Characterization of β1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium

1 Intrinsic activity and beta (1)-selectivity are important features of beta -blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and beta (1)-selectivity of the novel beta -adrenoceptor antagonist nebivolol have not yet been determined. 2 The study examines intrinsic activity, beta -adrenoceptor-G-protein coupling and beta (1)-selectivity of nebivolol and bisoprolol in human ventricular myocardium. Furthermore, intrinsic activity of both compounds is compared to the one of bucindolol, carvedilol and metoprolol in human atrial myocardium. 3 Radioligand binding studies ([I-125]-lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS-7 cells transfected with human beta (1)- and beta (2)-adrenoceptors, respectively. Functional experiments were carried out on isolated muscle preparations of human left ventricular and right atrial myocardium from failing and nonfailing hearts. 4 Radioligand binding studies reveal 3-4 fold beta (1)-selectivity for nebivolol and 16-20 fold beta (1)-selectivity for bisoprolol in human myocardium. In COS-7-cells, beta (1)-selectivity is 3 fold for nebivolol and 15 fold for bisoprolol. 5 Neither the binding of nebivolol nor of bisoprolol is affected by the presence of guanylylimidodiphosphate (Gpp(NH)p). 6 Nebivolol and bisoprolol exert similar inverse agonist activity in human ventricular as well as atrial myocardium. In atrial myocardium, inverse agonism of both compounds is higher compared to bucindolol, equal to carvedilol and lower compared to metoprolol. 7 Favourable haemodynamic effects of nebivolol in humans are not due to beta (1)-selectivity or partial agonist activity of this agent. Other mechanisms, i.e, the production of nitric oxide, may thus be responsible for its unique haemodynamic profile.