title: Role of brain aldosterone and mineralocorticoid receptors in aldosterone-salt hypertension in rats.
abstract: Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 μg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. Other sets of rats received chronic intra-cerebroventricular (icv) infusion of aldo synthase (AS) inhibitor FAD286, MR blocker eplerenone or vehicle, electrolytic or sham lesions of the SFO, or intra-PVN infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA. Infusion of aldo had no effect on 11βHSD2, MR and AT1R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) γ subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT1R mRNA in the PVN by ∼ 60%, but AT1aR-siRNA only decreased AT1R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼ 50% and hypertension by ∼ 70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: H-W
authors.initials: HW
authors.lastname: Wang
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: B S
authors.initials: BS
authors.lastname: Huang
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Chen
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: White
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada. Electronic address: fleenen@ottawaheart.ca.
authors.forename: F H H
authors.initials: FH
authors.lastname: Leenen
mesh_terms: D000450:Aldosterone / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D004327:Drinking Behavior / Q000187:drug effects; D000077545:Eplerenone; D017316:Fadrozole / Q000008:administration & dosage; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives; D013356:Subfornical Organ / Q000187:drug effects / Q000378:metabolism*; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; D000077545:Eplerenone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole; D003345:Corticosterone
keywords: aldosterone; aldosterone synthase; angiotensin II type 1 receptor; brain; gene expression knockdown; mineralocorticoid receptor