Characterization of β₁‐selectivity, adrenoceptor‐G_s‐protein interaction and inverse agonism of nebivolol in human myocardium

Abstract

1 Intrinsic activity and b 1 -selectivity are important features of b-blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and b 1 -selectivity of the novel b-adrenoceptor antagonist nebivolol have not yet been determined. 2 The study examines intrinsic activity, b-adrenoceptor-G-protein coupling and b 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 ([ 125 I]-lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS-7 cells transfected with human b 1 -and b 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 b 1 -selectivity for nebivolol and 16 ± 20 fold b 1 -selectivity for bisoprolol in human myocardium. In COS-7-cells, b 1 -selectivity is 3 fold for nebivolol and 15 fold for bisoprolol. 5 Neither the binding of nebivolol nor of bisoprolol is aected 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 eects of nebivolol in humans are not due to b 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 pro®le.

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

“…It has been shown in a variety of recombinant systems that long-term treatment with inverse agonists causes much larger increases in receptor density than do "neutral" antagonists (Milligan and Bond 1997). Thus, because the "second generation" β-1 AR blockers bisoprolol and metoprolol have been shown the exert considerable inverse agonism activity (Maack et al 2001), it might well be that the increase in β-AR density observed in human heart during longterm treatment with these β-1 AR blockers Gilbert et al 1996;Heilbrunn et al 1989;Michel et al 1988;Sigmund et al 1996;Waagstein et al 1989) is due to their inverse agonism activity. In this context, it is interesting to note that also carvedilol has been found to exert (weak) inverse agonism (Maack et al 2000), but as discussed earlier it did not increase cardiac β-AR density in CHF.…”

Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β1-Adrenoceptors in Human Myocardium

“…However, one would expect a similar effect after nebivolol treatment because nebivolol has low inverse agonistic activity comparable with bucindolol (Brixius et al, 2001;Maack et al, 2001). In addition, the positive inotropic effect of bucindolol was absent in the presence of bupranolol.…”

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

“…We also show that metoprolol significantly depresses basal myocardial cAMP levels in both human and rat heart, consistent with its previously reported inverse agonist properties. 24,27 Inverse agonists exist for many classes of G protein-coupled receptors; these ligands appear to stabilize the inactive conformation of their receptors and thereby reduce basal, agonist-independent signaling. 26,28 The clinical significance of this property of metoprolol is not clear, although inverse agonists have been shown to induce both homologous and heterologous receptor upregulation.…”