Introduction: Recovery of the Na channel from inactivation is essential to the normal conduction and refractoriness of the myocardium. In addition to fast recovery, occurring within several milliseconds at hyperpolarized potentials, a component of the current exhibits slow recovery occurring over hundreds of milliseconds. Long conditioning depolarizations potentiate slow recovery.
Methods and results: This study was designed to test conditioning durations (tc) between 0.25 and 4 seconds (s) as to whether recovery was slowed by an effect on the fast (tau f) and slow (tau s) time constants of recovery, the relative amplitude of the slow component (As), or both. We studied Na channel recovery at -150 mV from inactivation using whole cell voltage clamp of rat ventricular cells at 23 degrees C using a two-pulse recovery protocol. Longer conditioning durations dramatically increased A2 (from 12% for tc = 500 msec to 37% for tc = 4000 msec, P < 0.01). Neither tau f (6 vs 5 msec) nor tau s (115 vs 140 msec) were significantly affected. In a second set of experiments, the recovery potential was depolarized to a potential at which the sodium current was 70% available (approximately equal to - 105 mV). This recovery potential had no significant effect on A2, but both tau f and tau s were significantly slower (e.g., at tc = 2 s, tau s = 147 msec and As = 28% at Vr = - 150 mV, and tau s = 456 msec and As = 29% at Vr approximately equal to - 105 mV). In addition, a 1- to 2-msec lag in the onset of recovery was prominent at the depolarized recovery potentials.
Conclusions: Our results support a model for slow recovery where conditioning duration determines entry into an inactivated state from which Na channels recover slowly, and recovery potential determines the rate of recovery from this state. A kinetic scheme with at least three inactivated states is proposed. These results also have implications for cardiac excitability under conditions, such as ischemia, where membranes are depolarized.