Protective effects of non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig.
OBJECTIVE
The aim was to investigate the effects of the non-peptide endothelin receptor antagonist bosentan (Ro 47-0203) on haemodynamic variables, infarct size, myocardial overflow, and tissue content of endothelin-like immunoreactivity (ET-LI) during ischaemia and reperfusion in anaesthetised pigs, and to study the inhibitory effect of bosentan on ET-1 induced coronary constriction in vitro.


METHODS
Ischaemia was induced by ligation of the left anterior descending coronary artery for 45 min, followed by 4 h of reperfusion. Bosentan was given either intravenously (5 mg.kg-1) 15 min before ischaemia or as a 25 min local coronary venous retroinfusion (10(-4) M) starting at 30 min of ischaemia. ET-LI was analysed in myocardial tissue and in plasma from the anterior interventricular coronary vein and aorta. The effect of bosentan on endothelin-1 induced vasoconstriction was evaluated in isolated diagonal branches of left anterior descending coronary artery.


RESULTS
Intravenous bosentan slightly reduced arterial blood pressure (P < 0.05) but did not affect basal coronary vascular resistance. Local retroinfusion of bosentan did not change blood pressure. Intravenous and retroinfused bosentan significantly reduced infarct size by 58% and 48% respectively (P < 0.01) and enhanced the recovery of coronary blood flow by 65-90% compared to vehicle treated controls at the end of 4 h reperfusion. The basal plasma levels of ET-LI and the myocardial overflow of ET-LI during reperfusion increased twofold after bosentan. A threefold increase in the concentration of ET-LI was observed in the ischaemic/reperfused myocardium and this enhancement was significantly attenuated by bosentan. Bosentan effectively antagonised the endothelin-1 induced but not the serotonin induced, contractions of isolated coronary arteries and reversed the established contraction induced by endothelin-1.


CONCLUSIONS
The non-peptide endothelin receptor antagonist bosentan markedly protects the myocardium from ischaemia/reperfusion injury and improves blood flow to the reperfused area, indicating the involvement of endogenous endothelin-1 and the therapeutic value of bosentan in the treatment of ischaemia/reperfusion injury.
Wang
Q D
QD
Department of Cardiology, Karolinska Institute, Stockholm, Sweden.
Li
X S
XS
Lundberg
J M
JM
Pernow
J
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D003331:Coronary Vessels / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D013449:Sulfonamides / Q000627:therapeutic use*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D013449:Sulfonamides; D012701:Serotonin; D000077300:Bosentan