Comparative effects of the isomers of bepridil on isolated coronary and aortic arteries.
The vasodilator actions of racemic bepridil were compared with those of its laevo-(l) and dextro-(d) rotatory isomers in isolated rabbit aorta and pig coronary artery. The actions of bepridil (B), (l) 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. (l) 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 (l) B in relaxing tonic contractions induced by potassium (K+). Both (d) B and (l) B relaxed K+-induced contractions in coronary artery and, in higher concentrations, inhibited 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 (l) B and (d) B in this tissues. 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.
Winslow
E
E
Department of Pharmacology, Organon Laboratories Ltd., Newhouse, Lanarkshire, Scotland.
Wright
P
P
Campbell
J K
JK
Marshall
R J
RJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D015764:Bepridil / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D006633:Histamine Antagonists; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013552:Swine
D006633:Histamine Antagonists; D010656:Phenylephrine; D015764:Bepridil; D011188:Potassium; D002118:Calcium