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CARDIOVASCULAR

Brainstem Adenosine A₁ Receptor Signaling Masks Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Dependent Hypotensive Action of Clonidine in Conscious Normotensive Rats

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

Central adenosine A₁ and A_2A receptors mediate pressor and depressor responses, respectively. The adenosine subtype A_2A receptor (A_2AR)-evoked enhancement of phosphorylated extracellular signal-regulated kinase (pERK) 1/2 production in the rostral ventrolateral medulla (RVLM), a major neuroanatomical target for clonidine, contributes to clonidine-evoked hypotension, which is evident in conscious aortic barodenervated (ABD) but not in conscious sham-operated (SO) normotensive rats. We conducted pharmacological and cellular studies to test the hypothesis that the adenosine A_2AR-mediated (pERK1/2-dependent) hypotensive action of clonidine is not expressed in SO rats because it is counterbalanced by fully functional central adenosine subtype A₁ receptor (A₁R) signaling. We first demonstrated an inverse relationship between A₁R expression in RVLM and clonidine-evoked hypotension in ABD and SO rats. The functional (pharmacological) relevance of the reduced expression of RVLM A₁R in ABD rats was verified by the smaller dose-dependent pressor responses elicited by the selective A₁R agonist N⁶-cyclopentyladenosine in ABD versus SO rats. It is important that after selective blockade of central A₁R with 8-cyclopentyl-1,3-dipropylxanthine in conscious SO rats, clonidine lowered blood pressure and significantly increased neuronal pERK1/2 in the RVLM. In contrast, central A₁R blockade had no influence on the hypotensive response or the increase in RVLM pERK1/2 elicited by clonidine in ABD rats. These findings support the hypothesis that central adenosine A₁R signaling opposes the adenosine A_2AR-mediated (pERK1/2-dependent) hypotensive response and yield insight into a cellular mechanism that explains the absence of clonidine-evoked hypotension in conscious normotensive rats.

Address correspondence to: Dr. Abdel A. Abdel-Rahman, Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville, NC 27858. E-mail: abdelrahmana{at}ecu.edu