title: Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model.
abstract: 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 CCl(4) 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(-/-) CCl(4)-exposed mice. SPP, Qao, and Qpv increased rapidly in wild-type CCl(4)-exposed mice, but HPVPP did not. In eNOS(-/-) CCl(4) 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 CCl(4)-induced fibrosis. Consequently, increased portal pressure following chronic CCl(4) exposure is linked to hyperdynamic circulation in wild-type mice and increased hepatic resistance in eNOS(-/-) mice.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Theodorakis
authors.forename: Yining N
authors.initials: YN
authors.lastname: Wang
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Wu
authors.forename: Mary A
authors.initials: MA
authors.lastname: Maluccio
authors.forename: James V
authors.initials: JV
authors.lastname: Sitzmann
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skill
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001012:Aorta, Abdominal / Q000503:physiopathology; D002251:Carbon Tetrachloride; D005838:Genotype; D006940:Hyperemia / Q000201:enzymology / Q000503:physiopathology; D006975:Hypertension, Portal / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008099:Liver / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017082:Portal Pressure; D011168:Portal System / Q000503:physiopathology*; D012039:Regional Blood Flow; D012720:Severity of Illness Index; D013997:Time Factors; D014655:Vascular Resistance
chemical_list: D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000410:Alanine Transaminase