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

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 relaxationucontraction of isolated preconstricted aortic rings to acetylcholine (10 10 –10 4 molul), sodium nitroprusside (10 10 –10 4 molul), ET-1 (10 10 –10 7 molul) and big ET-1 (10 10 –10 7 molul), 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-N G -nitroarginine methyl ester (L-NAME, 10 4 molul). 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 nitrateunitrite 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 endotheliumdependent 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.