A PRECURSOR OF THE NITRIC-OXIDE DONOR SIN-1 MODULATES THE STRESS PROTEIN HEME OXYGENASE-1 IN RAT-LIVER

In this study the effect of increased nitric oxide (NO) production on the expression of rat liver heme oxygenase-1, an inducible stress prot ein responsible for the catalysis of heme to biliverdin and carbon mon oxide, was investigated. Rats were injected intraperitoneally with mol sidomine (SIN-10), a long acting drug that is enzymatically converted in the liver to yield the active NO-releasing agent 3-morpholinosydnon imine (SIN-1). Administration of SIN-10 resulted in a significant time - and dose-dependent increase in plasma levels of nitrite/nitrate, an index of NO release. A time course of heme oxygenase-1 mRNA levels in liver showed a gradual increase in the expression of the gene encoding for this protein, which was maximal at 4 hours and returned to normal levels by 6 hours after SIN-10 treatment. Heme oxygenase activity als o increased by 50% at 4 hours and was maximal 12 hours after SIN-10 ad ministration (63% increase over baseline). These results indicate a po ssible role for locally generated NO in the modulation of hepatic stre ss response in vivo suggesting that NO mediates cell adaptation to str ess by activation of endogenous defensive mechanisms. (C) 1996 Academi c Press, Inc.