Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production.

Abstract

Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat-storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine. The precise mechanism that controls NO production in stellate cells was characterized recently. Kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L-arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. The L-arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT-1 and CAT-2B (Km approximately 50 microM). IFN-gamma in combination with TNF-alpha induced NO production with an enhancement in CAT-2B mRNA expression and L-arginine transport, whereas L-arginine transport and NO production were suppressed by coincubated ethanol. In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L-arginine transport in the presence of TNF-alpha and IFN-gamma. The estimated Km of L-arginine transporter in hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L-arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.