ELECTROCARDIOGRAPHIC INTERACTIONS BETWEEN PINACIDIL, A POTASSIUM CHANNEL OPENER AND CLASS-I ANTIARRHYTHMIC AGENTS IN GUINEA-PIG ISOLATED-PERFUSED HEART

1 Drugs that shorten action potential duration could decrease the Na-c hannel blocking effect of class I antiarrhythmic agents by reducing th e availability of Na channel in the inactivated state. 2 This hypothes is was tested in guinea-pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 mu M mexiletine, 10 mu M quinidine and 3 mu M flecainide) in the presence of increasing concentrations of pinacidil (10 mu M, 30 mu M, 50 mu M), a potassium channel opener that shortens action potential du ration. 3 The ECG parameters measured were: the QRS interval, i.e. the intraventricular conduction time; the JT interval, which reflects the duration of ventricular repolarization; the ratio between JTpeak (the time from the end of QRS and the peak of T wave) and JT interval, whi ch quantifies changes in the morphology of the T wave. 4 At the concen trations tested all the antiarrhythmic drugs widened the QRS complex b y 55-60%. Flecainide did not significantly change JT interval, but qui nidine prolonged and mexiletine shortened it. Mexiletine also decrease d the JTpeak/JT ratio. Pinacidil by itself decreased the JT interval a nd the JT peak/JT ratio in a dose-dependent way, but did not affect QR S duration. 5 In the presence of fixed antiarrhythmic drug concentrati ons, however, pinacidil decreased the QRS prolongation induced by mexi letine (-17%) and quinidine (-8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 mu M) and there was no relationship between pinacidil-induced JT shor tening and QRS changes. To explain this unexpected result it has been supposed that, at the driving frequency used (4 Hz), myocardial cells were partially depolarized and that pinacidil could repolarize them, t hus decreasing the number of inactivated Na channels and the effects o f drugs that (mainly or partly) block the channels in the inactivated state. In agreement with this hypothesis, an additional series of expe riments carried out with 15 mu M mexiletine at a lower stimulation rat e (2 Hz) showed only a negligible loss of QRS effect (-2.3%) at any pi nacidil concentration. 6 Flecainide, but not quinidine and mexiletine, antagonized the JT shortening induced by pinacidil; furthermore, no d rug modified the JTp/JT decrease induced by pinacidil. 7 These results indicate that: (a) an antagonism between class I: antiarrhythmic drug s and pinacidil is possible; (b) mexiletine is the most involved among the drugs tested; (c) the interaction is not related to pinacidil-ind uced repolarization shortening, but probably to changes in membrane re sting potential. The possible clinical implications need to be defined .