Endogenous endothelin-1 impairs endothelium-dependent relaxation after myocardial ischemia and reperfusion.
Endothelin (ET)-1 is produced in response to myocardial ischemia and reperfusion. It is a potent constrictor of coronary resistance vessels and may therefore contribute to myocardial injury and postischemic microvascular dysfunction. Isolated buffer-perfused rabbit hearts, under conditions of constant flow and isovolumic contraction, underwent 60 min of global ischemia and 60 min of reperfusion after pretreatment with selective ETA receptor antagonist BQ-123 (10(-7) M) in perfusate, exogenous ET-1 (10(-11) M), or control. Release of ET increased significantly at 20 and 60 min of reperfusion. BQ-123 did not enhance the recovery of left ventricular developed pressure or coronary perfusion pressure, whereas exogenous ET tended to worsen them. Cumulative creatine kinase release over 20 min of reperfusion did not differ significantly between groups. Maximum endothelium-dependent dilation to acetylcholine (ACh) was initially 62 +/- 6, 71 +/- 6, and 63 +/- 8% (SE) of U-46619-induced preconstriction in control, BQ-123-, and ET-treated hearts. At 20 min of reperfusion it was 37 +/- 5, 73 +/- 9, and 22 +/- 5%, and at 60 min of reperfusion it was 35 +/- 7, 79 +/- 6, and 22 +/- 3% (P < 0.001 for BQ-123 vs. control at 20 min and P < 0.0001 at 60 min). Endothelium-independent dilation to nitroglycerin was unaltered by ischemia and reperfusion. Neither BQ-123 alone nor a 1-h infusion of ET (10(-10) M) altered the response to ACh in nonischemic hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
University of California, Irvine 92714.
J M
JM
Hagar
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology* / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)