Sodium Channel Inactivation from Resting States in Guinea-pig Ventricular Myocytes

1. Unitary Na+ channel currents were recorded from isolated guinea-pig ventricular myocytes using the cell-attached patch-clamp technique with high [Na+] in the pipette to enhance the signal-to-noise ratio. 2. The probability that the channel enters the inactivated state (I) directly from resting states (C) was investigated over a wide range of membrane potentials. 3. At membrane potentials of -60 mV or more positive, Markov chain theory was used to estimate the probability of C----I from histograms of the number of channel openings per depolarizing period. Holding potentials at least as negative as -136 were required to ensure that all channels resided in C prior to depolarization. 4. At membrane potentials negative to -60 mV, a two-pulse protocol was employed to determine the probability of C----I from the fraction of blank sweeps during the pre-pulse with correction for missed events. 5. The probability of C----I was found to be steeply voltage dependent at negative potentials, falling from 0.87 +/- 0.03 (mean +/- S.D.) at -91 mV to 0.42 +/- 0.01 at -76 mV. At potentials positive to -60 mV, this probability was less steeply voltage dependent and decayed to near zero at 0 mV. 6. Under physiological conditions, C----I transitions may produce appreciable Na+ channel inactivation at diastolic potentials. At potentials above the action potential threshold, inactivation is much more likely to occur from the open state.