Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regul Integr Comp Physiol 2013 May 15;304(10):R818-28
Date
03/29/2013Pubmed ID
23535460Pubmed Central ID
PMC3652167DOI
10.1152/ajpregu.00082.2013Scopus ID
2-s2.0-84878651210 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
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.
Author List
Littlejohn NK, Siel RB Jr, Ketsawatsomkron P, Pelham CJ, Pearson NA, Hilzendeger AM, Buehrer BA, Weidemann BJ, Li H, Davis DR, Thompson AP, Liu X, Cassell MD, Sigmund CD, Grobe JLAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinCurt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntidiuretic Hormone Receptor Antagonists
Benzazepines
Blood Pressure
Brain
Gene Expression
Hypertension
Hypothalamus
Mice
Mice, Transgenic
Receptors, Vasopressin
Renin-Angiotensin System
Vasopressins
