Distinct modulation of the endothelin-1 pathway iniNOS−/−andeNOS−/−miceThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.

Abstract

We hypothesized that constitutive endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) have opposite effects on the regulation of endothelin and its receptors. We therefore sought to determine whether deletions of iNOS or eNOS genes in mice modulate pressor responses to endothelin and the expression of ETAand ETBreceptors in a similar fashion. Despite unchanged baseline hemodynamic parameters, anesthetized iNOS−/−mice displayed reduced pressor responses to endothelin-1, but not to that of IRL-1620, a selective ETBagonist. Protein content of cardiac ETAreceptors was reduced in iNOS−/−mice compared with wild-type mice, but that of ETBreceptors was unchanged. Anesthetized eNOS−/−mice presented a hypertensive state, accompanied by an enhanced pressor response to intravenous endothelin-1, whereas the pressor response to IRL-1620 was reduced. Protein levels were also found to be increased for ETAreceptors, but reduced for ETBreceptors, in cardiac tissues of eNOS−/−mice. In conscious animals, both strains responded equally to the hypotensive effect of an ETAantagonist, ABT-627, whereas orally administered A-192621, an ETBantagonist, increased MAP to a greater extent in eNOS−/−than in wild-type mice. Furthermore, significant levels of immunoreactive endothelin were found in mesenteric arteries in eNOS−/−but not in iNOS−/−or wild-type congeners. Our study shows that repression of iNOS or eNOS has differential effects on endothelin-1 and its receptors. We have also shown that the heart is the main organ in which iNOS or eNOS repression induces important alterations in protein content of endothelin receptors in adult mice.