A ROLE FOR ENDOTHELIN AND NITRIC-OXIDE IN THE PRESSOR-RESPONSE TO DIASPIRIN CROSS-LINKED HEMOGLOBIN

Diaspirin-cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp) has potential for clinical use as a hemoglobin-based oxygen-carrying solut ion. We have previously shown that DCLHb administration is associated with a self-limiting increase in mean arterial pressure (MAP). Based o n in vitro studies with other hemoglobin solutions, this vasopressor e ffect is thought to be mediated at least in part by the release or inh ibition (or both) of endothelium-derived vasoactive substances. The pu rpose of our studies was to determine the role of endothelin (ET), a p otent vasoconstrictor peptide, and nitric oxide, a vasodilator, in med iating the pressor effect of DCLHb in conscious rats. Intravenous admi nistration of DCLHb has been shown to elicit an immediate increase in MAP that peaks within 30 minutes and returns to baseline by 300 minute s in a dose-dependent fashion. Phosphoramidon, an inhibitor of proendo thelin conversion to ET, attenuated the elevation of MAP when administ ered before DCLHb. Administration of cyanomet DCLHb, a DCLHb molecule that is unable to interact with NO, was not associated with an elevati on of MAP. L-arginine, the substrate for NO synthesis, and nitroglycer ine, an NO donor, significantly reduced MAP when infused 15 minutes af ter DCLHb administration. Based on these findings, we conclude that th e DCLHb-induced elevation of MAP in vivo is mediated at least in pari by ET and the inhibition of NO. Although these data support earlier re ports of hemoglobin binding NO, this is the first report of the presso r response to hemoglobin being attenuated by an agent that blocks the conversion of proendothelin to ET.