Lack of endothelial nitric oxide synthase promotes endothelin-induced hypertension : Lessons from endothelin-1 transgenic/endothelial nitric oxide synthase knockout mice

• Published in: Journal of the American Society of Nephrology Vol. 18; no. 3; pp. 730 - 740
• Main Authors: QUASCHNING, Thomas, VOSS, Florian, WANNER, Christoph, THEURING, Franz, GALLE, Jan, HOCHER, Berthold, RELLE, Katharina, KALK, Philipp, VIGNON-ZELLWEGER, Nicolas, PFAB, Thiemo, BAUER, Christian, THEILIG, Franziska, BACHMANN, Sebastian, KRAEMER-GUTH, Annette
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.03.2007
• Subjects: Acetylcholine - pharmacology; Animals; Aorta - drug effects; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Body Weight; Cardiology. Vascular system; Endothelin-1 - genetics; Endothelin-1 - metabolism; Endothelium - metabolism; Hypertension - etiology; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Nephrology. Urinary tract diseases; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Organ Size; RNA, Messenger - metabolism; Hypertension; Nephrology; Enzyme; Animal; Knockout mouse; Cardiovascular disease; Endothelin 1; Oxidoreductases; Nitric-oxide synthase; Urology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2006050541

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.