simply a 2-fold more potent form of the racemic mixture, but rather is pharmacologically distinct from the racemic mixture since the R (+)-enantiomer also contributes to the oq-adrenoceptor blockade. This unusual phenomenon occurs only rarely and is analogous to the situation that exists for ( + )-dobutamine and its enantiomers (Ruffolo 1987).

Conclusions

The data accumulated to date indicate that carvedilol is a potent competitive antagonist of [~1-, 132-,and oq-adrenoceptors. In addition, it is a calcium channel blocker at higher concentrations. The vasodilator activity of carvedilol results primarily from ~l-adrenoceptor blockade, with little or no contribution to the antihypertensive effect being derived from calcium channel blockade. However, calcium channel blockade by carvedilol may be important in certain regional vascular beds, such as the cutaneous circulation, where carvedilol is an extremely potent vasodilator. Throughout the antihypertensive dose range of carvedilol, reflex tachycardia is not observed, and this effect is due largely to the [31-adrenoceptor blocking property of carvedilol that results predominantly from the S(-)-enantiomer. Although carvedilol is being developed as a racemic mixture of the S ( - )- and R ( + )-enantiomers, it is important to emphasize that the pharmacologic profile of ( + )-carvedilol is not mimicked by either of the individual enantiomers, since only the S ( - )-enantiomer is a 131-adrenoceptor antagonist, whereas both enantiomers contribute equally to cq-adrenoceptor blockade. We conclude that carvedilol is a unique antihypertensive agent with several mechanisms of action, including 13-adrenoceptor blockade and vasodilation. These combined mechanisms produce a reduction in blood

S 88 pressure that is m e d i a t e d by a decrease in peripheral vascular resistance, with no c o m p e n s a t o r y increase in heart rate.

References Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonism. Br J Pharmaco114:45-58 Eggertsen R, Sivertsson R, Andren L, Hansson L (1987) Acute and long-term hemodynamic effects of carvedilol, a combined betaadrenoceptor blocking and precapillary vasodilating agent, in hypertensive patients. J Cardiovasc Pharmacol 10 [Suppl 11]: 97100 Nichols AJ, Ruffolo RR Jr (1988) The relationship of c~-adrenoceptor reserve and agonist intrinsic efficacy to calcium utilization in the vasculature. Trends Pharmacol Sci 9:236-241 Rodeheffer RJ, Rommer JA, Wigley E Smith CR (1983) Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomena. N Engl J Med 308:880-883 Ruffolo RR Jr (1982) Important concepts of receptor theory. J Auton Pharmacol 2:277-295 Ruffolo RR Jr (1984) Stereochemical requirements for activation and blockade of alpha-1 and alpha-2 adrenoceptors. Trends Pharmacol Sci 5:160-164 Ruffolo RR Jr (1987) The pharmacology of dobutamine. Am J Med Sci 294:244-248

R. R. Ruffolo et al.: The pharmacology of carvedilol Ruffolo RR Jr (1988) Cardiovascular adrenoceptors: physiology and critical care implications. In: Chernow B (ed) The pharmacologic approach to the critically ill patient. Williams and Wilkins, Baltimore, pp 166-183 Seki N, NagaoT, Komori K, Suzuki H (1988) Alpha- and betaadrenoceptor blocking action of carvedilol in the canine mesenteric artery and vein. J Pharmacol Exp Ther 246:1116-1122 Smith CD, McKendry RJR (1982) Controlled trial of nifedipine in the treatment of Raynaud's phenomenon. Lancet II: 1299-1301 Sponer G, Strein K, Muller-Beckmann B, Bartsch W (1987) Studies on the mode of vasodilating action of carvedilol. J Cardiovasc Pharmaco110 [Supp111]: 42-48 Strein K, Sponer G, Muller-Beckmann G, Bartsch W (1987) Pharmacological profile of carvedilol, a compound with beta-blocking and vasodilating properties. J Cardiovasc Pharmacol 10 [Supp111]: 33-41 Sundberg S, Tiihonen K, Gordin A (1987) Vasodilatory effects of carvedilol and pindolol. J Cardiovas Pharmacol 10 [Supp111]: 76-80

Dr. R. R. Ruffolo Jr, Ph.D. Department of Pharmacology, L523 Smith Kline Beecham, p. 1.c. 709 Swedeland Road King of Prussia, Pennsylvania 194064)939 USA