Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium

Abstract

The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly β1‐selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). The rank order of β1‐selectivity as judged by competition experiments to 3H‐CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l−1, Kiβ2) or ICI 118.551 (50 nmol l−1, Kiβ1) were NEB(Kiβ2/Kiβ1: 40.7)>BIS(15.6)>MET(4.23)>CAR(0.73)>BUC(0.49). The rank order of the negative inotropic potency of the β‐adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 μmol l−1)‐stimulated force (IC50) was: MET (0.6 μmol l−1)>CAR (4.1 μmol l−1)>NEB (7.0 μmol l−1). NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 μmol l−1) pre‐treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 μmol l−1)‐stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl‐5′‐yl imidodiphosphate (Gpp(NH)p). Although all studied β‐adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the β1‐selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with β‐adrenoceptor antagonists. British Journal of Pharmacology (2001) 133, 1330–1338; doi:

Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β1-Adrenoceptors in Human Myocardium

“…However, one would expect a similar effect after nebivolol treatment because nebivolol has low inverse agonistic activity comparable with bucindolol (Brixius et al, 2001;Maack et al, 2001). In addition, the positive inotropic effect of bucindolol was absent in the presence of bupranolol.…”

“…These data suggest an unfavorable role of any agonistic property in heart failure. In contrast, metoprolol and carvedilol have been shown to exert no ISA in human myocardium (Brixius et al, 2001). However, in ␤ 1 -adrenoceptor transgenic mice, a slight, but not statistically significant stimulation of spontaneous beating frequency of isolated right atria was detected after carvedilol treatment .…”

“…Despite investigations that did not reveal ISA (Hershberger et al, 1990;Sederberg et al, 2000), Maack et al (2000) detected ISA in three of eight specimens from human left ventricular myocardium, suggesting that ISA of bucindolol may depend on the examined tissue. In a recent study we did not reveal any agonistic activity (Brixius et al, 2001). The present study provides new information about an "ISA-like" intrinsic activity that appears at high concentrations and is unmasked only if the classic ␤ 1 -and ␤ 2 -pathway is blocked.…”

Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human β 1 -Adrenergic Receptor

“…To elucidate whether the variability in the inotropic effects of bucindolol in previous studies on human myocardium [12][13][14][15] was due to different sensitization states of ␤-ARs, 16 failing myocardium was pretreated with isoproterenol, metoprolol, or vehicle for 90 minutes. The baseline force of contraction was not different among the 3 groups (Table 1).…”

The Place of Nebivolol in Rational Therapy of Congestive Heart Failure

“…Не менее важное значение имеет степень β-1 селективности препарата. По данным ряда авто-ров [5,6], из имеющихся в настоящее время β-АБ наибольшей β-1 селективностью обладает небиволол. Bundkirchen A. et al [6] показали, что индекс β-1 селективности у небиволола равен 1:22-46, у бисо-пролола -1:6-16, то есть небиволол превосходит бисопролол примерно в 3,5 раза, поэтому его назы-вают суперселективным, что важно учитывать при выборе препарата.…”