Reversible inhibition of potassium contractures by optical isomers of verapamil and D 600 on slow muscle fibres of the frog

Abstract

Potassium-induced contractures were measured isometrically in slow fibres of gastrocnemius muscle from the frog Leptodactylus ocellatus. Optical isomers of verapamil and of D 600 decreased the tension of K-contractures with the following characteristics: 90 min exposures of the muscles to the (-)isomers of the drugs were more effective in decreasing tension of 40 mM KCl-contractures when successive challenges to 40 mM KCl were made each 10–15 min than without challenges during the incubation time. In contrast to the depressing effect of (-)isomers of verapamil and D 600, the decrease of K-contractures by 1 mM EGTA in “Ca-free” solutions was independent on the history of 40 mM KCl-contractures. The threshold concentration of K to cause contractures was the lower the lower the Ca-concentration. This relationship was little affected by (-)verapamil at concentrations of the drug which depressed by 50% the tension of 40 mM KCl-contractures in 1.8 mM CaCl₂. Verapamil and its methoxy-derivative D 600 were equipotent in depressing 40 mM KCl-contractures. Their optical (-)isomers were 4 to 5 times more potent than their corresponding (+)isomers. K-tension curves in the presence of 6.1 μM (-)verapamil in 1.8 mM CaCl₂ were similar to curves in 0.18 mM CaCl₂ without the drug. K-tension curves in 10 mM CaCl₂ were shifted by (-)verapamil in nearly parallel manner towards higher K-concentrations. The stereoselective decrease of K-contractures by verapamil and D 600 may be due to blockade of inward Ca-flux and to retardation of the reavailability of Ca²⁺ for release during partial depolarizations with K.