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Am J Physiol Gastrointest Liver Physiol (July 31, 2002). doi:10.1152/ajpgi.00145.2002
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Articles in PresS, published online ahead of print July 31, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00145.2002
Submitted on April 15, 2002
Accepted on July 17, 2002

Mice with targeted gene deletion of eNOS develop the hyperdynamic circulation associated with portal hypertension

Yasuko Iwakiri1, Gregory W Cadelina2, William C Sessa3, and Roberto J Groszmann4*

1 Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University, New Haven, CT, USA; Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA; The Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT, USA
2 The Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT, USA
3 Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University, New Haven, CT, USA
4 Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA; The Hepatic Hemodynamic Laboratory, VA Connecticut Healthcare System, West Haven, CT, USA

* To whom correspondence should be addressed. E-mail: roberto.groszmann{at}yale.edu.

Backgound & Aims: 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 nitric oxide 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. Methods: To test this hypothesis, we used mice lacking eNOS (eNOS-/-) or eNOS/iNOS genes (eNOS/iNOS-/-). The partial portal vein ligation (PVL) was used to induce portal hypertension. The sham-operated animal was used as a control. The hemodynamic characteristics were tested 2 weeks after the surgery. Results: Similar to rats with chronic portal hypertension, the wild type mice with PVL showed a significant increase in eNOS protein expression (P<0.05) compared to that of sham animals. In both wild type control mice for eNOS-/- and eNOS/iNOS-/-, PVL significantly reduced peripheral resistance compared to that of sham group (0.242 ± 0.009 vs 0.284 ± 0.009 mmHg.min.kg body wt/mL, P=0.005; and 0.133 ± 0.008 vs 0.192 ± 0.03 mmHg.min.kg body wt/mL, P=0.03, respectively). As opposed to our hypothesis, PVL also caused significant reduction in peripheral resistance in eNOS-/-compared to sham animals (0.33 ± 0.02 vs 0.41 ± 0.03 mmHg.min.kg body wt/mL. P=0.04 ) and in eNOS/iNOS-/- animals with PVL compared to that of sham operated group (0.44 ± 0.02 vs 0.54 ± 0.04, P=0.03). Conclusion: This demonstrates that despite gene deletion of eNOS, the knockout mice developed the hyperdynamic circulation. Compensatory vasodilator molecule(s) are up-regulated in place of NO in the systemic and splanchnic circulation in portal hypertensive animals.






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