Peroxynitrite attenuates hepatic ischemia-reperfusion injury

In the present study, we examined the effects of peroxynitrite on reperfusi on injury using a rat model of hepatic ischemia-reperfusion (HI/R). The lef t and median lobes of the liver were subjected to 30 min of ischemia, follo wed by 4 h of reperfusion. Groups A and B rats were sham-operated controls that received vehicle or peroxynitrite; groups C and D rats were subjected to HI/R and received peroxynitrite or vehicle, respectively. A dose of 2 mu mol/kg body wt of peroxynitrite, diluted in saline (pH 9.0, 4 degreesC), w as administered as a bolus through a portal vein catheter at 0, 60, and 120 min after reperfusion. Results showed that superoxide generation in the is chemic lobes of the liver and plasma alanine aminotransferase (ALT) activit y of group C were decreased by 43% and 45%, respectively, compared with gro up D. Leukocyte accumulations in the ischemic lobes of liver and circulatin g leukocytes were decreased by 40% and 27%, respectively, in group C vs. D. The ratios of mRNA of P-selectin and intercellular adhesion molecule-1 (IC AM-1) to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA extracted fr om the ischemic lobes of the liver of group C were decreased compared with group D. There were no differences between the groups A and B in terms of p lasma ALT activity, circulating leukocytes, superoxide generation, and leuk ocyte infiltration in the ischemic lobes of the liver. Moreover, hemodynami c parameters (i.e., mean arterial blood pressure, cardiac index, stroke ind ex, and systemic vascular resistance) were not significantly different amon g groups B, C, and D. These results suggest that administration of peroxyni trite via the portal vein only has a local effect. Exogenous peroxynitrite at physiological concentrations attenuates leukocyte-endothelial interactio n and reduces leukocyte infiltration. The mechanism of the reduction of leu kocyte infiltration into ischemic lobes of the liver appears because of dec reased expression of mRNA of P-selectin and ICAM-1. The net effect of admin istration of peroxynitrite may be to reduce adhesion molecule-mediated, leu kocyte-dependent reperfusion injury.