Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis.

Abstract

This study investigated the expression of A(1) and A(2A) receptors in the rat colonic neuromuscular compartment, and characterized their roles in the control of motility during inflammation. Colitis was induced by 2,4-dinitrobenzenesulfonic acid. A(1), A(2A) receptors, and ecto-5'-nucleotidase (CD73, adenosine producing enzyme) mRNA expression was examined by RT-PCR. The effects of DPCPX (A(1) receptor antagonist), CCPA (A(1) receptor agonist), 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (A(2A) receptor antagonist), 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (A(2A) receptor agonist), AOPCP (CD73 inhibitor) were tested on electrically or carbachol-evoked contractions in colonic longitudinal muscle preparations. In normal colon, RT-PCR revealed the presence of A(1) receptors, A(2A) receptors and CD73, and an increased expression of A(2A) receptors and CD73 was detected in inflamed tissues. In normal colon, DPCPX or 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol enhanced electrically-induced contractions, while in inflamed preparations the effect of DPCPX no longer occurred. In normal colon, CCPA or 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride decreased electrically-induced contractions. Under inflammation, 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride reduced electrically evoked contractions with higher efficacy, while the inhibition by CCPA remained unchanged. A(1) and A(2A) receptor ligands did not affect carbachol-induced contractions. AOPCP enhanced electrically-induced contractions and prevented the contractile effects of 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, without interfering with DPCPX, both in normal and inflamed colons. These results indicate that, in normal colon, both A(1) and A(2A) receptors contribute to the inhibitory control of motor functions at neuronal level. Under bowel inflammation, A(1) receptor loses its modulating actions, while the recruitment of A(2A) receptor by CD73-dependent endogenous adenosine drives an enhanced inhibitory control of colonic neuromotility.

• Authors: Luca Antonioli, Matteo Fornai, Rocchina Colucci, Oriana Awwad, Narcisa Ghisu, Marco Tuccori, Mario Del Tacca, Corrado Blandizzi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 650 Issue 2-3 Pg. 639-49 (Jan 15 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21034735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Adenosine A1 Receptor Agonists
• Adenosine A1 Receptor Antagonists
• Adenosine A2 Receptor Agonists
• Adenosine A2 Receptor Antagonists
• Benzenesulfonates
• Receptor, Adenosine A1
• Receptors, Adenosine A2
• Xanthines
• 2-chloro-N(6)cyclopentyladenosine
• 2,4-dinitrobenzenesulfonic acid
• 1,3-dipropyl-8-cyclopentylxanthine
• 5'-Nucleotidase
• Adenosine

Topics

• 5'-Nucleotidase (metabolism)
• Adenosine (analogs & derivatives, pharmacology)
• Adenosine A1 Receptor Agonists (pharmacology)
• Adenosine A1 Receptor Antagonists (pharmacology)
• Adenosine A2 Receptor Agonists (pharmacology)
• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• Benzenesulfonates
• Colitis (drug therapy, metabolism, physiopathology)
• Colon (drug effects, metabolism, physiopathology)
• Disease Models, Animal
• In Vitro Techniques
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, innervation, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Adenosine A1 (metabolism)
• Receptors, Adenosine A2 (metabolism)
• Xanthines (pharmacology)