Submitted on June 12, 2003
Accepted on December 17, 2003
Nitric oxide mediates the protective effect of endothelin receptor antagonism during myocardial ischemia and reperfusion
Adrian T. Gonon1*, Deniz Erbas1, Anders Broijersen2, Guro Valen3, and John Pernow1
1 Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
2 Center for metabolism and endocrinology, Huddinge University Hospital, Huddinge, Sweden
3 Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: adrian.gonon{at}medks.ki.se.
Endothelin (ET) receptor antagonism protects from ischemia-reperfusion injury. We hypothesized that the cardioprotective effect is related to nitric oxide (NO)
bioavailability. Buffer-perfused rat and mouse hearts were subjected to ischemia and reperfusion. At the onset of ischemia the rat hearts received vehicle, the dual ETA/ETB receptor antagonist bosentan (10µM), the NO synthase inhibitor L-NMMA (100µM), the combination of bosentan and L-NMMA or the combination of bosentan, L-NMMA and the NO substrate L-arginine (1mM). Hearts from wild type and endothelial NO synthase (eNOS) deficient mice received either vehicle or bosentan. Myocardial performance, endothelial function, NO outflow and eNOS expression were monitored. Bosentan significantly improved myocardial function during reperfusion in rats and in wild type mice, but not in eNOS deficient mice. The functional protection afforded by bosentan was inhibited by L-NMMA, whereas it was restored by L-arginine.
Myocardial expression of eNOS (immunoblotting) increased significantly in bosentantreated rat hearts in comparison with vehicle hearts. Recovery of NO outflow during
reperfusion was enhanced in the bosentan treated rat heart. The endothelium-dependent vasodilator adenosine diphosphate increased coronary flow by 18±9% at the end of
reperfusion in the bosentan group, whereas it reduced coronary flow by 7±5% in the vehicle group (P<0.001). The response to the endothelium-independent dilator sodium nitroprusside was not different between the two groups. In conclusion, the dual ETA/ETB receptor antagonist bosentan preserved endothelial and cardiac contractile function during ischemia and reperfusion via a mechanism dependent on endothelial NO production.
