title: Lack of endothelial nitric oxide synthase promotes endothelin-induced hypertension: lessons from endothelin-1 transgenic/endothelial nitric oxide synthase knockout mice.
abstract: 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.
authors.affiliation: Department of Nephrology, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quaschning
authors.forename: Florian
authors.initials: F
authors.lastname: Voss
authors.forename: Katharina
authors.initials: K
authors.lastname: Relle
authors.forename: Philipp
authors.initials: P
authors.lastname: Kalk
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignon-Zellweger
authors.forename: Thiemo
authors.initials: T
authors.lastname: Pfab
authors.forename: Christian
authors.initials: C
authors.lastname: Bauer
authors.forename: Franziska
authors.initials: F
authors.lastname: Theilig
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Annette
authors.initials: A
authors.lastname: Kraemer-Guth
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Franz
authors.initials: F
authors.lastname: Theuring
authors.forename: Jan
authors.initials: J
authors.lastname: Galle
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000502:physiology*; D001835:Body Weight; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism*; D006973:Hypertension / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine