Slow inactivation of Vmax in guinea pig ventricular myocardium

Measurements of maximum upstroke velocity (Vmax) of guinea pig ventricular action potentials were used to investigate the effect of prolonged depolarization on the inactivation and recovery kinetics of cardiac sodium channels. Membrane potential before stimulated upstrokes was controlled by passing current across a sucrose gap. Two phases of inactivation ("slow" and "ultra-slow") having kinetics and voltage dependence different from the commonly observed fast inactivation process were observed. Ultra-slow inactivation developed exponentially with a time constant of several minutes between -60 and -20 mV. In contrast, slow inactivation developed with a time constant of 1-6 s between -60 and 40 mV. Under steady-state conditions slow and ultra-slow inactivations were virtually absent at -85 mV, while 50% of Vmax underwent slow inactivation at approximately 10 mV and 50% underwent ultra-slow inactivation at approximately -40 mV. Recovery from slow inactivation occurred exponentially with a time constant of about 2 s at -70 to -85 mV and 0.7 s at -100 mV. Recovery from ultra-slow inactivation was not completely characterized but was complete within 20 s at -85 mV. No significant effect of external [K+] (1-10 mM) on slow inactivation was found. The results suggest the existence of two additional inactivated states of the cardiac sodium channel distinctly different from the fast inactivated state.