β1-adrenoceptor selectivity of nebivolol and bisoprolol.: A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies

There is an ongoing discussion on whether or not high beta(1)-adrenoceptor selectivity of beta-adrenoceptor antagonists may be favorable in the treatment of patients with heart failure. The present study compared the beta(1)-adrenoceptor selectivity of nebivolol and bisoprolol with that of carvedilol in the human myocardium, using a binding assay in conjunction with either the hydrophilic ligand (+/-)-[H-3]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on HCI ([H-3]CGP 12.177) or the lipophilic ligand [I-125]iodocyanopindolol as radiolabeled compound. Measurements were made using membrane preparations obtained from identical nonfailing donor hearts. adrenoceptor density was found to be slightly higher when [I-125]iodocyanopindolol was used compared to [H-3]CGP 12.177 (256 +/- 15 and 213 +/- 18 fmol/mg protein, respectively). When the highly beta(1)-adrenoceptor-selective compound 2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4trifluoromethyl)-1-H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide (CGP 20.712A) and the highly beta(2)-adrenoceptor-selective compound erythro-(+/-)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-oI HCI (ICI 118.551) were used in competition experiments, a similar proportion of beta(1)-adrenoceptors was seen for [3 H]CGP 12.177 (69.3 +/- 1.6%) and for [I-125] iodocyanopindolol (67.0 +/- 2. 1 %). K-i(beta(1)) and Ki(beta(2)) were obtained in the presence of 50 nM ICI 118.551 and 300 nM CGP 20.712A. The rank order of beta(1)-adrenoceptor selectivity (K-i(beta(2))/K-i(beta(1)) ratio) was nebivolol (for [H-3]CGP 12.177 46.1 and for [I-125]iodocyanopindolol 22.5)>bisoprolol (13.1 and 6.4)>carvedilol (0.65 and 0.41). To investigate whether in vivo metabolized nebivolol retains high beta(1)-adrenoceptor selectivity, serum specimens were [I-125] collected before and 2 It after oral administration of 5 mg nebivolol. The samples were used for [I-125]iodocyanopindolol binding studies with the myocardial membrane preparations. In these samples, the binding of [I-125] iodocyanopindolol to [ beta(1)-adrenoceptors was inhibited by 46.4 +/- 5.3%, whereas the binding to beta(2)-adrenoceptors was inhibited by 20.5 +/- 1.1% compared to that of control samples. It is concluded that nebivolol is approximately 3.5 times more beta(1)-adrenoceptor-selective than bisoprolol in the human myocardium. Furthermore, in vivo metabolized nebivolol retains beta(1)-adrenoceptor selectivity. (C) 2002 Elsevier Science B.V. All rights reserved.