title: Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent.
abstract: An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Littlejohn
authors.forename: Rick B
authors.initials: RB
authors.lastname: Siel
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pelham
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Pearson
authors.forename: Aline M
authors.initials: AM
authors.lastname: Hilzendeger
authors.forename: Beth A
authors.initials: BA
authors.lastname: Buehrer
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Weidemann
authors.forename: Huiping
authors.initials: H
authors.lastname: Li
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thompson
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D000077602:Tolvaptan; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D017483:Receptors, Vasopressin; C106389:conivaptan; D014667:Vasopressins; D000077602:Tolvaptan
keywords: Vaprisol; antidiuretic hormone
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