CARDIAC ADRENERGIC-RECEPTOR EFFECTS OF CARVEDILOL

Carvedilol is an adrenoceptor antagonist which modulates the activity not only of beta(1) and beta(2) but also of alpha(1) adrenergic recept ors 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 affin ity agonist-binding receptors whose pharmacological signature is reduc tion in binding by incubation with guanine nucleotides (guanine nucleo tide-modulatable binding). This property is more prominent for the hum an 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 be ta(1)-like receptors present in cultured chick myocytes, and with a la ck of reversal of down-regulation of cardiac beta-receptors in patient s with heart failure, Carvedilol does not exhibit high levels of inver se agonist activity, which may contribute to its good tolerability in subjects with heart failure. These data indicate that carvedilol produ ces a high degree of adrenergic receptor blockade in the failing human heart, and does not re-sensitize the beta-receptor pathway to stimula tion by adrenergic agonists.