2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2006050541v1 18/3/730    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Quaschning, T. Articles by Hocher, B. Search for Related Content PubMed PubMed Citation Articles by Quaschning, T. Articles by Hocher, B.

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension: Lessons from Endothelin-1 Transgenic/Endothelial Nitric Oxide Synthase Knockout Mice

Thomas Quaschning^*, Florian Voss^,, Katharina Relle^,, Philipp Kalk^,, Nicolas Vignon-Zellweger, Thiemo Pfab^||, Christian Bauer^¶, Franziska Theilig^**, Sebastian Bachmann^**, Annette Kraemer-Guth^*, Christoph Wanner, Franz Theuring, Jan Galle and Berthold Hocher

^* Department of Nephrology, University Hospital of Freiburg, Freiburg, Department of Nephrology, University Hospital of Würzburg, Würzburg, and Center for Cardiovascular Research/Institute of Pharmacology, Institute of Vegetative Physiology, Charite, Campus Mitte, ^|| Department of Internal Medicine IV, Nephrology, Charite, Campus Benjamin Franklin, ^¶ Institute of Molecular Biology and Biochemistry, Free University Berlin, and ^** Institute of Anatomy, Charite, Campus Mitte, Berlin, Germany

Address correspondence to: Prof. Berthold Hocher, Humboldt University of Berlin, University Hospital Charité, Center for Cardiovascular Research & Institute for Pharmacology. Hessischestrasse 3-4, D-10115 Berlin, Germany. Phone: +49-30-450514098; Fax: +49-30-450514938; E-mail: berthold.hocher{at}charite.de; Web: http://www.ccr.charite.de/site/html/de/ag_hocher.html

Received for publication May 30, 2006. Accepted for publication January 2, 2007.

Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice that overexpress ET-1 exhibit normal BP. It was hypothesized that vascular effects of ET-1 may be antagonized by an increase of the endothelial counterpart of ET-1, nitric oxide (NO), which is produced by the endothelial NO synthase (eNOS). Therefore, cross-bred animals of ET transgenic mice (ET+/+) and eNOS knockout (eNOS–/–) mice and were generated, and BP and endothelial function were evaluated in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings. The tissue ET and NO system was determined in aortic rings by quantitative real-time PCR and Western blotting. Systolic BP was similar in ET+/+ and wild-type (WT) mice but was significantly elevated in eNOS–/– mice (117 ± 4 mmHg versus 94 ± 6 mmHg in WT mice; P < 0.001) and even more elevated in ET+/+ eNOS–/– cross-bred mice (130 ± 4 mmHg; P < 0.05 versus eNOS–/–). Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (103 ± 6 versus 87 ± 4% of preconstriction in WT littermates; P < 0.05) and was completely blunted in eNOS–/– (–3 ± 4%) and ET+/+ eNOS–/– mice (–4 ± 4%), respectively. Endothelium-independent relaxation was comparable among all groups. Quantitative real-time PCR as well as Western blotting revealed an upregulation of the aortic ET_A and ET_B receptors in ET+/+ eNOS–/–, whereas eNOS was absent in aortic rings of eNOS–/– and ET+/+ eNOS–/– mice. ET-1 aortic tissue concentrations were similar in WT mice and ET+/+ eNOS–/– mice most probably as a result of an enhanced clearance of ET-1 by the upregulated ET_B receptor. These data show for the first time that in transgenic mice that overexpress human ET-1, additional knockout of eNOS results in a further enhancement of BP as compared with eNOS–/– mice. The human ET+/+ eNOS–/– mice therefore represent a novel model of hypertension as a result of an imbalance between the vascular ET-1 and NO systems.

This article has been cited by other articles:

				A. Stoessel, A. Paliege, F. Theilig, F. Addabbo, B. Ratliff, J. Waschke, D. Patschan, M. S. Goligorsky, and S. Bachmann Indolent course of tubulointerstitial disease in a mouse model of subpressor, low-dose nitric oxide synthase inhibition Am J Physiol Renal Physiol, September 1, 2008; 295(3): F717 - F725. [Abstract] [Full Text] [PDF]

				G. Fink, M. Li, Y. Lau, J. Osborn, and S. Watts Chronic Activation of Endothelin B Receptors: New Model of Experimental Hypertension Hypertension, September 1, 2007; 50(3): 512 - 518. [Abstract] [Full Text] [PDF]

				T. Slowinski, P. Kalk, M. Christian, F. Schmager, K. Relle, M. Godes, H. Funke-Kaiser, H.-H. Neumayer, C. Bauer, F. Theuring, et al. Cell-type specific interaction of endothelin and the nitric oxide system: pattern of prepro-ET-1 expression in kidneys of L-NAME treated prepro-ET-1 promoter-lacZ-transgenic mice J. Physiol., June 15, 2007; 581(3): 1173 - 1181. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673