The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: studies in gene-knockout mice.
OBJECTIVE
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
In 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 cmH(2)O, 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 cmH(2)0) 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.
Department of Surgery, University of Rochester Medical Center, New York 14642, USA.
Nicholas G
NG
Theodorakis
Yi-Ning
YN
Wang
Nicholas J
NJ
Skill
Matthew A
MA
Metz
Paul A
PA
Cahill
Eileen M
EM
Redmond
James V
JV
Sitzmann
D000818:Animals; D001012:Aorta, Abdominal / Q000502:physiology; D004195:Disease Models, Animal; D006975:Hypertension, Portal / Q000201:enzymology / Q000503:physiopathology*; D008026:Ligation; D008102:Liver Circulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D011169:Portal Vein / Q000503:physiopathology; D014690:Venous Pressure / Q000502:physiology
D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse