Role of endogenous nitric oxide in TNF-alpha and IL-1 beta generation in hepatic ischemia-reperfusion

In the present study, we examined the role of nitric oxide (NO) in early-re sponse cytokine production by using a rat model of hepatic ischemia-reperfu sion (HI/R). The left and median lobes of the liver were subjected to 30 mi n of ischemia, followed by 4 h of reperfusion. Group I and II rats were sha m-operated controls that received saline (vehicle) or N-W-nitro-L-arginine methylester (L-NAME) (10 mg/kg, iv); group III and IV rats were subjected t o HI/R and received vehicle or L-NAME (10 mg/kg, iv, 10 min before reperfus ion), respectively. Administration of L-NAME to rats subjected to I/R resul ted in a fourfold decrease in plasma NO levels, accompanied by a marked inc rease of plasma alanine aminotransferase (ALT) activity relative to group I II. These changes in group IV were associated with elevation of superoxide generation in ischemic liver lobes by 2.1-fold and circulating leukocyte nu mber by 1.42-fold, compared with group III. Normalized for expression of gl yceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger ribonucleic acid ( mRNA), expression of tumor necrosis factor-alpha (TNF-alpha) and interleuki n-1 beta (IL-1 beta) mRNA in ischemic liver of group IV was augmented by 20 7% and 175% compared with Group III. The expression of (iNOS) mRNA was also increased (223%) relative to group III. Moreover, in group IV, plasma TNF- alpha levels at 4 h of reperfusion and IL-1 beta levels at 90 min and 4 h o f reperfusion were significantly increased compared with group III. No stat istically significant changes were observed between groups I and II in plas ma ALT activity, plasma NO levels, circulating leukocyte counts, superoxide generation in the ischemic lobes of liver, and plasma TNF-alpha and IL-1 b eta concentrations. The observed enhancement of I/R injury by L-NAME is con sistent with the hypothesis that endogenous NO down-regulates TNF-alpha and IL1 beta generation, thereby decreasing HI/R injury.