Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model

Theodorakis NG, Wang YN, Wu J, Maluccio MA, Sitzmann JV, Skill NJ. Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. Am J Physiol Gastrointest Liver Physiol 297: G792-G799, 2009. First published July 23, 2009; doi: 10.1152/ajpgi.00229.2009.-Portal hypertension (PHT) is a complication of liver cirrhosis and directly increases mortality and morbidity by increasing the propensity of venous hemorrhage. There are two main underlying causations for PHT, increased hepatic resistance and systemic hyperdynamic circulation. Both are related to localized aberrations in endothelial nitric oxide synthase ( eNOS) function and NO biosynthesis. This study investigates the importance of eNOS and systemic hyperdynamic-associated hyperemia to better understand the pathophysiology of PHT. Wild-type and eNOS(-/-) mice were given the hepatotoxin CCl4 for 4-12 wk. Hepatic fibrosis was determined histologically following collagen staining. Portal venous pressure, hepatic resistance, and hyperemia were determined by measuring splenic pulp pressure (SPP), hepatic portal-venous perfusion pressure (HPVPP), abdominal aortic flow (Qao), and portal venous flow (Qpv). Hepatic fibrosis developed equally in wild-type and eNOS(-/-) CCl4-exposed mice. SPP, Qao, and Qpv increased rapidly in wild-type CCl4-exposed mice, but HPVPP did not. In eNOS(-/-) CCl4 mice, Qao was not increased, SPP was partially increased, and HPVPP and Qpv were increased nonsignificantly. We concluded that the systemic hyperemia component of hyperdynamic circulation is eNOS dependent and precedes increased changes in hepatic resistance. Alternative mechanisms, possibly involving cyclooxygenase, may contribute. eNOS maintains normal hepatic resistance following CCl4-induced fibrosis. Consequently, increased portal pressure following chronic CCl4 exposure is linked to hyperdynamic circulation in wild-type mice and increased hepatic resistance in eNOS(-/-) mice.