USE OF SELECTIVE AND NONSELECTIVE NITRIC-OXIDE SYNTHASE INHIBITORS INRAT ENDOTOXEMIA - EFFECTS ON HEPATIC MORPHOLOGY AND FUNCTION

Endotoxin has profound effects on nitric oxide (NO) production, and co nsiderable controversies exist as to whether these alterations are ben eficial or deleterious. Increased mortality has been reported from non selective inhibition of NO synthase. Results from selective inhibition of the inducible isoform (iNOS) appear largely positive. In a model o f rat endotoxemia we have compared the early effects on hepatic morpho logy and function of selective and nonselective NO inhibition. Two hou rs after endotoxin injection (5 mg/kg intraportally) the rats were tre ated with either the selective iNOS inhibitor aminoethyl isothiourea ( AE-ITU, 10 mg/kg), the nonselective NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or normal saline. The animals were o bserved for another hour. Using an immunohistochemical method, inducti on of iNOS was demonstrated in various tissues in all slices examined. No unequivocal benefit from NO inhibition was noted. Electron microsc opic examination revealed widespread alterations of liver morphology, without obvious differences between the groups. Liver function, as ass essed by ketone body ratio, hepatic venous acid base values, and bile production, was generally more adversely affected after NO inhibition. Even with the iNOS selective inhibitor AE-ITU no benefit was noted. W e conclude that during the early phases of endotoxemia therapeutic red uction of NO production has no positive effects on liver function or m orphology.