The role of intraspinal adenosine A 1 receptors in sympathetic regulation

Abstract

Using a splanchnic nerve-spinal cord preparation in vitro, we have previously demonstrated that tonic sympathetic activity is generated from the thoracic spinal cord. Here, we sought to determine if adenosine receptors play a role in modulating this spinally generated sympathetic activity. Various adenosine analogs were applied. N 6-Cyclopentyladenosine (CPA, adenosine A 1 receptor agonist) and 5′- N-ethylcarboxamidoadenosine (NECA, adenosine A 1/A 2 receptor agonist) reduced, while N 6-[2-(4-aminophenyl)ethyl]adenosine (APNEA, non-selective adenosine A 3 receptor agonist) did not alter sympathetic activity. The inhibitory effect of CPA or NECA on sympathetic activity was reversed by 8-cyclopentyltheophylline (CPT, adenosine A 1 receptor antagonist) or abolished by CPT pretreatment. In the presence of 3,7-dimethyl-1-propargylxanthine (DMPX, adenosine A 2 receptor antagonist), sympathetic activity was still reduced by CPA or NECA. Sympathetic activities were not changed by applications of the more selective adenosine A 2 or A 3 receptor agonists or antagonists, including 4-[2-[[6-amino-9-( N-ethyl-β- d-ribofuranuronamidosyl)-9 H-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS21680), 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385), 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (Chloro-IB-MECA), and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191). These findings exclude a possible involvement of A 2 or A 3 receptors in sympathetic regulation at the spinal levels. Interestingly, CPT alone did not affect sympathetic activity, suggesting that adenosine A 1 receptors are endogenously quiescent under our experimental conditions. We conclude that intraspinal adenosine A 1 receptors may down-regulate sympathetic outflow and serve as a part of the scheme for neuroprotection.