PROARRHYTHMIC EFFECTS OF PINACIDIL ARE PARTIALLY MEDIATED THROUGH ENHANCEMENT OF CATECHOLAMINE RELEASE IN ISOLATED PERFUSED GUINEA-PIG HEARTS

Abstract The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30 μ M ), an opener of ATP-sensitive potassium channels (K + ATP ), was tested in an isolated guinea-pig heart model of global ischemia (10 min) and reperfusion (10 min). None (0%) of the control hearts ( n =10) elicited arrhythmias during ischemia or reperfusion. In the pinacidil-treated group, one heart (5%) experienced episodes of ventricular tachycardia (VT)/fibrillation (VF) during normoxia. During ischemia, 63% (12 out of 19) of pinacidil-treated hearts exhibited episodes of VT or VF. Hearts not in VT or VF ( n =7) at the time of reperfusion, exhibited 71% VT and 43% VT/VF upon reperfusion. Proarrhythmic effects of pinacidil during ischemia or reperfusion were completely reversed by glyburide ( n =9; 10 μ M ), a K + ATP antagonist, or nadolol ( n =9; 3 μ M ), a β -adrenergic antagonist. Isoproterenol ( n =10; 50 n M ), a β -adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine ( n =10; 10 μ M ), an α -adrenergic agonist, demonstrated little proarrhythmia (20% VT/VF at reperfusion only). Proarrhythmic effects of isoproterenol were reversed by nadolol, but not glyburide. Pinacidil caused a slight potentiation of tachycardia induced by a bolus injection of tyramine (30 μ g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 μ g) had no effect on heart rate. Nisoxetine, a catecholamine uptake1 inhibitor, had no proarrhythmic effects when given alone. Catecholamine levels were reduced in pinacidil-treated hearts relative to vehicle-treated. In conclusion, it is suggested that the proarrhythmic effects of pinacidil following global ischemia and reperfusion in the isolated perfused guinea-pig heart appears to involve stimulation of β -adrenoceptors. These proarrhythmic effects of pinacidil do not appear to be mediated solely through direct opening of K + ATP , but rather through an indirect enhancement of catecholamine release.