© 1995 by European Society of Cardiology
Copyright © 1995, European Society of Cardiology
Protective effects of non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig
aDepartment of Cardiology Karolinska Institute, Stockholm, Sweden
bDepartment of Physiology and Pharmacology Karolinska Institute, Stockholm, Sweden
* Correspondence to Dr Pernow, at Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
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.
KEYWORDS endothelin; bosentan; receptors; antagonist; ischaemia/reperfusion; myocardial; blood flow
The present study was supported by grants from the Swedish Medical Research Council (10857, 6554), the King Gustav Vth and Queen Victoria Foundation, the Swedish Heart and Lung Foundation, the Laerdal Foundation, the Swedish Society of Medicine, and the Karolinska Institute.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Q.-D. Wang, J. Pernow, P.-O. Sjoquist, and L. Ryden Pharmacological possibilities for protection against myocardial reperfusion injury Cardiovasc Res, July 1, 2002; 55(1): 25 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Basso, G. Thiene, M. Della Barbera, A. Angelini, M. Kirchengast, and S. Iliceto Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs Cardiovasc Res, July 1, 2002; 55(1): 113 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Sharif, K. A. Kane, and C. L. Wainwright Endothelin and ischaemic arrhythmias-antiarrhythmic or arrhythmogenic? Cardiovasc Res, September 1, 1998; 39(3): 625 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T Gonon, Q.-D. Wang, and J. Pernow The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion Cardiovasc Res, September 1, 1998; 39(3): 674 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Szabo, L. Fazekas, S. Bahrle, D. MacDonald, N. Stumpf, C. F Vahl, and S. Hagl Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model Cardiovasc Res, September 1, 1998; 39(3): 683 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Kallner, A. Gonon, and A. Franco-Cereceda Calcitonin gene-related peptide in myocardial ischaemia and reperfusion in the pig Cardiovasc Res, May 1, 1998; 38(2): 493 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pernow and Q.-D. Wang Endothelin in myocardial ischaemia and reperfusion Cardiovasc Res, March 1, 1997; 33(3): 518 - 526. [Abstract] [PDF]
|
|