Effects of MDL 11,939 on action potential and contractile force in cardiac tissues: a comparison with bretylium, clofilium, and sotalol.
The effect of MDL 11,939 hydrochloride [alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol HCl], a novel antiarrhythmic agent, was studied using microelectrode recording techniques. MDL 11,939 (10(-7) - 10(-6) M increased the action potential (AP) duration in both guinea pig papillary muscle and dog Purkinje fiber with a maximum effective concentration of 10(-6) to 3 x 10(-6) M. MDL 11,939 up to and including 10(-6) M did not alter upstroke velocity (Vmax) of the AP in either tissue but 10(-5) M decreased the Vmax in Purkinje fibers. Compared to the other class III antiarrhythmic agents (bretylium, clofilium, and d-sotalol), MDL 11,939 was among the most potent in increasing AP duration in the papillary muscle, while being relatively less effective in increasing AP duration in Purkinje fiber. Bretylium did not increase the AP duration in papillary muscle unless it was reserpinized. MDL 11,939, clofilium, and d-sotalol all produced negative inotropic effects in papillary muscle, whereas bretylium produced a positive inotropic effect. The positive inotropic effect of bretylium was abolished by reserpinization. In papillary muscle preparations depolarized with 22 mM K+, MDL 11,939 at concentrations greater than or equal to 10(-5) M depressed Vmax of the slow AP, suggesting that it inhibited the inward Ca2+ current, and such an effect may contribute to the negative inotropic effect of this agent. In the depolarized preparations, the slow AP duration was still increased by concentrations of MDL 11,939 greater than or equal to 10(-6) M. In conclusion, MDL 11,939 has cellular electrophysiological properties that suggest a class III antiarrhythmic activity.
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Merrell Dow Research Institute, Cincinnati, Ohio 45215.
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001949:Bretylium Compounds / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D001949:Bretylium Compounds; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; C022799:clofilium; D012110:Reserpine; D013015:Sotalol