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Activation of the Central Renin‐Angiotensin System (RAS) Causes Selective Cerebrovascular Dysfunction
Author(s) -
De Silva T Michael,
Lynch Cynthia,
Grobe Justin,
Faraci Frank
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.646.4
Subject(s) - myograph , endocrinology , medicine , vasodilation , cerebral arteries , angiotensin ii , cerebral circulation , endothelial dysfunction , vasoconstriction , endothelium , renin–angiotensin system , in vivo , blood pressure , biology , microbiology and biotechnology
Although the central RAS is known to play important roles in several homeostatic mechanisms, its impact on the cerebral vasculature is unknown. We tested the hypothesis that activation of the central RAS with deoxycorticosterone (DOCA)‐salt (which simultaneously suppresses the peripheral RAS) alters cerebrovascular function. We treated male C57Bl/6 mice with DOCA and gave them drinking water both with and without 0.9% salt for 3 weeks and measured reactivity of arteries and arterioles in vitro in a pressure myograph and small pial arterioles in vivo using a cranial window. Blood pressure was elevated modestly after DOCA‐salt treatment (79±2 vs 95±3 mmHg; P <0.01). Endothelium‐dependent dilation of middle cerebral arteries was markedly impaired in DOCA‐salt treated mice compared to shams whereas dilation in similarly sized mesenteric arteries was normal. These striking cerebrovascular effects extended to brain parenchymal arterioles and to pial arterioles in vivo. Endothelium‐independent vasodilation to nitroprusside, nifedipine, and papaverine was similar between groups. In pial arterioles in vivo, local inhibition of angiotensin type 1 (AT1R), mineralocorticoid receptors (MR) or Rho kinase reversed endothelial dysfunction in DOCA‐salt treated mice. These findings suggest that activation of the central RAS with DOCA‐salt profoundly, but selectively, impairs endothelial function throughout the brain. Our findings identify AT1R, MR and Rho kinase as key contributors to DOCA‐salt‐induced endothelial dysfunction in brain. Studies were supported by the NIH, Department of Veterans Affairs, Fondation Leducq, and NHMRC.