Characterization of beta(1)-selectivity, adrenoceptor-G(s)-protein interaction and inverse agonism of nebivolol in human myocardium.

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. 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. 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 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. 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. Neither the binding of nebivolol nor of bisoprolol is affected by the presence of guanylylimidodiphosphate (Gpp(NH)p). 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. 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.

Binding properties of beta-blockers at recombinant beta1-, beta2-, and beta3-adrenoceptors.

The human heart contains at least four distinct beta-adrenoceptor subtypes, three of which have been cloned. However, the binding properties of beta-blockers to the different beta-adrenoceptor subpopulations are not yet thoroughly characterized. Human beta1-, beta2- and beta3-adrenoceptors were expressed in COS-7 cells and [125I]iodocyanopindolol saturation binding, and competition experiments with commonly used beta-blockers were performed in the respective membrane preparations. Atenolol and metoprolol were about fivefold selective for beta1- versus beta2- and beta3-adrenoceptors. Bisoprolol was approximately 15-fold selective for beta1- versus beta2- and approximately 31-fold selective for beta1- versus beta3-adrenoceptors. Carvedilol was nonselective for any beta-adrenoceptor subtype. We conclude that the beta1-selectivities of atenolol, metoprolol, and bisoprolol are lower in COS cell membranes compared with previous investigations performed in native membranes. All beta-blockers investigated bind to beta3-adrenoceptors. Differential binding properties to beta3-adrenoceptors might imply different responses as to body weight, cardiac contractility, heart rate, and growth regulation. This might imply differential indications for the drugs investigated.