Membrane potential-dependent effects of SC-36602, a new class I antiarrhythmic agent on cardiac action potentials

The in vitro electrophysiological properties of a new class I antiarrhythmic agent, SC-36602, were evaluated by recording action potentials (APs) from guinea pig papillary muscle. SC-36602 and its (+) and (-) enantiomers (10(-6)-10(-4) M) caused a concentration- and only slight frequency-dependent depression of Vmax (maximum rate of rise of the AP). At stimulation rates of 30, 60, 120, and 200 pulses/min, SC-36602 (10(-4) M) reduced Vmax to 64 +/- 2.2, 62 +/- 2.8, 60 +/- 2.4, and 58 +/- 2.7% of control, respectively, and significantly shortened effective refractory period (ERP) (20-40%). The rate constants for onset of block of Vmax during trains of stimuli at 1 or 3.3 Hz were similar (approximately 0.2 AP-1). Slow recovery from Vmax block following a stimulus train recorded in tissue depolarized by 10 mM [K+]o Tyrode's solution was enhanced following exposure to SC-36602. The normalized relationship between Vmax and membrane potential was shifted 3 and 12 mV in the hyperpolarizing direction at stimulation frequencies of 0.2 and 1 Hz, respectively. These results suggest that SC-36602 would preferentially depress conduction in depolarized tissue in vivo.