The type 2 angiotensin receptor (AT2R) has been suggested to counterbalance the type 1 angiotensin receptor (AT1R) in the central regulation of blood pressure and sympathetic tone. In the present study we investigated the blood pressure responses to stimulation of central AT2Rs by the selective agonist Compound 21 in conscious spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKY rats). We also assessed the impact on noradrenaline [norepinephrine (NE)] plasma levels, autonomic function, spontaneous baroreflex sensitivity, and the possible involvement of the nitric oxide (NO) pathway and the AT1Rs. Chronic intracerebroventricular Compound 21 infusion lowered blood pressure and NE plasma levels in both rat strains. The night-time hypotensive effect was greater in SHRs compared with WKY rats. Compound 21 improved spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These effects were abolished by co-administration of the AT2R antagonist PD123319 or the NO synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME). Central AT1R blockade did not enhance the hypotensive response to Compound 21. Chronic selective stimulation of central AT2Rs lowers blood pressure through sympathoinhibition, and improves spontaneous baroreflex sensitivity more in SHRs than in WKY rats. These responses appear to require a functioning central NO pathway, but are not modified by central AT1R blockade. Collectively, the data demonstrate specific beneficial effects of stimulation of central AT2Rs in hypertension associated with increased sympathetic tone, and suggest that central AT2Rs may represent a potential new therapeutic target for the treatment of neurogenic hypertension.
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Research Article|
April 15 2015
Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats
Sofie Brouwers;
*Department of Pharmacology and Cardiovascular Centre, Universitair Ziekenhuis Brussel, Brussels, Belgium
†Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Centre for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium
‡Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, U.S.A.
Correspondence: Dr Sofie Brouwers (email [email protected])
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Ilse Smolders;
Ilse Smolders
†Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Centre for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium
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Richard D. Wainford;
Richard D. Wainford
1
‡Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, U.S.A.
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Alain G. Dupont
Alain G. Dupont
1
†Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Centre for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium
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Publisher: Portland Press Ltd
Received:
November 25 2014
Revision Received:
January 26 2015
Accepted:
February 06 2015
Accepted Manuscript online:
February 06 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 129 (1): 81–92.
Article history
Received:
November 25 2014
Revision Received:
January 26 2015
Accepted:
February 06 2015
Accepted Manuscript online:
February 06 2015
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Citation
Sofie Brouwers, Ilse Smolders, Richard D. Wainford, Alain G. Dupont; Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats. Clin Sci (Lond) 1 July 2015; 129 (1): 81–92. doi: https://doi.org/10.1042/CS20140776
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