Endothelin antagonists diminish postischemic microvascular incompetence and necrosis in the heart

The endothelin receptor antagonists BQ-610 and BQ-123 were used to clarify the role of endothelin in the pathogenesis of postischemic microvascular in competence in the myocardium. Forty-five isolated rat hearts were perfused with Krebs-Henseleit buffer (KHB) for 15 min and then subjected to 0, 15, o r 60 min of ischemia followed by 5 min of reperfusion with KHB, KHB + BQ-61 0, or KHB + BQ-123. They were fixed by perfusion with 2.5% glutaraldehyde a nd then perfused with nuclear track emulsion as an indicator of vascular fl ow. Transmural sections of resin-embedded myocardium were examined by scann ing and transmission electron microscopy. Following 60 min of ischemia, the subendocardial third of the LV wall of hearts treated with BQ-123 showed n early three times the proportion (P < 0.001) of competent capillaries in un treated hearts. Reperfusion after 15 min of ischemia of hearts treated with BQ-123 showed a 30% increase in the proportion of competent capillaries co mpared to controls (P < 0.002). Treatment of corresponding groups with BQ-6 10 increased the proportion of competent capillaries but these differences were not statistically significant. In addition, both ET-T antagonists dram atically reduced the amount of ultrastructural change evident in myocardium reperfused after 60 min of ischemia. Thus endothelin plays a significant r ole in the pathogenesis of postischemic microvascular incompetence in the m yocardium and, probably by its effects on Ca2+ uptake, contributes also to the ultrastructural dam age to the myocytes and endothelium which follows p ostischemic reperfusion of irreversibly injured myocardium. (C) 2000 Academ ic Press.