Oral Citrulline Mitigates Inflammation and Jejunal Damage via the Inactivation of Neuronal Nitric Oxide Synthase and Nuclear Factor–κB in Intestinal Ischemia and Reperfusion

Background: Intestinal ischemia and reperfusion (I/R) is a life‐threatening emergency accompanied by inflammation and organ damage. We compared the mechanisms and the effects of arginine, citrulline, and glutamine on inflammation and intestinal damage. Materials and Methods: Male Wistar rats underwent 60 minutes of superior mesenteric artery occlusion and either 3 (I/R3) or 24 (I/R24) hours of reperfusion and were orally administered vehicle, arginine, citrulline, or glutamine 15 minutes before reperfusion and at 3, 9, and 21 hours of reperfusion. Results: I/R3 rats experienced jejunal damage and apoptosis, and I/R24 rats had liver dysfunction compared with normal rats (one‐way ANOVA, P < .05). Arginine and citrulline administrations improved jejunal morphology, and citrulline and glutamine administrations alleviated the loss of jejunal mass in I/R3 rats. I/R3‐increased circulating nitrate/nitrite (NOx), tumor necrosis factor–α, and interleukin‐6 were significantly decreased by citrulline, glutamine and citrulline, and arginine, glutamine, and citrulline, respectively. These amino acids decreased plasma NOx and interferon‐γ in I/R24, decreased jejunal neuronal nitric oxide synthase (NOS) protein in I/R3 rats, and alleviated jejunal apoptosis in I/R3 and I/R24 rats. In addition, the jejunal phosphorylated to total nuclear factor–κB (NF‐κB) ratio was decreased by arginine and citrulline in I/R24 rats. Conclusion: Oral administration of arginine, citrulline, and glutamine may alleviate systemic inflammation, jejunal apoptosis, and neuronal NOS in intestinal I/R. Citrulline may further attenuate jejunal damage by preserving jejunal mass, partially via the inactivation of NOS and the NF‐κB pathway. In conclusion, oral citrulline may have more benefits than arginine and glutamine in mitigating intestinal ischemia and reperfusion‐induced adverse effects.