The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: Studies in gene-knockout mice

Nicholas G. Theodorakis, Yi Ning Wang, Nicholas J. Skill, Matthew A. Metz, Paul A. Cahill, Eileen M. Redmond, James V. Sitzmann

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Background & Aims: Considerable debate exists concerning which isoform of nitric oxide synthase (NOS) is responsible for the increased production of NO in PHT. We used the portal vein ligation model of PHT in wild-type and eNOS- or iNOS-knockout mice to definitively determine the contribution of these isoforms in the development of PHT. Methods: The portal vein of wild-type mice, or those with targeted mutations in the nos2 gene (iNOS) or the nos3 gene (eNOS), was ligated and portal venous pressure (Ppv), abdominal aortic blood flow (Qao), and portosystemic shunt determined 2 weeks later. Results: wild-type mice, as compared with sham-operated controls, portal vein ligation (PVL) resulted in a time-dependent increase in Ppv (7.72 ± 0.37 vs 17.57 ± 0.51 cmH2O, at 14 days) concomitant with a significant increase in Qao (0.12 ± 0.003 vs 0.227 ± 0.005 mL/min/g) and portosystemic shunt (0.47% ± 0.01% vs 84.13% ± 0.09% shunt). Likewise, PVL in iNOS-deficient mice resulted in similar increases in Ppv, Qao, and shunt development. In contrast, after PVL in eNOS-deficient animals, there was no significant change in Ppv (7.52 ± 0.22 vs 8.07 ± 0.4 cmH2O) or Qao (0.111 ± 0.01 vs 0.14 ± .023 mL/min/g). However, eNOS (-/-) mice did develop a substantial portosystemic shunt (0.33% ± 0.005% vs 84.53% ± 0.19% shunt), comparable to that seen in wild-type animals after PVL. Conclusions: These data support a key role for eNOS, rather than iNOS, in the pathogenesis of PHT.

Original languageEnglish (US)
Pages (from-to)1500-1508
Number of pages9
JournalGastroenterology
Volume124
Issue number5
DOIs
StatePublished - May 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Theodorakis, N. G., Wang, Y. N., Skill, N. J., Metz, M. A., Cahill, P. A., Redmond, E. M., & Sitzmann, J. V. (2003). The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: Studies in gene-knockout mice. Gastroenterology, 124(5), 1500-1508. https://doi.org/10.1016/S0016-5085(03)00280-4