ENDOTHELIUM-DEPENDENT VASCULAR HYPORESPONSIVENESS WITHOUT DETECTION OF NITRIC-OXIDE SYNTHASE INDUCTION IN AORTAS OF CIRRHOTIC RATS

The present experiments were designed to test if induction of nitric o xide synthase (NOS) plays a role in the systemic vasodilation observed in hepatic cirrhosis, Because endotoxin levels are elevated in cirrho sis, and endotoxin stimulates inducible nitric oxide synthase (iNOS) e xpression in several cell Lines, aortas of carbon tetrachloride-induce d cirrhotic rats with ascites were evaluated for iNOS expression, Endo toxin-treated rats were studied as positive controls, Phenylephrine co ntraction was decreased in aortic rings with endothelium from both end otoxin-treated and cirrhotic rats as compared with controls, However, after endothelium denudation, the reduced contractility persisted in e ndotoxin-treated rats but disappeared in cirrhotic rats, L-Nitro-argin ine-methylester (L-NAME), a nonselective inhibitor of NOS, potentiated the phenylephrine contraction of aortic rings with and without endoth elium from endotoxin-treated rats but only rings with endothelium from cirrhotic rats, Moreover, aminoguanidine (AG), a preferential inhibit or of iNOS, did not affect phenylephrine contraction of rings with or without endothelium from cirrhotic rats but reversed the blunted respo nse in endotoxin-treated rats, Northern analysis detected iNOS RNA (mR NA) expression in aortas of endotoxin-treated rats but did not detect it hom cirrhotic rats, In summary, although several previous studies p rovide evidence for in vivo overproduction of nitric oxide in cirrhosi s, the present results do not support iNOS induction as the source of nitric oxide in aortas of cirrhotic rats, Rather, because the aortic v ascular hyporesponsiveness in cirrhosis is endothelium-dependent, over expression or overstimulation of the endothelial constitutive isoform of NOS appears to be involved.