Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent.

First published March 27, 2013; doi:10.1152/ajpregu.00082.2013.--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 neuronspecific 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 V₂-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (～15 mmHg) hypertension in sRA mice. Abdominal aortas and secondorder mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V1A receptor mRNA, but no significant changes in V₂ 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 brainspecific hyperactivity of the RAS and suggest a primary role of V2 receptors. [ABSTRACT FROM AUTHOR]