Lack of iNOS impairs endothelial function in endothelin-1 transgenic mice.

Background: Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation.

Methods: We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS-/-) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788.

Results: Systolic blood pressure was similar in ET+/+, iNOS-/- and wild-type mice, but was significantly elevated in ET+/+ iNOS-/- crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 +/- 5 vs. 78 +/- 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS-/- animals (75 +/- 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 +/- 4%), iNOS-/- mice (38 +/- 5%) and ET+/+ iNOS-/- mice (44 +/- 4%) to a similar extent as compared with wild-type littermates (66 +/- 4%; p < 0.05).

Conclusions: Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS-/- animals.