Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

Abstract

Background-Most clinical studies have shown that ␤-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective ␤-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results-Myocardial strips (Ϸ1 mm3 ) obtained from rat and nonfailing human hearts were confirmed to be viable for Ն48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to ␤-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full ␤-adrenergic agonist isoproterenol raised cAMP levels by Ͼ2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by Ϸ25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64Ϯ0.25-fold and 2.00Ϯ0.27-fold over control, respectively, PϽ0.01 for human tissue). Conclusions-Bucindolol exhibits Ϸ60% of the ␤-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

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

“…Bucindolol induced rapid and prominent phosphorylation of the human ␤ 1 -AR. Together with recent data demonstrating cAMP stimulation in response to bucindolol, 15 this clearly classifies bucindolol as a partial agonist at the human ␤ 1 -AR.…”

“…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).…”

“…Some groups did not observe partial agonist activity, 12,13 whereas we and others observed partial agonist activity of bucindolol in human myocardium. 14,15 Partial agonist activity of bucindolol, however, was not constant in human failing myocardium and varied, depending on the respective tissue investigated. 14 To determine whether the putative partial agonist activity of bucindolol is species dependent, we compared the effect of bucindolol on atria from wild-type mice (murine ␤ 1 -AR) and transgenic mice with cardiac-specific overexpression of the human ␤ 1 -AR.…”

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

“…Thus, it is well possible that such firmly bound carvedilol may mask increases in β-AR. On the other hand, for bucindolol, several authors have found that it exerts partial intrinsic sympathomimetic activity (ISA) in the human myocardium (Maack et al 2000(Maack et al , 2003Andreka et al 2002). Previous studies had shown, however, that β-AR blockers with intrinsic sympathomimetic activity decrease cardiac β-AR density (Michel et al 1988), and this would explain the lack of cardiac β-AR up-regulation during chronic bucindolol treatment.…”

Antiadrenergic Therapy of Chronic Heart Failure

“…13 There has been controversy about bucindolol possessing ISA on the basis of evidence of this property in functioning rat myocardium 14 and perhaps in nonfunctioning human myocardial tissue cultures. 15 However, three independent studies in functioning isolated human nonfailing or failing human myocardial preparations have demonstrated no ISA for bucindolol, even under conditions of augmented signal transduction. 16 -18 Moreover, in the most sensitive method of ISA detection, Holter Monitoring of 24-hour heart rate, xamoterol, and celiprolol demonstrate ISA, but bucindolol does not.…”