Endothelin A and B receptor antagonist bosentan reduces postischemic myocardial injury in the rat: critical timing of administration.
The purpose of this study was to investigate the effects of bosentan, a mixed endothelin receptor A and B subtype antagonist, on myocardial ischemia-reperfusion injury and to explore the influence of the timing of bosentan administration on its cardioprotective effects. Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit solution (KH) at a constant flow rate at 10 mL/min. Global myocardial ischemia was induced by stopping KH perfusion for 40 min, and this was followed by 60 min of reperfusion. Hearts were randomized to 1 of 3 experimental groups (n = 7 each): untreated control; treatment with bosentan 1 micromol/L 10 min prior to, during 40 min global ischemia, and for 15 min of reperfusion (BOS); or treatment with bosentan 1 micromol/L after 15 min of reperfusion (BOS-R). We observed that BOS-R, but not the BOS treatment regimen, significantly reduced the release of cardiac-specific creatine kinase and postischemic myocardial infarct size (P < 0.05 vs. control) without affecting myocardial contractility. Left ventricular developed pressure in the BOS group was significantly (P < 0.01) lower than that in the control group throughout reperfusion. It is concluded that pharmacologically delayed antagonism of endothelin-1 during reperfusion attenuates postischemic myocardial injury. Endothelin-1 antagonist application during early reperfusion may exacerbate postischemic myocardial dysfunction.
Xia
Zhengyuan
Z
Centre for Anesthesia and Analgesia, Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Kuo
Kuo-Hsing
KH
McNeill
John H
JH
Ansley
David M
DM
D000818:Animals; D000077300:Bosentan; D003402:Creatine Kinase / Q000378:metabolism*; D052279:Creatine Kinase, MB Form; D004334:Drug Administration Schedule; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D017725:Ventricular Pressure / Q000187:drug effects
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D007527:Isoenzymes; D013449:Sulfonamides; D003402:Creatine Kinase; D052279:Creatine Kinase, MB Form; D000077300:Bosentan