NO as an indicator of portal hemodynamics and the role of INOS in increased NO production in CCl4-induced liver cirrhosis

it is well known that nitric oxide, a vasodilator, is overproduced in liver cirrhosis. This study was designed to elucidate the role of nitric oxide (NO) in portal hemodynamics and 60 determine the mecharaism underlying the increased serum NO levels in rats with liver cirrhosis induced by the oral intake of CCl4. Using rats, liver cirrhosis was induced by oral administration of CCl4, The serum levels of NO2-/NO3-(NOx) were measured, and portal hemodynamic parameters were evaluated with and without the administration of the NO synthase inhibitor N-omega-nitro-L-arginine (NNA), Furthermore, Northern blot analysis was used to detect iNOS and cNOS mRNA, and immunohistochemical methods were used to detect iNOS-like immunoreactivity, In cirrhotic rats, the portal Row had increased significantly and the portal resistance had decreased significantly when compared with normal control rats. Hepatic, capillary flow in the cirrhotic rats was similar to the control rats, NNA decreased portal flow and increased portal resistance in both groups, but the change was greater in the cirrhotic rats than. in controls. The serum levels of NOx were significantly higher in cirrhotic rats than in normal control rats and were positively correlated with portal Row and negatively correlated with portal resistance, The expression of iNOS mRNA, which was barely detectable in control rats, had increased in all organs of the cirrhotic rats, whereas Pro significant increase in cNOS mRNA was found in any of the organs from cirrhotic rats. The immunohistochemical analysis was generally consistent with the results of the Northern blot analysis. In the control rats, only the bronchial epithelial cells were stained with the anti-iNOS antibody, but in cirrhotic rats, the bronchial cells in the lungs as well as the histiocytic mesenchymal cells in all organs, and the alveolar epithelial cells of the lungs, were stained. This study demonstrated that NO plays a significant role in portal hypertensive hemodynamics in CCl4-induced liver cirrhosis, and that NO is a useful indicator for the evaluation of portal hypertension. Furthermore, the increased serum levels of NO were found to be derived at least in part from the increased expression of iNOS mRNA in the liver, spleen, and lung. (C) 1997 Academic Press.