Inhibitory activity of blockers of the slow inward current in rat myocardium, a study in steady state and of rate of action

The inhibitory effects of verapamil (84.4% inhibition) and D-600 (70.4% inhibition) on the conductance of the slow inward current were compared with that of Mn²⁺ (99.7% inhibition). Hill coefficients of 2 for Mn²⁺ and D-600 and one for verapamil were found. For racemic mixtures of verapamil and D-600 the apparent dissociation constants (K_0.5) were 1.4 and 3.6 μm respectively, whereas the apparent dissociation constant of Mn²⁺ was 625 μm. With such high affinities, as compared to Mn²⁺, time constants of inhibition for D-600 and verapamil were larger and their offset rates were slower. It is concluded that Mn²⁺ and the organic blockers have different mechanisms of action, that varapamil and D-600 have to pass through or enter into the membrane, and that the molecules of D-600 and verapamil possess one and two active groups respectively.