Proarrhythmic Effects of Pinacidil are Partially Mediated Through Enhancement of Catecholamine Release in Isolated Perfused Guinea-pig Hearts

The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30μ ), 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; 10μ ), a K+ATPantagonist, or nadolol (n=9; 3μ ), aβ-adrenergic antagonist. Isoproterenol (n=10; 50 n ), aβ-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10μ ), anα-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 (30μg), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100μg) 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 ofβ-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.