Brainstem phosphorylated extracellular signal-regulated kinase 1/2-nitric-oxide synthase signaling mediates the adenosine A2A-dependent hypotensive action of clonidine in conscious aortic barodenervated rats.
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(2A)R) are not known. We tested the hypothesis that A(2A)R-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 I(1) and alpha(2A) adrenergic receptors (alpha(2A)R)] 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(2A)R was evident and was complemented with enhanced central A(2A)R [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(2A)R blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]pyrimidine; SCH58261] or NOS inhibition (N(omega)-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(2A)R signaling in the ABD rat.
Nassar
Noha
N
Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Abdel-Rahman
Abdel A
AA
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D001012:Aorta, Abdominal / Q000294:innervation; D003000:Clonidine; D003714:Denervation; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism*; D054755:Imidazoline Receptors / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism
D058917:Adenosine A2 Receptor Antagonists; C547770:Adra2a protein, rat; D000959:Antihypertensive Agents; D054755:Imidazoline Receptors; D043705:Receptor, Adenosine A2A; D018341:Receptors, Adrenergic, alpha-2; C410887:imidazoline I1 receptors; D019001:Nitric Oxide Synthase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003000:Clonidine; D019331:NG-Nitroarginine Methyl Ester