Background: Increased intrahepatic vascular tone in cirrhosis has been attributed to decrease hepatic nitric oxide (NO) secondary to disturbances in the posttranslational regulation of the enzyme eNOS. Recent data has shown that scavenging of NO by superoxide (O2-) further contributes to reduce NO bioavailability in cirrhotic livers.
Aim: To investigate whether removing increased O2- levels could be a new therapeutic strategy to increase intrahepatic NO, improve endothelial dysfunction and reduce portal pressure in cirrhotic rats with portal hypertension.
Methods: Adenoviral vectors expressing extracellular SOD (AdECSOD) or β-galactosidase (Adgal) were injected intravenously in control and CCl4-induced cirrhotic rats. After 3 days, liver O2- levels by dihydroethidium staining, NO bioavailability by hepatic cGMP levels, nitrotyrosinated proteins, endothelial function by responses to acetylcholine (Ach) in perfused rat livers and in vivo mean arterial pressure (MAP) and portal pressure were evaluated.
Results: Transfection of cirrhotic livers with AdECSOD produced a significant reduction in O2- levels, a significant increase in hepatic cGMP, and a decrease in liver nitrotyrosinated proteins which were associated with a significant improvement in the endothelium-dependent vasodilatation to Ach. In addition, in cirrhotic livers AdECSOD transfection produced a significant reduction in portal pressure (17.3±2 mmHg vs. 15±1.6 mmHg; p<0.05) without significant changes in MAP.
Conclusions: In cirrhotic rats, reduction of O2- by AdECSOD, increases NO bioavailability, improves intrahepatic endothelial function and reduces portal pressure. These findings suggest that scavenging of O2- might be a new therapeutic strategy in the management of portal hypertension.
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