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 (30 mu 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 mu M), a K-ATP(+) antagonist, or nadolol (n=9; 3 mu M), a beta-adrenergic antagonist. Isoproterenol (n=10; 50 nM), a beta-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10 mu M), an alpha-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 mu g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 mu g) had no effect on heart rate. Nisoxetine, a catecholamine uptake 1 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 beta-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. (C) 1998 Academic Press Limited.