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

Abstract

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.