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 pathophysiological alterations and multiple organ damage caused by hemorrhagic shock, we employed NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO 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 end of resuscitation diminished the fall in mean arterial pressure (MAP) and significantly increased the cardiac index and stroke volume, together with remarkable protection from multiple organ damage compared with the controls. The 48-h survival rate was significantly improved from 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 strong blood pressure response, but a marked reduction in cardiac index and stroke volume concomitant with an increased total peripheral resistance index within the observation period, and tended to increase damage to various organs at 2 h after treatment. In addition, marked elevation in both endotoxin and tumor necrosis factor levels were observed in animals subjected to shock insult. The results suggest that NO induced by hemorrhagic shock in rats is an important mediator for pathophysiological alterations associated with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. Regulation of NO generation and use of NO inhibitors might provide new aspects in the treatment of hemorrhage-related disorders, whereas the administration of L-NMMA would be either deleterious or salutary in a dose-dependent manner.