Mechanisms of closure of cardiac sodium channels in rabbit ventricular myocytes: single-channel analysis.

We have examined the kinetics of closure of sodium channels using single-channel recordings in cell-attached and excised membrane patches of rabbit ventricular myocytes. Sodium-channel closure was dependent on membrane potential. The closing rate initially decreased with depolarization. The rate then passed through a minimum and increased at strongly depolarized potentials. We attempted to determine the separate voltage dependence of the deactivation and inactivation rate constants using the method of Aldrich, Corey, and Stevens. In a majority of experiments, the method did not give internally consistent results. As an alternative approach, batrachotoxin was used to remove inactivation and determine the voltage dependence of deactivation rate. The deactivation rate decreased with depolarization. To account for the increase in the closing rate at strongly depolarized test potentials, one must postulate voltage dependence of inactivation. The ensemble average current relaxed with a time course that was usually best described by the sum of two exponentials. The larger of the two rate constants that described the relaxation was strongly voltage-dependent, increasing with depolarization. The larger rate constant may reflect voltage-dependent inactivation. We found evidence of two possible mechanisms for the slow component of relaxation: 1) cardiac sodium channels may open repetitively during a given depolarizing epoch, and 2) channels may return from the inactivated state with low probability and burst for as much as 200 msec with open times that are longer than those during usual gating. The slow component appears to be more prominent in cardiac muscle than in nerve and may play an important role in the control of the action potential duration and the inotropic state of the heart.