Electrocardiographic interactions between pinacidil, a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart.

1Drugs that shorten action potential duration could decrease the Na-channel blocking effect of class I antiarrhythmic agents by reducing the availability of Na channel in the inactivated state. 2This hypothesis was tested in guinea-pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 μm mexiletine, 10 μm quinidine and 3 μm flecainide) in the presence of increasing concentrations of pinacidil (10 μm, 30 μm, 50 μm), a potassium channel opener that shortens action potential duration. 3The 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, which quantifies changes in the morphology of the T wave. 4At the concentrations tested all the antiarrhythmic drugs widened the QRS complex by 55–60%. Flecainide did not significantly change JT interval, but quinidine prolonged and mexiletine shortened it. Mexiletine also decreased the JTpeak/JT ratio. Pinacidil by itself decreased the JT interval and the JT peak/JT ratio in a dose-dependent way, but did not affect QRS duration. 5In the presence of fixed antiarrhythmic drug concentrations, however, pinacidil decreased the QRS prolongation induced by mexiletine (−17%) and quinidine (− 8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 μm) and there was no relationship between pinacidil-induced JT shortening 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, thus decreasing the number of inactivated Na channels and the effects of drugs that (mainly or partly) block the channels in the inactivated state. In agreement with this hypothesis, an additional series of experiments carried out with 15 μm mexiletine at a lower stimulation rate (2 Hz) showed only a negligible loss of QRS effect (−2.3%) at any pinacidil concentration. 6Flecainide, but not quinidine and mexiletine, antagonized the JT shortening induced by pinacidil; furthermore, no drug modified the JTp/JT decrease induced by pinacidil. 7These results indicate that: (a) an antagonism between class I antiarrhythmic drugs and pinacidil is possible; (b) mexiletine is the most involved among the drugs tested; (c) the interaction is not related to pinacidil-induced repolarization shortening, but probably to changes in membrane resting potential. The possible clinical implications need to be defined.