Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat

Abstract

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.