Journal Article

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

Thomas Quaschning, Serkan Koçak, Christian Bauer, Hans‐Hellmut Neumayer, Jan Galle and Berthold Hocher

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 18, issue 3, pages 479-483
Published in print March 2003 | ISSN: 0931-0509
Published online March 2003 | e-ISSN: 1460-2385 | DOI:
Increase in nitric oxide bioavailability improves endothelial function in endothelin‐1 transgenic mice

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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 lNG‐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.

Keywords: endothelin; endothelium; hypertension; nitric oxide; relaxation

Journal Article.  3218 words.  Illustrated.

Subjects: Nephrology

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