Brainstem adenosine A1 receptor signaling masks phosphorylated extracellular signal-regulated kinase 1/2-dependent hypotensive action of clonidine in conscious normotensive rats.
Central adenosine A(1) and A(2A) receptors mediate pressor and depressor responses, respectively. The adenosine subtype A(2A) receptor (A(2A)R)-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(2A)R-mediated (pERK1/2-dependent) hypotensive action of clonidine is not expressed in SO rats because it is counterbalanced by fully functional central adenosine subtype A(1) receptor (A(1)R) signaling. We first demonstrated an inverse relationship between A(1)R expression in RVLM and clonidine-evoked hypotension in ABD and SO rats. The functional (pharmacological) relevance of the reduced expression of RVLM A(1)R in ABD rats was verified by the smaller dose-dependent pressor responses elicited by the selective A(1)R agonist N(6)-cyclopentyladenosine in ABD versus SO rats. It is important that after selective blockade of central A(1)R 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 A(1)R 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 A(1)R signaling opposes the adenosine A(2A)R-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.
Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville, NC 27858, USA.
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Abdel-Rahman
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000294:innervation; D001794:Blood Pressure / Q000187:drug effects*; D001933:Brain Stem / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology*; D003243:Consciousness; D003714:Denervation; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D043682:Receptor, Adenosine A1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003000:Clonidine