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

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

Research output: Contribution to journalArticle

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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

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Gene Knockout Techniques
Portal Hypertension
Portal Vein
Knockout Mice
Nitric Oxide Synthase
Protein Isoforms
Ligation
Surgical Portasystemic Shunt
Genes
Portal Pressure
Wild Animals
Mutation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Theodorakis, N. G., Wang, Y. N., Skill, N., 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

The role of nitric oxide synthase isoforms in extrahepatic portal hypertension : Studies in gene-knockout mice. / Theodorakis, Nicholas G.; Wang, Yi Ning; Skill, N.; Metz, Matthew A.; Cahill, Paul A.; Redmond, Eileen M.; Sitzmann, James V.

In: Gastroenterology, Vol. 124, No. 5, 01.05.2003, p. 1500-1508.

Research output: Contribution to journalArticle

Theodorakis, NG, Wang, YN, Skill, N, Metz, MA, Cahill, PA, Redmond, EM & Sitzmann, JV 2003, 'The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: Studies in gene-knockout mice', Gastroenterology, vol. 124, no. 5, pp. 1500-1508. https://doi.org/10.1016/S0016-5085(03)00280-4
Theodorakis, Nicholas G. ; Wang, Yi Ning ; Skill, N. ; Metz, Matthew A. ; Cahill, Paul A. ; Redmond, Eileen M. ; Sitzmann, James V. / The role of nitric oxide synthase isoforms in extrahepatic portal hypertension : Studies in gene-knockout mice. In: Gastroenterology. 2003 ; Vol. 124, No. 5. pp. 1500-1508.
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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.",
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T2 - Studies in gene-knockout mice

AU - Theodorakis, Nicholas G.

AU - Wang, Yi Ning

AU - Skill, N.

AU - Metz, Matthew A.

AU - Cahill, Paul A.

AU - Redmond, Eileen M.

AU - Sitzmann, James V.

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N2 - 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.

AB - 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.

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