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.

Abstract

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.

• Authors: Noha Nassar, Abdel A Abdel-Rahman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 324 Issue 1 Pg. 79-85 (Jan 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 17934014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adenosine A2 Receptor Antagonists
• Adra2a protein, rat
• Antihypertensive Agents
• Imidazoline Receptors
• Receptor, Adenosine A2A
• Receptors, Adrenergic, alpha-2
• imidazoline I1 receptors
• Nitric Oxide Synthase
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Clonidine
• NG-Nitroarginine Methyl Ester

Topics

• Adenosine A2 Receptor Antagonists
• Animals
• Antihypertensive Agents
• Aorta, Abdominal (innervation)
• Clonidine
• Denervation
• Hypotension (chemically induced, metabolism)
• Imidazoline Receptors (metabolism)
• Male
• Medulla Oblongata (physiology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neurons (physiology)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Receptor, Adenosine A2A (physiology)
• Receptors, Adrenergic, alpha-2 (metabolism)