Lipopolysaccharide tolerance and ethanol modulate hepatic nitric oxide production in a gender-dependent manner

This study was directed at the role of tolerance to endotoxin (lipopolysacc haride, LPS) and ethanol (EtOH) intoxication in modulating hepatic nitric o xide (NO) production, and the demonstration of gender differences. Previous studies demonstrated that tolerance to either LPS or EtOH was associated w ith reduced hepatic production of superoxide anions. We now tested the hypo thesis that the reduced hepatic production of superoxide anions during tole rance to LPS and the altered response to EtOH are accompanied by increased sensitivity of hepatic NO release to stimulation. Age-matched male and fema le Sprague-Dawley rats were made tolerant to LPS by an i.v. injection of LP S (0.5 or 0.45 mg/kg) 2 days prior to an in vivo EtOH infusion for 3 h (LPS -EtOH group). Control groups were saline-pretreated, saline-infused; saline -pretreated, EtOH-infused; and LPS-pretreated, saline-infused. At the end o f the infusion, isolated hepatocytes, Kupffer, and sinusoidal endothelial c ells were cultured for 20 h for subsequent measurement of basal (spontaneou s) and in vitro-stimulated nitrite release. LPS-tolerance resulted in signi ficantly enhanced stimulated NO production by hepatocytes and Kupffer cells in both male and female rats. EtOH abolished this priming effect in hepato cytes from male, but not from female rats. The priming effect was markedly diminished by EtOH in Kupffer cells of female rats only. LPS-tolerance incr eased NO production by stimulated endothelial cells of males, and decreased NO production by cells of females. EtOH infusion did not influence NO prod uction by endothelial cells from male rats and it reversed the LPS-toleranc e-induced inhibition in females. These data demonstrate that modulation by LPS-tolerance of hepatic NO release in EtOH-treated rats leads to enhanced stimulated NO production, while hepatic superoxide anion release was previo usly shown to be reduced within the same time frame. Since NO is able to sc avenge superoxide, the LPS-tolerance-induced alterations in the EtOH effect s on NO production may have a potential significance in modulating - in a t ime-dependent manner - oxidative injury associated with LPS and acute EtOH intake. (C) 2000 Elsevier Science Inc. All rights reserved.