Abstract
We tested the hypothesis that clonidine-evoked hypotension is dependent on central adenosinergic pathways. Five groups of male, conscious, aortic baroreceptor-denervated (ABD) rats received clonidine (10 μg/kg i.v.) 30 min after i.v. 1) saline, 2) theophylline (10 mg/kg), or 3) 8-(p-sulfophenyl)theophylline (8-SPT) (2.5 mg/kg) or 1 h after i.p. 4) dipyridamole (5 mg/kg) or 5) an equal volume of sesame oil. Blockade of central (theophylline) but not peripheral (8-SPT) adenosine receptors abolished clonidine hypotension. In contrast, dipyridamole substantially enhanced the bradycardic response to clonidine. In additional groups, intracisternal (i.c.) dipyridamole (150 μg) and 8-SPT (10 μg) enhanced and abolished, respectively, clonidine (0.6 μg i.c.)-evoked hypotension. Because clonidine is a mixed I1/α2 agonist, we also investigated whether adenosine signaling is linked to the I1 or the α2A receptor by administering the selective I1 (rilmenidine, 25 μg) or α2A [α-methylnorepinephrine (α-MNE), 4 μg] agonist 30 min after central adenosine receptor blockade (8-SPT; 10 μg i.c.) or artificial cerebrospinal fluid. The hypotensive response elicited by rilmenidine or α-MNE was abolished in 8-SPT-pretreated rats. To delineate the role of the adenosine A2A receptor in clonidine-evoked hypotension, i.c. clonidine (0.6 μg) was administered 30 min after central adenosine receptor A2A blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]-pyrimidine (SCH58261); 150 μg i.c.]. The latter virtually abolished the hypotensive and bradycardic responses elicited by clonidine. In conclusion, central adenosine A2A signaling plays a key role in clonidine-evoked hypotension in conscious aortic barodenervated rats.
Footnotes
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This study was supported by 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.105.100495.
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ABBREVIATIONS: RVLM, rostral ventrolateral medulla; ABD, aortic barodenervated rat; α-MNE, α-methylnorepinephrine; SCH58261, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]pyrimidine; BP, blood pressure; HR, heart rate; 8-SPT, 8-(p-sulfophenyl)theophylline; i.c., intracisternal; aCSF, artificial cerebrospinal fluid; DMSO, dimethyl sulfoxide; MAP, mean arterial pressure; CNS, central nervous system; PDE, phosphodiesterase inhibitor; ZM241385, 4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol.
- Received December 22, 2005.
- Accepted March 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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