Voltage‐ and rate‐dependent reduction of Vmax of cardiac action potentials by SC‐40230

Abstract

AbstractThe voltage‐, rate‐, and concentration‐dependent effects of a new antiarrhythmic agent, SC‐40230, which is chemically similar to disobutamide, on cardiac action potentials were evaluated. Racemic SC‐40230 and its two stereoisomers caused equipotent reduction of the maximum rate of depolarization (V̇max) of action potentials recorded from guinea pig papillary muscle. Action potential duration and effective refractory period were shortened by the drug in papillary muscle and canine Purkinje fibers, but were not altered in guinea pig atria. Depression of V̇max by racemic drug was similar in all three preparations. SC‐40230 did not cause significant reduction of V̇max following a long rest period (no “rested state” reduction). Rate‐dependent depression of V̇max was observed when papillary muscles were stimulated at rates slower, but not greater than 30 pulses/min. In papillary muscles depolarized by 10 mK Ko+, steady‐state depression of V̇max during a stimulus train of 200 pulses/min was 18% in the absence of drug and 56% in the presence of 30 μM SC‐40230. Onset of V̇max reduction was monoexponential (rate constant = 0.064 [action potentials]−1). Recovery from depression of V̇max following the train of stimuli was monoexponential in both control (tau = 11.0 sec) and in the presence of 30 μM SC‐40230 (tau = 27.8 sec). Thus, SC‐40230 appears to slow recovery from slow inactivation of Na current. Rate‐dependent depression of V̇max was voltage dependent. The V1/2 for the relationship between V̇max and resting membrane potential was shifted by −8 mV when determined at a stimulation rate of 120 pulses/min, but was not altered at 12 pulses/min by the drug. Thus, SC‐40230 has typical class I activity on isolated cardiac muscle, but lacks the toxicity of disobutamide.