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CARDIOVASCULAR

Brainstem Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Nitric-Oxide Synthase Signaling Mediates the Adenosine A_2A-Dependent Hypotensive Action of Clonidine in Conscious Aortic Barodenervated Rats

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

The cellular mechanisms that underlie the enhancement of clonidine-evoked hypotension in aortic barodenervated (ABD) rats and its dependence on central adenosine A_2A receptor (A_2AR) are not known. We tested the hypothesis that A_2AR-mediated phosphorylation of extracellular signal-regulated kinase (pERK)1/2 in the rostral ventrolateral medulla (RVLM) and its downstream activation of nitric-oxide synthase (NOS)-NO signaling underlie the centrally (clonidine)-mediated hypotension. We first demonstrated an up-regulation of the molecular targets for clonidine [imidazoline I₁ and _2A adrenergic receptors (_2AR)] in the RVLM of ABD compared with sham-operated (SO) rats; this finding might explain the enhanced clonidine hypotension in ABD rats. A similar anatomical up-regulation of the RVLM A_2AR was evident and was complemented with enhanced central A_2AR [2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5'-N-ethylcarboxamidoadenosine; CGS21680]-mediated hypotension in ABD rats. The hypotension produced by intracisternal CGS21680 or clonidine, in conscious ABD rats, was associated with a significant increase in pERK1/2 level in the RVLM. Whereas selective A_2AR blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-]-1,2,4-triazolo[1,5-c]pyrimidine; SCH58261] or NOS inhibition (N-nitro-L-arginine methyl ester) virtually abolished clonidine-evoked hypotension, clonidine-evoked enhancement of RVLM pERK1/2 production was only abrogated by SCH58261 pretreatment. These findings suggest that interventions that act centrally to increase RVLM neuronal pERK1/2 production elicit hypotension via the activation of downstream NOS-NO signaling. The findings also yield insight into a cellular mechanism that might explain the dependence of centrally (clonidine)-mediated hypotension on central A_2AR signaling in the ABD rat.

Address correspondence to: Dr. Abdel A. Abdel-Rahman, Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville, NC 27834. E-mail: abdelrahmana{at}ecu.edu