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1 Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven 06536; 2 Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven 06520; and 3 Hepatic Hemodynamic Laboratory, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
Systemic vasodilation is the
initiating event of the hyperdynamic circulatory state, being most
likely triggered by increased levels of vasodilators, primarily nitric
oxide (NO). Endothelial NO synthase (eNOS) is responsible for this
event. We tested the hypothesis that gene deletion of eNOS and
inducible NOS (iNOS) may inhibit the development of the hyperdynamic
circulatory state in portal hypertensive animals. To test this
hypothesis, we used mice lacking eNOS (eNOS
/) or eNOS/iNOS
(eNOS/iNOS/) genes. A partial portal vein ligation (PVL) was used
to induce portal hypertension. Sham-operated animals were used as a
control. Hemodynamic characteristics were tested 2 wk after surgery. As
opposed to our hypothesis, PVL also caused significant reduction in
peripheral resistance in eNOS/ compared with sham animals
(0.33 ± 0.02 vs. 0.41 ± 0.03 mmHg · min · kg body wt · ml
1;
P = 0.04) and in eNOS/iNOS/ animals with PVL
compared with that of the sham-operated group (0.44 ± 0.02 vs.
0.54 ± 0.04; P = 0.03). This demonstrates that,
despite gene deletion of eNOS, the knockout mice developed hyperdynamic
circulation. Compensatory vasodilator molecule(s) are upregulated in
place of NO in the systemic and splanchnic circulation in portal
hypertensive animals.
liver diseases; nitric oxide; vasodilatation; and portal vein ligation.
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