Beta-blocker selectivity at cloned human beta1- and beta2-adrenergic receptors

The ratio between the affinities of beta-blockers for the beta(2)- and beta(1)-receptors is often used to predict the cardioselectivity and the potential consequences of blocking beta(2)-receptor-mediated effects of adrenergic receptor blockers. These ratios have been traditionally determined using various in vitro models of beta(2) and beta(1)-receptor antagonist activity, including isolated organ preparations and radioligand binding in tissues from various species. The data from these studies, while useful, are complicated by the use of different preparations, techniques, and nonhuman models. Recombinant cell lines expressing human beta(2) and beta(1) receptors have been developed, allowing for the direct comparison of the affinities of the beta-blockers for the beta(2) and beta(1) receptors under identical conditions, and allowing a precise determination of the beta(1)-receptor selectivity of the beta-blockers. Bisoprolol, atenolol, propranolol, betaxolol, metoprolol, carvedilol, and ICI 118, 551 were compared for their beta-receptor selectivity using membranes prepared from recombinant cells selectively expressing human beta(2) and beta(1) receptors. Bisoprolol was found to have the highest selectivity for the beta1 receptor, displaying a beta(2)/beta(1) ratio of 19 (a 19-fold higher affinity for the beta receptor than for the beta(2) receptor). Atenolol, metoprolol, and betaxolol displayed lower, although significant, selectivity for the beta(1) receptor, whereas propranolol and carvedilol displayed no signiicant beta-adrenergic selectivity. ICI 118,55 was selective for the beta(2) receptor. The equilibrium dissociation constants of the beta-blockers for the beta1 and beta(2) receptors were generally similar to previously reported values. The affinity ratios were also generally similar to previously reported values.