title: Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats.
abstract: 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.
authors: *Department of Pharmacology and Cardiovascular Centre, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors: Sofie
authors: S
authors: Brouwers
authors: †Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Centre for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Ilse
authors: I
authors: Smolders
authors: ‡Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, U.S.A.
authors: Richard D
authors: RD
authors: Wainford
authors: †Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Centre for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Alain G
authors: AG
authors: Dupont
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D003243:Consciousness; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D011725:Pyridines / Q000494:pharmacology; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000502:physiology*; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013565:Sympatholytics; D013876:Thiophenes; C073402:PD 123319; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine
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