Jpn. J. Pharmacol. 83 (2), 107-112 (2000)

Electrophysiological and Cardiohemodynamic Effects of AH-1058, a New Type Calcium Channel Blocker, Assessed by the In Vivo Canine Model

Akira Takahara¹, Atsushi Sugiyama^2,*, Hideki Dohmoto¹, Ryota Yoshimoto¹ and Keitaro Hashimoto²

¹PharmaceuticalﾊResearch Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan
²Departmentﾊof Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan
*ﾊTo whom correspondence should be addressed.

Abstract: AH-1058ﾊ(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride) is a novel calcium channel blocker whose chemical structure is quite different from those of typical calcium channel blockers. In this study, electrophysiological and hemodynamic effects of AH-1058 were assessed in the halothane-anesthetized, closed-chest canine model. Intravenous administration of a canine antiarrhythmic dose of 100ﾊmg/kg of AH-1058 (n=6) did not affect the cardiovascular variables, except that the cardiac output was decreased at 30ﾊmin after the drug administration. Additional administration of 200ﾊmg/kg of AH-1058 (n=6) suppressed the sinus nodal automaticity, AV nodal conduction and ventricular contraction and decreased the mean blood pressure, cardiac output and double product. The effects gradually appeared, while no change was detected in the intraventricular conduction, ventricular repolarization period, ventricular effective refractory period, preload to the left ventricle and total peripheral vascular resistance during the observation period of 30ﾊmin. The cardiosuppressive effects of AH-1058 can be explained by its calcium channel blocking action demonstrated in a previous in vitro experiment, while the lack of the effect on the vascular resistance would suggest that AH-1058 may become a slow-acting cardioselective calcium channel blocker.

Keywords: AH-1058, Calcium channel blocker, Electrophysiologic effect, Hemodynamic action,
Monophasic action potential