Abstract 351: Activation Of The Central Renin Angiotensin System (RAS) Causes Selective Cerebrovascular Dysfunction
Approximately 30% of hypertensive patients have low plasma renin. The deoxycorticosterone (DOCA)/salt model of hypertension exhibits low peripheral RAS activity, but activation of the central RAS. The impact of central RAS activation on the cerebrovasculature is not defined. We tested the hypothesis that activation of the central RAS would impair endothelial function in brain. We produced mild hypertension in male C57BL/6 mice using subcutaneous DOCA and 0.9% salt in their drinking water for 3 weeks (no nephrectomy was performed) followed by studies of isolated arteries in vitro. Blood pressure was elevated modestly after DOCA/salt treatment (79±2 vs 95±3 mmHg). Endothelial function was severely impaired in cerebral arteries from mice treated with DOCA/salt (e.g. 10 μM acetylcholine: 33±3% vs 4±4%) but was unaffected in similar-sized mesenteric arteries. Because microvascular dysfunction is a key feature of small vessel disease in brain that increases the risk of stroke and cognitive impairment, we examined responses of small cerebral arterioles (baseline diameter ~30 μm) in vivo using a cranial window. Endothelium-dependent dilation to acetylcholine in cerebral arterioles was reduced by ~75% following DOCA/salt treatment (e.g. 10 μM acetylcholine: 26±5% vs 6±3%). In contrast, endothelium-independent vasodilation to nitroprusside (NO donor) or nifedipine (Ca2+ channel blocker) was similar between groups. Microvascular endothelial dysfunction was not affected by a scavenger of superoxide but was restored to normal by local inhibition of Rho kinase (ROCK) with Y27632. Activation of AT1 receptors by angiotensin II can increase ROCK signaling. Local inhibition of AT1 receptors with losartan or inhibition of mineralocorticoid receptors (MR) with eplerenone improved endothelium-dependent dilation in DOCA/salt treated mice to normal levels. RhoA and ROCK2 mRNA expression and total endothelial NO synthase protein expression was similar between groups. These findings suggest that activation of the central RAS profoundly but selectively impairs endothelial function in brain. Our findings identify AT1 receptors, MR and ROCK as key contributors to endothelial microvascular dysfunction in this model of mild DOCA/salt-induced hypertension.
Author Disclosures: T. De Silva: None. C.M. Lynch: None. J.L. Grobe: None. F.M. Faraci: None.
- © 2014 by American Heart Association, Inc.