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 incompetence in the myocardium. Forty-five isolated rat hearts were perfused with Krebs-Henseleit buffer (KHB) for 15 min and then subjected to 0, 15, or 60 min of ischemia followed by 5 min of reperfusion with KHB, KHB + BQ-610, or KHB + BQ-123. They were fixed by perfusion with 2.5% glutaraldehyde and then perfused with nuclear track emulsion as an indicator of vascular flow. Transmural sections of resin-embedded myocardium were examined by scanning and transmission electron microscopy. Following 60 min of ischemia, the subendocardial third of the LV wall of hearts treated with BQ-123 showed nearly three times the proportion (P < 0.001) of competent capillaries in untreated hearts. Reperfusion after 15 min of ischemia of hearts treated with BQ-123 showed a 30% increase in the proportion of competent capillaries compared to controls (P < 0. 002). Treatment of corresponding groups with BQ-610 increased the proportion of competent capillaries but these differences were not statistically significant. In addition, both ET-I antagonists dramatically reduced the amount of ultrastructural change evident in myocardium reperfused after 60 min of ischemia. Thus endothelin plays a significant role in the pathogenesis of postischemic microvascular incompetence in the myocardium and, probably by its effects on Ca(2+) uptake, contributes also to the ultrastructural damage to the myocytes and endothelium which follows postischemic reperfusion of irreversibly injured myocardium.