Mechanisms of inhibition of nitric oxide production in a murine model of splanchnic artery occlusion shock

Abstract

Nitric oxide has been thought to be a major endothelium-derived relaxing factor which is synthesized from L-arginine and can be selectively inhibited by L-NG-monomethyl arginine. On the other hand, another endothelium-derived vasorelaxant, defined as endothelium-derived hyperpolarizing factor, has been reported. We compared their role in regulating the splanchnic vascular tone in splanchnic artery occlusion shock in the rat. Administration of L-NG-monomethyl arginine (100 mg/kg) given 5 min prior to reperfusion of splanchnic arteries which were occluded for 45 min, produced a significant increase in mean arterial blood pressure. However, the indices of the severity of shock status, including survival time, survival rate and increases in hematocrit, plasma cathepsin D and myocardial depressant factor activity following splanchnic artery occlusion shock were not exacerbated by administration of L-NG-monomethyl arginine. Addition of L-NG-monomethyl arginine (1 mg/ml) induced a small but significant increase in basal vascular tone of superior mesenteric artery rings, but it failed to totally block acetylcholine-induced vasorelaxation (48 +/- 4% relaxation). Although there were no significant changes in basal vascular tone after administration of glibenclamide (30 micrograms/ml), acetylcholine-induced vasorelaxation was significantly attenuated (58 +/- 4% relaxation). When L-NG-monomethyl arginine and glibenclamide were added together, acetylcholine-induced vasorelaxation was almost totally abolished (18 +/- 2% relaxation). Our results indicate that rat splanchnic artery endothelial cells may produce both endothelium-derived relaxing and hyperpolarizing factor. Endothelium-derived relaxing factor plays an important role in the regulation of basal vascular tone of the splanchnic circulation, while endothelium-derived hyperpolarizing factor may be important in modulating the mesenteric blood flow following splanchnic artery occlusion shock.