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+ (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.
Belin
V
V
Drug Safety Department, Rhône-Poulenc Rorer, Vitry-sur-Seine, France.
Hodge
T
T
Picaut
P
P
Jordan
R
R
Algate
C
C
Gosselin
S
S
Nohynek
G
G
Cavero
I
I
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000473:pathology*; D010847:Picolines / Q000633:toxicity*; D015221:Potassium Channels / Q000819:agonists*; D011714:Pyrans / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000633:toxicity*
D000319:Adrenergic beta-Antagonists; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D014665:Vasodilator Agents; C061043:aprikalim; D001262:Atenolol