The effects of mexiletine on action potential duration and its restitution in guinea pig ventricular muscles.

To clarify the mechanism of mexiletine-induced changes in action potential duration (APD), we studied the effects of mexiletine (2 micrograms/ml) on APD at 0 mV (APD0mV) and 90% (APD90%) repolarization and on restitution of premature responses in guinea pig ventricular muscle at three extracellular potassium concentrations [( K]0) and three stimulation rates using standard microelectrode techniques. The rates at which APD0mV and APD90% were shortened by mexiletine (S-APD0mV and S-APD90%) expressed as percent change from control were most pronounced at [K]0 = 5.4 mM. The percent changes at the three concentrations were 5.0 +/- 2.1% at a [K]0 of 2.7 mM, 6.0 +/- 3.2% at 5.4 mM and 1.8 +/- 1.2% at 10.0 mM for S-APD0mV and 2.0 +/- 1.9%, 4.7 +/- 2.0% and 1.3 +/- 1.5% for S-APD90% at the same concentrations, respectively. S-APD0mV and S-APD90% were more markedly affected when stimulated at a frequency of 1 Hz than when stimulated at 0.2 or 0.5 Hz. Mexiletine failed to produce any additional APD shortening beyond that produced by the introduction of tetrodotoxin (2.5 X 10(-6) M). Mexiletine and tetrodotoxin did not influence APD restitution that fitted a single exponential curve. We conclude that the shortening of APD by mexiletine results from inhibition of a tetrodotoxin-sensitive sodium current.