The effects of arginine and nitric oxide synthase inhibitors on intestinal damage in guanylyl cyclase‐G gene knockout mice with intestinal ischemia and reperfusion

Abstract

Previous study demonstrated that membrane‐bound guanylyl cyclase (mGC)‐G gene knockout (KO) mice with intestinal ischemia and reperfusion (II/R) had significantly alleviated jejunal damage and apoptosis compared to wild type (WT) mice. It is known that apoptosis is controlled by guanylyl cyclase‐generated cGMP and arginine‐derived nitric oxide (NO). Therefore, we investigated the roles of NO and mGC‐G gene in II/R‐induced intestinal damage. mGC‐G KO mice suffered with 45 min intestinal ischemia were intra‐peritoneally administered with arginine (300 mg/kg) or inhibitors of nitric oxide synthase (NOS), i.e., aminoguanidine (100 mg/kg) or L‐NAME (10 mg/kg), and were executed after 3 or 24 hours of reperfusion. KO mice had significantly decreased jejunal mass and villus height and increased plasma IL‐6 and mucosal nitrate/nitrite (NOx) and cGMP compared to WT mice. However, II/R‐induced jejuanl atrophy and systemic and local inflammatory responses were attenuated in KO mice as shown in the less increases in plasma NOx and mucosal TNF‐alpha (p<0.05). At 3 hr reperfusion, arginine significantly increased plasma IL‐6 and mucosa TNF‐alpha; AMG increased mucosal TNF‐alpha; and L‐NAME increased plasma TNF‐alpha and mucosal cGMP in KO mice. At 24 hr reperfusion, arginine, AMG, and L‐NAME decreased mucosal TNF‐alpha, plasma IL‐6, and muscularis width, respectively. In addition, AMG and L‐NAME further decreased plasma NOx at 3 and 24 hr reperfusion. However, mGC‐G KO‐and II/R‐induced jejunal atrophy was not significantly altered by arginine or NOS inhibitors. These results suggest that mGC‐G may play certain roles in affecting the effects of NO on jejunal histology and inflammatory response (NSC 96–2320‐B‐309–003‐MY2).