SIGNIFICANCE OF NO IN HEMORRHAGE-INDUCED HEMODYNAMIC-ALTERATIONS, ORGAN INJURY, AND MORTALITY IN RATS

In an attempt to evaluate the role of nitric oxide (NO) in pathophysio logical alterations and multiple organ damage caused by hemorrhagic sh ock, we employed N-G-monomethyl-L-arginine (L-NMMA), an inhibitor of N O synthase, in anesthetized rats subjected to a prolonged hypovolemic insult (30-35 mmHg for 180 min). Infusion of 2.0 mg/kg L-NMMA at the e nd of resuscitation diminished the fall in mean arterial pressure (MAP ) and significantly increased the cardiac index and stroke volume, tog ether with remarkable protection from multiple organ damage compared w ith the controls. The 48-h survival, rate was significantly improved f rom 26.7% in the control group to 68.8% in the treatment group (P < 0. 05). In contrast, the high dose of 20.0 mg/kg L-NMMA resulted in a str ong blood pressure response, but a marked reduction in cardiac index a nd stroke volume concomitant with an increased total peripheral resist ance index within the observation period, and tended to increase damag e to various organs at 2 h after treatment. In addition, marked elevat ion in both endotoxin and tumor necrosis factor levels were observed i n animals subjected to shock insult. The results suggest that NO induc ed by hemorrhagic shock in rats is an important mediator for pathophys iological alterations associated with cardiovascular abnormalities, mu ltiple organ dysfunction, and even lethality. Regulation of NO generat ion and use of NO inhibitors might provide new aspects in the treatmen t of hemorrhage-related disorders, whereas the administration of L-NMM A would be either deleterious or salutary in a dose-dependent manner.