Resting and Rate-Dependent Depression of Maximum Rate of Depolarisation (Vmax) in Guinea Pig Ventricular Action Potentials by Mexiletine, Disopyramide, and Encainide

The influence of stimulation rate on the ability of mexiletine, disopyramide, and encainide to depress the maximum rate of depolarisation (Vmax) of intracellular action potentials has been studied in guinea pig ventricular myocardium, using standard microelectrode techniques. Mexiletine and disopyramide produced modest depression of Vmax even in the absence of stimulation (resting block), while encainide did not. All three drugs produced progressive depression of Vmax as stimulation rate was increased over a wide range of interstimulus intervals (rate-dependent block). This relationship between interstimulus interval (ISI) and depression of Vmax was steepest for mexiletine, least marked for disopyramide, and intermediate for encainide. Mexiletine also exhibited the fastest response to a sudden change of frequency. During a train of stimuli at ISI of 300 ms after a rest period, Vmax fell rapidly, reaching 61% of its final value by the second beat. In response to a similar train of stimuli, disopyramide and encainide produced exponential falls of Vmax with rate constants of -0.113 AP (AP = action potential) and -0.025 AP, respectively. Similar trends were seen in the recovery of cells from this rate-dependent block at the end of a train of stimuli. Time constants for this process for mexiletine, disopyramide, and encainide were 471.2 ms, 12.2 s, and 20.3 s, respectively. It is concluded that the rapid onset of and recovery from rate-dependent block seen with mexiletine may explain its lack of effect on conduction of sinus beats at concentrations that suppress extrasystoles and tachycardias.