Comparative effects of the isomers of bepridil on isolated coronary and aortic arteries

Abstract

The vasodilator actions of racemic bepridil were compared with those of its laevo-(1) and dextro-(d) rotatory isomers in isolated rabbit aorta and pig coronary artery. The actions of bepridil (B), (1) B and (d) B were further compared with those of drugs known to act either by blockade of calcium entry or to inhibit calmodulin in pig coronary artery. (1) B and (d) B were equipotent in relaxing tonic contractions induced by phenylephrine in rabbit aorta but (d) B was approximately twice as potent as (1) B in relaxing tonic contractions induced by potassium (K +). Both (d) B and (1) B relaxed K +-induced contractions in coronary artery and, in higher concentrations, inhibited phasic contractions produced by histamine in depolarized preparations. The calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W7) were equipotent against both types of contraction whilst nifedipine and verapamil failed to reduce histamine-induced contractions. Both isomers of bepridil (like W7) shifted concentration-response curves to histamine in non-depolarized coronary artery in a noncompetitive manner. No potency differences were found between (1) B and (d) B in this tissue. It is concluded that intracellular actions, possibly calmodulin inhibition, play a substantial role in the vasodilator action of bepridil, a conclusion supported by the relative lack of stereospecificity shown by the bepridil isomers.