ROLE OF NITRIC-OXIDE IN HEPATIC ISCHEMIA-REPERFUSION WITH ENDOTOXEMIA

Reactive oxygen species such as nitric oxide (NO) and/or superoxide ha ve been proposed as mediators in the pathogenesis of reperfusion injur y and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia fol lowed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increases in plasma alanine aminotransferase (ALT) levels compared to sham controls. An a brupt increase in liver nitrite/nitrate levels was also observed in I/ R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbati on of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90-min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There runs a significant increase in neutrophils in liver lobes subjected to isc hemia-reperfusion and LPS compared to sham controls and to non-ischemi c lobes which received LPS. The number of neutrophils in the liver inc reased further in rats given L-NAME. These results suggest that the pr ogressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not am eliorate fiver damage possibly because of an increase in tissue accumu lation of activated polymorphonuclear leukocytes (PMN). Lung NO produc tion increased in I/R + LPS rats after 4 hr reperfusion compared to sh am controls. Prior administration of L-NAME did not prevent a signific ant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, comp ared to sham controls). This unexpected rise of pulmonary NO in the L- NAME treated group of rats was associated with a tendency for increase d PMN accumulation (based on myeloperoxidase data) and superoxide gene ration. The results suggest that endogenous NO protected against exces sive neutrophil infiltration in the lung in this model of hepatic isch emia-reperfusion and endotoxemia, and the use of L-NAME, a nonselectiv e NOS inhibitor, may aggravate lung injury. (C) 1996 Wiley-Liss, Inc.