THE MYOCARDIAL LESIONS PRODUCED BY THE POTASSIUM CHANNEL OPENER APRIKALIM IN MONKEYS AND RATS ARE PREVENTED BY BLOCKADE OF CARDIAC BETA-ADRENOCEPTORS

Aprikalim is a potent, specific, and selective opener of ATP-sensitive K+ (K-ATP) channels. By virtue of this pharmacological property, apri kalim affords cardioprotection in experimental models of ischemia/repe rfusion injury, and, at higher doses, also causes peripheral or corona ry vasodilatation. Direct-acting peripheral vasodilators can cause myo cardial 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 myocardi al lesions were the direct or indirect consequence of the vascular eff ects of aprikalim. Cynomologus monkeys were given the beta-adrenocepto r antagonist nadolol (2 mg/kg po, twice daily) for 4 consecutive days. On the third and fourth day of the experiment, they received aprikali m (1 mg/kg po). In another series, two monkeys carrying telemetry tran smitters for blood pressure and heart rate measurements were also give n aprikalim or its vehicle. Finally, aprikalim (1 mg/kg po for 2 days) or its vehicle was administered to rats which were concurrently treat ed with the beta-adrenoceptor antagonist atenolol (5 mg/kg sc) or its vehicle. In cynomologus monkeys, aprikalim produced focal and multifoc al 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 bloo d pressure, accompanied by an even more prolonged tachycardia. These r esults 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 monke ys. More importantly, these effects were prevented by blocking cardiac beta-adrenoceptors. Thus, the myocardial lesions produced by aprikali m may be attributed to its profound and prolonged hemodynamic effects. (C) 1996 Society of Toxicology