title: Central mineralocorticoid receptors and the role of angiotensin II and glutamate in the paraventricular nucleus of rats with angiotensin II-induced hypertension.
abstract: A chronic increase in circulating angiotensin II (Ang II) activates an aldosterone-mineralocorticoid receptor-ouabain neuromodulatory pathway in the brain that increases neuronal activation in hypothalamic nuclei, such as the paraventricular nucleus (PVN) and causes progressive hypertension. Several models of chronic sympathetic hyperactivity are associated with an increase in AT1 and glutamate receptor activation in the PVN. The current study evaluated whether increased angiotensin type 1 (AT1) and glutamate receptor-dependent signaling in the PVN contributes to the maintenance of blood pressure (BP) in Ang II-hypertensive Wistar rats, and the role of aldosterone-mineralocorticoid receptor pathway in this enhanced signaling. After subcutaneous infusion of Ang II for 2 weeks, in conscious rats BP and heart rate were recorded after (1) 10-minute bilateral infusions of candesartan and kynurenate in the PVN; (2) 1 hour intracerebroventricular infusion of eplerenone, and (3) candesartan and kynurenate after eplerenone. Candesartan or kynurenate in the PVN fully reversed the increase in BP from circulating Ang II. Kynurenate after candesartan or candesartan after kynurenate did not further lower BP. Intracerebroventricular infusion of eplerenone at 16 hours after its infusion fully reversed the increase in BP from circulating Ang II. After eplerenone, candesartan and kynurenate in the PVN did not further decrease BP. These findings suggest that increased mineralocorticoid receptor activation in the brain activates a slow neuromodulatory pathway that maintains enhanced AT1 and glutamate receptor-dependent signaling in the PVN, and thereby the hypertension from a chronic increase in circulating Ang II.
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gabor
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000077545:Eplerenone; D018698:Glutamic Acid / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D007262:Infusions, Intravenous; D057967:Infusions, Intraventricular; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D017470:Receptors, Glutamate; D018161:Receptors, Mineralocorticoid; D013777:Tetrazoles; D000804:Angiotensin II; D013148:Spironolactone; D018698:Glutamic Acid; D000077545:Eplerenone; D007736:Kynurenic Acid; C081643:candesartan