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.
Maxwell
L
L
Department of Pathology, School of Medicine, Auckland, New Zealand. 1.maxwell@auckland.ac.nz
Harrison
W R
WR
Gavin
J B
JB
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000648:ultrastructure; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C087220:BQ 610; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium