Effects of hyperkalaemia on the depression of maximum rate of depolarization by class I antiarrhythmic agents in guinea‐pig myocardium

Abstract

Standard microeletrode methods were used to record intracellular action potentials from strips of guinea‐pig right ventricular myocardium superfused with either standard physiological saline ([K+] = 5.6 mm) or the same solution modified to contain [K+] = 11.2 mm. The effects on action potential parameters of three therapeutic concentrations of mexiletine, quinidine and disopyramide were studied under both conditions at four different drive rates (interstimulus intervals = 2400, 1200, 600 and 300 ms). Hyperkalaemia in the absence of drugs produced reductions in resting potential (−86.7 ± 2.5 mV to −71.8 ± 3.7 mV; n = 30; P < 0.001), maximum rate of depolarization (300 ± 46.5 Vs−1 to 205.6 ± 37.6 Vs−1; P < 0.0001), and action potential duration (205 ± 26 ms to 188 ± 32 ms; P < 0.05). All three drugs produced increased depression of maximum rate of depolarization in hyperkalaemia compared to control conditions, but at all three concentrations this enhancement of effect was greater for mexiletine than for quinidine, with disopyramide exhibiting intermediate behaviour. Mexiletine behaved very similarly to therapeutic concentrations of lignocaine as described in previous reports from this laboratory. Quinidine behaved very similarly to Class Ic agents. It is concluded that mexiletine demonstrated significantly greater selectivity for depolarized myocardium than quinidine and that this may have implications in terms of proarrhythmic potential. Disopyramide exhibited intermediate selectivity for depolarized myocardium between mexiletine and quinidine. 1993 British Pharmacological Society