ROLE OF ADRENERGIC-MECHANISMS IN THE PRESSER EFFECT OF DIASPIRIN CROSS-LINKED HEMOGLOBIN

Diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp., Blo od Substitutes Division) is a promising hemoglobin-based oxygen-carryi ng resuscitative solution. DCLHb (400 mg/kg, intravenously) produces a n immediate increase in blood pressure when administered to conscious or anesthetized rats. To determine the role of the central nervous sys tem and the peripheral vascular system in the presser effect of DCLHb, experiments were performed in cervical-sectioned rats. Intravenous ad ministration of DCLHb produced an increase in blood pressure in cervic al-sectioned animals (41.2 +/- 2.5 mm Hg), which was similar to that o bserved in normal rats. To test whether the presser effect was due to release of catecholamines or other presser substances from the adrenal medulla, DCLHb was administered to bilateral adrenal demedullated rat s. DCLHb was found to produce a presser effect in bilateral adrenal de medullated rats (42.0 +/- 6.4 mm Hg) that was similar to normal rats. To determine whether DCLHb alters the responsiveness of peripheral vas cular adrenoceptors, the effect of DCLHb pretreatment on the blood pre ssure and heart rate responses of adrenergic agonists was studied. DCL Hb significantly potentiated (66.7%) the presser response to norepinep hrine (0.5 to 2.0 mu g/kg, intravenously) but did not affect the heart rate response to norepinephrine. Phenoxybenzamine completely blocked the DCLHb-induced potentiation of the norepinephrine responses. Phenyl ephrine produced a dose dependent (5 to 20 mu g/kg, intravenously) pre sser and reflex bradycardic effect. DCLHb significantly potentiated th e presser (40.6%) and bradycardic (-22.8%) effect of phenylephrine, wh ich were completely blocked by prazosin. Clonidine produces a fall in blood pressure by acting on the central alpha-adrenoceptors and a rise in blood pressure by stimulating the peripheral vascular alpha-adreno ceptors. DCLHb produced a marked potentiation of the presser response to clonidine (75 mu g/kg, intravenously) that masked the central depre ssor effect. Prazosin pretreatment did not attenuate the DCLHb-induced potentiation of the presser effect of clonidine in intact rats. Howev er, yohimbine pretreatment completely blocked the DCLHb-induced potent iation of the clonidine-induced presser response in intact rats. To ex clude the contribution of a centrally induced cardiovascular effect of clonidine, further studies were carried out in cervical-sectioned rat s. DCLHb markedly potentiated the presser effect of clonidine (25 mu g /kg, intravenously) in cervical-sectioned rats. This potentiation coul d be attenuated by prazosin and yohimbine. Pretreatment with either yo himbine (2 mg/kg, intravenously) or prazosin (1 mg/kg, intravenously) significantly attenuated the DCLHb-induced presser effect. The attenua tion of DCLHb-induced presser effect was more marked with prazosin as compared to yohimbine. The conclusion is that the presser effect of DC LHb is not mediated through the CNS; however, it appears that in rats both alpha(1)- and alpha(2)-adrenoceptors in the peripheral vascular s ystem are sensitized by DCLHb.