Increase in nitric oxide bioavailability improves endothelial function in endothelin-1 transgenic mice

Abstract

Background. Endothelin-1 (ET-1) has been described as a very potent vasoconstrictor. Nevertheless, transgenic mice overexpressing ET-1 have been shown to exhibit normal blood pressure. We thus hypothesized that vascular ET-1 effects may be antagonized by increased activity of other regulatory systems, such as the increase in bioavailability of the endothelial counterpart of ET-1, nitric oxide (NO). Methods. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine (10-10-10-4 mol/l), sodium nitroprusside (10-10-10-4 mol/l), ET-1 (10-10-10-7 mol/l) and big ET-1 (10-10-10-7 mol/l), respectively, in ET-1 transgenic mice and corresponding controls. To unmask the impact of the NO system, we furthermore analysed vessel rings incubated in vitro with the NO-synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10-4 Mol/l). Results. Maximum endothelium-dependent relaxation was enhanced in ET-1 transgenic mice (93±3% vs 84±4% for wild-type littermates; P<0.05) and was inhibited by preincubation with L-NAME in both ET-transgenic mice and wild-type littermates (11±5% vs 9±4% maximum relaxation, respectively). Endothelium-independent relaxation was similar among all groups. Maximum vascular contraction to ET-1 and big ET-1 was reduced in ET-1 transgenic mice (P<0.05 vs wild-type littermates). Preincubation with L-NAME reduced this difference, indicating the involvement of augmented NO availability. Correspondingly, urinary nitrate/nitrite excretion was significantly elevated in ET-1 transgenic mice. Conclusions. These data suggest that in transgenic mice overexpressing ET-1, increased NO bioavailability counteracts the contractile potency of elevated ET-1 levels and leads to an improvement of endothelium-dependent relaxation. Thus, in the presence of an activated ET system, up-regulation of NO production may be capable of maintaining vascular tone in a normal range and therefore may prevent the development of hypertension.