ROLE OF ENDOTHELIN-CONVERTING ENZYME IN THE SYSTEMIC HEMODYNAMICS ANDREGIONAL CIRCULATORY EFFECTS OF PROENDOTHELIN-1 (1-38) AND DIASPIRIN CROSS-LINKED HEMOGLOBIN IN RATS

Diaspirin cross-linked hemoglobin (DCLHb) is a promising hemoglobin-ba sed, oxygen-carrying resuscitative solution. DCLHb (400 mg/kg, Iv) pro duces significant cardiovascular effects, along with an increase in pl asma endothelin-1 (ET-1) level, when administered to conscious or anes thetized rats. Present studies were performed to determine whether the cardiovascular effects of DCLHb are due to an increase in the convers ion of proendothelin-1 (1-38) (proET-1) to ET-1 by endothelin-converti ng enzyme (ECE). The regional circulatory and systemic hemodynamic eff ects of proET-1 (20 mu g/kg, Iv) and DCLHb (400 mg/kg, Iv) were determ ined by using a radioactive microsphere technique in control rats and rats pretreated with phosphoramidon (ECE inhibitor). Administration of proET-1 produced an immediate increase in mean arterial pressure (MAP )(52%) and total peripheral resistance (TPR) (55%); stroke volume (SV) and cardiac output were not affected in the initial phase but were de creased subsequently. Heart rate (HR) was not affected after administr ation of proET-1. A significant increase in blood flow to the heart (3 9%), brain (46%), kidneys (74%), portal system (40%), and gastrointest inal tract (GIT)(42%) was also observed after administration of proET- 1. Vascular resistance was found to be significantly increased in the mesentery and pancreas (168%) and in the musculoskeletal system (147%) and decreased in the kidneys (-11%) after administration of proET-1. Phosphoramidon (4 mg/kg, rv) pretreatment attenuated the increase in M AP and TPR induced by proET-1. Phosphoramidon pretreatment significant ly attenuated the proET-1-induced increase in blood flow to the heart, brain, kidneys, portal system, and GIT, The increase in vascular resi stance induced by proET-1 in the mesentery and pancreas and in the mus culoskeletal system was also attenuated by phosphoramidon. DCLHb incre ased MAP (63%) and TPR (54%) without affecting HR, DCLHb increased blo od flow to the heart (95%), GIT (45%), portal system (43%), and skin ( 79%) and increased vascular resistance in the musculoskeletal system ( 58%). In phosphoramidon-treated rats, DCLHb increased MAP (99%), HR (2 5%), cardiac output (37%), and TPR (60%). DCLHb increased blood flow t o the heart (104%), brain (66%), kidneys (49%), GIT (59%), portal syst em (63%), and skin (100%) when administered to phosphoramidon-treated rats. Phosphoramidon did not attenuate any of the DCLHb-induced cardio vascular effects. It is concluded that proET-1 increases blood flow to various organs and that phosphoramidon, an ECE inhibitor, could block the proET-1-induced increases in regional blood flow. The DCLHb-induc ed increase in blood flow to several organs could not be blocked by ph osphoramidon, indicating that the cardiovascular effects of DCLHb are not due to an increase in the conversion of proET-1 to ET-1.