Protective effects of the K+ ATP channel opener, aprikalim, against free radicals in isolated rabbit hearts.
Aprikalim, a K+ ATP channel opener, is a potent vasodilator with demonstrated cardioprotective properties against ischemia/reperfusion injury. It is still unknown if K+ ATP channel openers exert their beneficial effects via interaction with oxygen-derived free radicals. Therefore, we investigated the cardioprotective effects of aprikalim against oxygen-derived free radicals. Isolated rabbit hearts were perfused at constant pressure (85 cm H2O) or constant flow (30-35 ml/min). Heart rate, left ventricular developed pressure (LVDP), and either coronary flow or coronary perfusion pressure (CPP) were monitored. Free radicals were produced by electrolysis of the perfusate (0.6 mA, direct current), and 10 microM aprikalim was infused before and after exposure to free radicals. In the constant perfusion pressure experiments, 10 min of exposure to free radicals resulted in a significant reduction of heart rate (137 to 129 beats/min), LVDP (112 to 91 mmHg) and coronary flow (37 to 29 ml/min); coronary flow was more markedly impaired than contractile function. Acetylcholine-induced coronary dilation was also significantly attenuated in the presence of free radicals. After 30 min of recovery, both coronary flow and LVDP were still significantly decreased while acetylcholine-induced coronary dilation had fully recuperated. Aprikalim completely abated the coronary and cardiac depressant actions of free radicals. Constant flow experiments indicated that exposure to free radicals increased CPP (+40%, p < 0.05), an effect totally suppressed by aprikalim. These results demonstrate that aprikalim reverses the cardiodepressant actions of free radicals. The cardioprotection it afforded involves both contractile function and the coronary vasculature. Acetylcholine-induced coronary dilation was blunted by free radicals, an indication of complex interactions at the coronary endothelial level.
Pignac
J
J
Département de Pharmacologie, Université de Montréal, Canada.
Lacaille
C
C
Dumont
L
L
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010847:Picolines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011714:Pyrans / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D016166:Free Radical Scavengers; D005609:Free Radicals; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D014665:Vasodilator Agents; C061043:aprikalim; D000255:Adenosine Triphosphate; D000109:Acetylcholine