Aprikalim is a potent, specific, and selective opener of
ATP-sensitive K+ (
KATP) channels. By virtue of this pharmacological property,
aprikalim affords cardioprotection in experimental models of
ischemia/reperfusion injury, and, at higher doses, also causes peripheral or coronary vasodilatation. Direct-acting peripheral
vasodilators can cause myocardial lesions, particularly in rats and dogs. However, unexpectedly,
aprikalim produced this effect also in monkeys. Thus, the primary aim of this investigation was to assess whether in monkeys these myocardial lesions were the direct or indirect consequence of the vascular effects of
aprikalim. Cynomologus monkeys were given the
beta-adrenoceptor antagonist nadolol (2 mg/kg p.o., twice daily) for 4 consecutive days. On the third and fourth day of the experiment, they received
aprikalim (1 mg/kg p.o.). In another series, two monkeys carrying telemetry transmitters for blood pressure and heart rate measurements were also given
aprikalim or its vehicle. Finally,
aprikalim (1 mg/kg p.o. for 2 days) or its vehicle was administered to rats which were concurrently treated with the
beta-adrenoceptor antagonist atenolol (5 mg/kg s.c.) or its vehicle. In cynomologus monkeys,
aprikalim produced focal and multifocal myocardial
necrosis of minimal to moderate intensity in or near the papillary muscles of the left ventricle. These effects were abrogated by
nadolol. Similarly, necrotic lesions were caused by
aprikalim only in those rats which had not been pretreated with
atenolol. In monkeys,
aprikalim produced a marked and long-lasting decrease in aortic blood pressure, accompanied by an even more prolonged
tachycardia. These results demonstrate that
aprikalim can produce myocardial
necrosis not only in rats but also in monkeys. To our knowledge, this is the first time that such adverse effects are reported for a
vasodilator in monkeys. More importantly, these effects were prevented by blocking cardiac beta-
adrenoceptors. Thus, the myocardial lesions produced by
aprikalim may be attributed to its profound and prolonged hemodynamic effects.