MODULATION OF RESUSCITATIVE EFFECT OF DIASPIRIN CROSS-LINKED HEMOGLOBIN BY L-NAME IN RATS

Diaspirin Cross-linked Hemoglobin (DCLHb(TM)), a hemoglobin-based oxyg en carrier, improves regional blood circulation and systemic hemodynam ics in normal and hemorrhaged rats. The action of DCLHb is partly medi ated by its scavenging effect on nitric oxide. This study was undertak en to determine the effect of DCLHb on nitric oxide mechanism in hemor rhagic conditions. We studied the modulation of cardiovascular effects of DCLHb by a nitric oxide synthase inhibitor, N-G-nitro-t-arginine m ethyl ester (L-NAME) in hemorrhaged rats. The base deficit, survival t ime, oxygen consumption, and blood circulation to the brain, heart, ga strointestinal tract, and kidneys were determined in 1) DCLHb (100 mg/ kg, intravenously (i.v.), 2) L-NAME (2 mg/kg, i.v.), 3) L-NAME (2 mg/k g, i.v.) + DCLHb (100 mg/kg, i.v.), and 4) L-arginine (100 mg/kg/h, i. v.) + DCLHb (100 mg/kg, i.v.) treated rats. Hemorrhage was induced in urethane-anesthetized male rats by bleeding them at a rate of approxim ately .5 to 1 mL/min, until a mean arterial pressure of 35-40 mmHg was achieved. This blood pressure was maintained for 30 min. Sham-operate d nonhemorrhaged rats survived for >300 min, whereas hemorrhaged rats survived for only 85 +/- 31 min. Hemorrhage significantly increased ba se deficit and decreased oxygen consumption. A significant decrease in heart rate, mean arterial pressure, cardiac output, stroke volume, an d in blood flow to the gastrointestinal tract and kidneys was observed after hemorrhage. Resuscitation with DCLHb produced a significant inc rease in survival time, oxygen consumption, heart rate, mean arterial pressure, cardiac output, total peripheral resistance, and blood flow to the brain, heart, and kidneys. In contrast, resuscitation with L-NA ME did not improve base deficit, survival time, oxygen consumption, sy stemic hemodynamics, or regional blood flow. L-arginine pretreatment d id not affect DCLHb-induced resuscitation of hemorrhaged rats. Further more, L-NAME (pretreated or co-administered) attenuated the resuscitat ive effect of DCLHb. These data suggest that nitric oxide mechanism ma y not be the only mechanism involved in the resuscitative effect of DC LHb.