Third-generation dihydropyridine-type calcium channel blocker labedipinedilol-B displays α/β-adrenoceptor blocking activities

The pharmacological properties of labedipinedilol-B {N-[4-[2-hydroxy-3-(2-methoxy-1-oxyethylaminobenzene) propoxy]-benzyl]-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine} were investigated in vivo and in vitro in comparison with labedipinedilol-A. Intravenous labedipinedilol-B (0.5, 1.0, and 3.0 mg kg^-1), produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. Pretreatment with labedipinedilol-B (1.0 mg kg^-1, iv) also inhibited phenylephrine (10 μg kg^-1)-induced hypertensive and (-)isoproterenol (0.5 μg kg^-1)-induced tachycardia effects. In the isolated Wistar rat right and left atria and guinea pigs tracheal strips experiments, labedipinedilol-B (10^-7, 10^-6, and 10^-5 M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that labedipinedilol-B was a β₁/ β₂-adrenoceptor competitive antagonist. Labedipinedilol-B (10^-7, 10^-6, and 10^-5 M) also prevented the rate-increasing effects of increased extracellular Ca²⁺ (3.0-9.0 mM) in a concentration-dependent manner. In the isolated rat aorta, labedipinedilol-B (10^-7, 10^-6, and 10^-5 M) competitively antagonized the CaCl₂ and norepinephrine-induced contractions with pKCa^-1 and pA₂ values of 8.02 ± 0.04 and 7.55 ± 0.05 in a concentration-dependent manner. The parallel shift to the right of the concentration-response curves of norepinephrine suggested that labedipinedilol-B was an α-adrenoceptor competitive antagonist. Furthermore, labedipinedilol-B, in an equal antagonist activity, inhibited norepinephrine-induced phasic and tonic contraction. In the isolated rat aorta, labedipinedilol-B also competitively antagonized CaCl₂-induced contractions and made the parallel shift to the right of the concentration-response curve of CaCl₂. In cultured blood vessel smooth muscle cells (A7r5 cell lines), Bay K 8644-induced intracellular calcium changes were decreased after application of labedipinedilol-B, suggesting that the compound was a calcium channel blocker. The binding characteristics of labedipinedilol-B were evaluated in [³H]CGP-12177 binding to ventricle and lung and [³H]prazosin binding to brain membranes in rats. Labedipinedilol-B also was evaluated in [³H]nitrendipine binding to brain membranes in rats. These results indicated that labedipinedilol-B, similar to labedipinedilol-A, has α-adrenoceptor blocking, β-adrenoceptor blocking, and calcium entry blocking activities in a single compound. We suggest that these two compounds represent a new generation of 1,4-dihydropyridine-type calcium channel blockers.