Carvedilol is an adrenoceptor antagonist which modulates the activity not only of P, and P 2 but also of a, adrenergic receptors present on the cell surface membrane of the human cardiac myocyte. In the heart, carvedilol has approximately 7 times higher potency for p, and p^ adrenoceptors, but in the doses 50-100 mg . day" ' used in clinical practice, it is essentially non-selective. In human myocardial preparations and in cultured heart cells, carvedilol has no intrinsic sympathomimetic

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... y 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 P 2 than for the P, adrenoceptor. The property of gaunine nucleotide-modulatable binding for carvedilol and structurally related bucindolol correlates with their ability to directly down-regulate P,-like receptors present in cultured chick myocytes, and with a lack of reversal of down-regulation of cardiac P-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 P-receptor pathway to stimulation by adrenergic agonists. (Eur Heart J (1996) 17 (Suppl B): 8-16)