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

Nicholas G. Theodorakis, Yining N. Wang, Jian Ming Wu, Mary Maluccio, James V. Sitzmann, N. Skill

Research output: Contribution to journalArticle

20 Citations (Scopus)

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-/- 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume297
Issue number4
DOIs
StatePublished - 2009

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Carbon Tetrachloride
Nitric Oxide Synthase Type III
Portal Hypertension
Liver Cirrhosis
Portal Pressure
Liver
Hyperemia
Fibrosis
Perfusion
Pressure
Prostaglandin-Endoperoxide Synthases
Causality
Collagen
Staining and Labeling
Hemorrhage
Morbidity
Mortality

Keywords

  • Mice

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology
  • Medicine(all)

Cite this

Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. / Theodorakis, Nicholas G.; Wang, Yining N.; Wu, Jian Ming; Maluccio, Mary; Sitzmann, James V.; Skill, N.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 297, No. 4, 2009.

Research output: Contribution to journalArticle

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