Effects of the optical isomers of D 600 on cardiovascular parameters and on arrhythmias caused by aconitine and coronary artery ligation in anesthetized rats.
We examined the effects of the optical isomers of D 600 on cardiovascular parameters and on arrhythmias caused by aconitine infusion and ligation of left coronary artery in urethane-anesthetized rats. (-)-D 600 decreased blood pressure and LV dP/dtmax with respective Ed30% of 0.045 and 0.018 mg/kg i.v.; increased PQ duration with an ED20% of 0.045 mg/kg i.v.: and caused AV-block with an ED50 of 0.07 mg/kg i.v., thereby showing a potency 20--50 times that of (+)-D 600 and about twice that of the racemate. (+)-D 600 in the effective dose range additionally widened QRS complex (ED20%, 2.44 mg/kg i.v.) and increased arrhythmogenic aconitine dose (ED75% 4.97 mg/kg i.v.) with a potency about equal to quinidine. In contrast to the (-)-isomer and the racemate of D 600 and to (+/-)-verapamil, (+)-D 600, at a dose slightly below AV block-generating ED50 of 2.15 mg/kg i.v., significantly attenuated ventricular arrhythmias following left coronary artery ligation with a potency similar to 4.64 mg/kg i.v. quinidine but inferior to 4.64 mg/kg i.v. lidocaine. It is concluded that the optical isomers of D 600 exert stereospecific actions in vivo with respect to Ca2+-antagonistic potency. While (-)-D 600 in the effective dose range shows cardiovascular actions indicative of pure Ca2+-antagonistic properties, and activity of the racemate resides in the Ca2+-antagonistic properties of the (-)-isomer, cardiovascular effects of (+)-D 600 and its effectiveness against ventricular arrhythmias are indicative of parallel Ca2+-antagonistic and membrane-stabilizing properties.
D000157:Aconitine / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000502:physiology; D005711:Gallopamil / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008026:Ligation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014700:Verapamil / Q000031:analogs & derivatives*
D005711:Gallopamil; D014700:Verapamil; D000157:Aconitine