Abstract
Central adenosine A1 and A2A receptors mediate pressor and depressor responses, respectively. The adenosine subtype A2A receptor (A2AR)-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 A2AR-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 A2AR-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.
Footnotes
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This study was supported in part by the National Institutes of Health [Grant 2R01 AA07839].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143883.
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ABBREVIATIONS: ABD, aortic barodenervated rat; A2AR, adenosine subtype A2A receptor; A1R, adenosine subtype A1 receptor; SO, sham operated; RVLM, rostral ventrolateral medulla; SHR, spontaneously hypertensive rat; pERK, phosphorylated extracellular signal-regulated kinase; i.c., intracisternal; CPA, N6-cyclopentyladenosine; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; BP, blood pressure; HR, heart rate; aCSF, artificial cerebrospinal fluid; DMSO, dimethyl sulfoxide; MAP, mean arterial pressure; ANOVA, analysis of variance; ir, immunoreactive; CGS21680, 2-[4-[(2-carboxyethyl) phenyl] ethylamino]-5′-N-ethylcarboxamidoadenosine.
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↵1 Current affiliation: Department of Pharmacology, Faculty of Pharmacy, Cairo University, Egypt.
- Received July 22, 2008.
- Accepted October 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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