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

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is th ought to participate in the hemodynamic effects elicited by drugs that bloc k the biosynthesis and release of endothelium-derived nitric oxide (NO), su ch as NO synthase inhibitors. Using the nonpeptide endothelin receptor anta gonists bosentan and LU-135252, we tested the hypothesis that endothelins c ontribute to the presser activity of diaspirin-crosslinked hemoglobin (DCLH b), a hemoglobin-based oxygen carrier, whose presser activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase in hibitor nitro-L-arginine methyl ester (L-NAME), ET-I, and noradrenaline (NA ) were used as reference drugs. Bosentan markedly reduced the presser effec ts elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-1352 52 attenuated the pressor effect elicited by DCLHb and ET-1, but not that p roduced by L-NAME or NA. The decreases in heart rate, associated with the p resser effect of DCLHb and L-NAME were reduced by LU-135252, whereas only t hose elicited by DCLHb, were attenuated by bosentan. In contrast with bosen tan, LU-135252 caused a decrease in the baseline blood pressure and heart r ate. These results suggest that endothelins may participate in the presser activity of DCLHb. They suggest also that nonpeptide endothelin receptor an tagonists such as bosentan or LU-135252 may be useful to counteract endothe lin-mediated undesirable hemodynamic effects of drugs that inhibit the acti vity of the NO system.