NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R

The anti-inflammatory role of nitric oxide (NO) was studied in a model of h epatic ischemia-reperfusion (I/R) in rats. Male Fischer rats were subjected to 30 min of no-flow ischemia of the left and median lobes of the liver, a nd animals were examined for a 4-h period of reperfusion. The animals were divided into the following groups: control-vehicle; I/R-vehicle; I/R-N-omeg a-nitra-L-arginine methyl ester (L-NAME, 10 mg/kg iv, 10 min before reperfu sion); sham control-L-NAME, and I/R-S-nitroso-N-acetyl-penicillamine (SNAP, 25 mu mol/kg iv, 10 min before reperfusion, followed by 20 mu mol . kg(-1) . h(-1) in 1.0 ml saline infused for 4 h). Results showed that mean arteri al blood pressure was significantly increased in the sham control-L-NAME or I/R-L-NAME groups compared with either the I/R-vehicle or I/R-SNAP groups. However, cardiac index (CI) and stroke volume index (SVI) were markedly de creased, and systemic vascular resistance index (SVRI) was dramatically inc reased. Interestingly, the CI and SVI in rats treated with SNAP were marked ly improved over that of the I/R group. Plasma nitrate and nitrite levels w ere significantly decreased in the I/R-L-NAME group; however, superoxide ge neration in the ischemic lobes and plasma alanine aminotransferase activity were higher compared with IR-SNAP rats. The L-NAME-induced enhancement of hepatic injury in rats with I/R may be due in part to neutrophil infiltrati on, which was significantly increased compared with animals subjected to I/ R or I/R-SNAP. The mechanism of L-NAME-enhanced neutrophil infiltration may be due to the fact that the ratios of P-selectin and intercellular adhesio n molecule 1 (ICAM-1) mRNA to glyceraldehyde-3-phosphate dehydrogenase mRNA extracted from the ischemic lobes of IIR-L-NAME rats were significantly in creased when compared with the I/R-SNAP group. These results suggest that 1 ) endogenous NO reduces the SVRI and permits an increased CI and SVI; 2) ex ogenous NO further improves CI and SVI; and 3) endogenous, but not exogenou s, NO decreases P-selectin and ICAM-1 mRNA expression, thereby reducing pol ymorphonuclear neutrophil-dependent reperfusion tissue injury.