FAILURE OF L-NAME TO CAUSE INHIBITION OF NITRIC-OXIDE SYNTHESIS - ROLE OF INDUCIBLE NITRIC-OXIDE SYNTHASE

We addressed the hypothesis that administration of nitric oxide syntha se inhibitor. N-G-nitro-L-arginine methyl ester (L-NAME) does not resu lt in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS) . L-NAME was administered in the drinking water (0.1-1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [ 1] ex vivo formation of nitrite in blood vessels and intestine [2] tis sue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diapho rase staining [5] direct assessment of NO release in tissue explants u sing a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p < 0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pi gs and novel sites of NADPH diaphorase staining in the intestine. We c onclude that iNOS expression is responsible for a compensatory increas e or normalization of NO synthesis during sustained administration of L-NAME.