β 1-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 β 1-adrenoceptor selectivity of β-adrenoceptor antagonists may be favorable in the treatment of patients with heart failure. The present study compared the β 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 (±)-[ 3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on HCl ([ 3H]CGP 12.177) or the lipophilic ligand [ 125I]iodocyanopindolol as radiolabeled compound. Measurements were made using membrane preparations obtained from identical nonfailing donor hearts. β-adrenoceptor density was found to be slightly higher when [ 125I]iodocyanopindolol was used compared to [ 3H]CGP 12.177 (256±15 and 213±18 fmol/mg protein, respectively). When the highly β 1-adrenoceptor-selective compound 2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4-trifluoromethyl)-1- H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide (CGP 20.712A) and the highly β 2-adrenoceptor-selective compound erythro-(±)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-ol HCl (ICI 118.551) were used in competition experiments, a similar proportion of β 1-adrenoceptors was seen for [ 3H]CGP 12.177 (69.3±1.6%) and for [ 125I]iodocyanopindolol (67.0±2.1%). K i(β 1) and K i(β 2) were obtained in the presence of 50 nM ICI 118.551 and 300 nM CGP 20.712A. The rank order of β 1-adrenoceptor selectivity ( K i(β 2)/ K i(β 1) ratio) was nebivolol (for [ 3H]CGP 12.177 46.1 and for [ 125I]iodocyanopindolol 22.5)>bisoprolol (13.1 and 6.4)>carvedilol (0.65 and 0.41). To investigate whether in vivo metabolized nebivolol retains high β 1-adrenoceptor selectivity, serum specimens were collected before and 2 h after oral administration of 5 mg nebivolol. The samples were used for [ 125I]iodocyanopindolol binding studies with the myocardial membrane preparations. In these samples, the binding of [ 125I]iodocyanopindolol to β 1-adrenoceptors was inhibited by 46.4±5.3%, whereas the binding to β 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 β 1-adrenoceptor-selective than bisoprolol in the human myocardium. Furthermore, in vivo metabolized nebivolol retains β 1-adrenoceptor selectivity.