Third-generation dihydropyridine-type calcium channel blocker labedipinedilol-B displays alpha/beta-adrenoceptor blocking activities

The pharmacological properties of labedipinedilol-B {N-[4-[2-hydroxy-3-(2-m ethoxy-1-oxyethylaminobenzene) propoxy]-benzyl]-2,6-dimethyl-3,5-dicarbomet hoxy-1,4-dihydropyridine} were investigated in vivo and in vitro in compari son 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 labedipinedil ol-B (1.0 mg kg(-1), iv) also inhibited phenylephrine (10 mug kg(-1))-induc ed hypertensive and (-)isoproterenol (0.5 mug kg(-1))-induced tachycardia e ffects. In the isolated Wistar rat right and left atria and guinea pigs tra cheal strips experiments, labedipinedilol-B (10(-7),10(-6), and 10(-5) M) c ompetitively 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-res ponse curve of (-)isoproterenol suggested that labedipinedilol-B was a beta (1)/beta (2)-adrenoceptor competitive antagonist. Labedipinedilol-B (10(-7 ), 10(-6), and 10(-5) M) also prevented the rate-increasing effects of incr eased 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 contraction s with pKCa(-1) and pA(2) values of 8.02 +/- 0.04 and 7.55 +/- 0.05 in a co ncentration-dependent manner. The parallel shift to the right of the concen tration-response curves of norepinephrine suggested that labedipinedilol-B was an a-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 c ompetitively antagonized CaCl2-induced contractions and made the parallel s hift to the right of the concentration-response curve of CaCl2. In cultured blood vessel smooth muscle cells (A7r5 cell lines), Bay K 8644-induced int racellular calcium changes were decreased after application of labedipinedi lol-B, suggesting that the compound was a calcium channel blocker. The bind ing characteristics of labedipinedilol-B were evaluated in [H-3]CGP-12177 b inding to ventricle and lung and [H-3]prazosin binding to brain membranes i n rats. Labedipinedilol-B also was evaluated in [H-3]nitrendipine binding t o brain membranes in rats. These results indicated that labedipinedilol-B, similar to labedipinedilol-A, has a-adrenoceptor blocking, beta -adrenocept or blocking, and calcium entry blocking activities in a single compound. We suggest that these two compounds represent a new generation of 1,4-dihydro pyridine-type calcium channel blockers. (C) 2001 Wiley-Liss, Inc.