Sodium current in freshly isolated and in cultured single rat myocardial cells: frequency and voltage-dependent block by mexiletine.

Effects of mexiletine on the rapid inward sodium current (INa) were studied in freshly isolated single cells of the ventricular myocardium of adult rats and in single cultured ventricular muscle cells of newborn rats. The current was measured in internally perfused, voltage-clamped cells by a single suction pipette technique. Mexiletine was applied extracellularly. INa was reduced by the drug in both preparations when the membrane was depolarized to -20 mV by short (8 ms) pulses delivered at a frequency of 0.1 Hz from a holding potential of -100 mV. Mexiletine in a concentration of 50 microM diminished the INa under this condition by 70 +/- 8% (mean +/- S.D.) in the adult myocardial cells. A nearly equal reduction of the current (65 +/- 10%) was caused in the neonatal myocardial cells by 15 microM mexiletine. A use-dependent block of INa was produced in the presence of 10 and of 20 to 30 microM mexiletine, respectively, in the neonatal and the adult myocardial cells by repetitive depolarizing test pulses applied at frequencies between 1 and 7 Hz. Prolongation of the pulse duration from 10 to 100 ms enhanced the use-dependent block of INa in both preparations. The frequency-dependent action of mexiletine could be modulated by 100-ms hyperpolarizing prepulses from -80 to -140 mV. The time course of the use-dependent block (prepulse off) and unblock (prepulse on) was monitored. The slope of the inactivation curve of INa in the neonatal heart cells was reduced in the presence of mexiletine and the midpoint of the curve was shifted in the hyperpolarizing direction. These findings are interpreted as suggesting that binding of mexiletine to the sodium channel of the rat myocardial cells studied is enhanced when the cell membrane becomes depolarized.