Role of endothelin during reperfusion after ischemia in isolated perfused rat heart.
We assessed the role of endogenous endothelin (ET) in reperfusion injury using a novel nonpeptidic ET antagonist of ETA and ETB receptors: bosentan (Ro 47-0203). In preliminary experiments in nonischemic rat hearts, we confirmed that bosentan 10(-5) M could block the changes in coronary flow (CF) and release of prostacyclin induced by ET-1 and the ETB-selective agonist sarafotoxin S6c (SRTX S6c). Thereafter, we induced global ischemia in paced hearts by closing the perfusion line for 20 min; this was followed by reperfusion. In one group of rats, bosentan (10(-5) M) was added to the perfusion medium before ischemia. In preischemic conditions, bosentan slightly increased CF by 14% (p = 0.094) in nonpaced hearts and by 35% (p = 0.001) in paced hearts, but did not influence cardiac contractility. Global ischemia produced severe ischemic damage, as shown by electromechanical dissociation (EMD) and decreased cardiac contractility. Bosentan did not influence recovery of cardiac function and did not ameliorate postischemic hemodynamic variables as compared with those of the control group. We conclude that endogenous ET does not play a major role in induction of reperfusion injury in isolated perfused rat heart.
Dagassan
P H
PH
Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Breu
V
V
Clozel
M
M
Clozel
J P
JP
D000818:Animals; D000077300:Bosentan; D003326:Coronary Circulation / Q000187:drug effects; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D011464:Epoprostenol / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology*; D013449:Sulfonamides / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D011464:Epoprostenol; D000077300:Bosentan