Cardiac adrenergic receptor effects of carvedilol

Abstract

Carvedilol is an adrenoceptor antagonist which modulates the activity not only of beta 1 and beta 2 but also of alpha 1 adrenergic receptors present on the cell surface membrane of the human cardiac myocyte. In the heart, carvedilol has approximately 7 times higher potency for beta 1 and beta 2 adrenoceptors, but in the doses 50-100 mg . day-1 used in clinical practice, it is essentially non-selective. In human myocardial preparations and in cultured heart cells, carvedilol has no intrinsic sympathomimetic activity but is able to identify high affinity agonist-binding receptors whose pharmacological signature is reduction in binding by incubation with guanine nucleotides (guanine nucleotide-modulatable binding). This property is more prominent for the human beta 2 than for the beta 1 adrenoceptor. The property of gaunine nucleotide-modulatable binding for carvedilol and structurally related bucindolol correlates with their ability to directly down-regulate beta 1-like receptors present in cultured chick myocytes, and with a lack of reversal of down-regulation of cardiac beta-receptors in patients with heart failure. Carvedilol does not exhibit high levels of inverse agonist activity, which may contribute to its good tolerability in subjects with heart failure. These data indicate that carvedilol produces a high degree of adrenergic receptor blockade in the failing human heart, and does not re-sensitize the beta-receptor pathway to stimulation by adrenergic agonists.

Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by β-Adrenergic Receptor Stimulation and Blockade

“…We hypothesized that this may play a role in the beneficial effects of certain ␤-blockers in the treatment of heart failure. Thus, in addition to atenolol, we examined myocardial GRK expression in mice after long-term treatment with carvedilol, a novel ␤-blocker (also possessing ␣-adrenergic receptor antagonism) 17 that has been shown to dramatically increase survival in patients with heart failure. 11 Interestingly, 14 days of a carvedilol infusion in the mouse significantly decreased ␤ARK1 levels in a selective manner.…”

“…As expected, isoproterenol decreased ␤AR density and atenolol treatment induced an increase in the number of ␤ARs in a dose-dependent manner ( Table 2). Carvedilol is an atypical ␤-antagonist that has been shown to decrease ␤AR density, 17 which was seen after 14 days of treatment ( Table 2).…”

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

“…However, the ␤-nonselective drug carvedilol does not cause ␤-receptor upregulation. 25,29 Thus, the primary benefit of ␤-blockade may be to counteract the toxic effects of circulating catecholamines.…”

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

“…These six β-blockers possess intrinsic sympathomimetic activity (ISA) [10][11][12], indicating that they are in fact, like xamoterol, partial β-adrenergic agonists. The remaining compounds do not possess ISA [12][13][14][15], demonstrating that the preparation is extremely sensitive in distinguishing compounds with or without ISA.…”