title: Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine.
abstract: We tested the novel hypothesis that endogenous adenosine (eADO) activates low-affinity A3 receptors in a model of neurogenic diarrhea in the guinea pig colon. Dimaprit activation of H2 receptors was used to trigger a cyclic coordinated response of contraction and Cl(-) secretion. Contraction-relaxation was monitored by sonomicrometry (via intracrystal distance) simultaneously with short-circuit current (I(sc), Cl(-) secretion). The short interplexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5-hydroxytryptamine 4 receptor (RS39604), neurokinin-1 receptor (GR82334), or nicotinic (mecamylamine) receptors. The A1 agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) abolished coordinated responses, and A1 antagonists could restore normal responses. A1-selective antagonists alone [8-cyclopentyltheophylline (CPT), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), or 8-cyclopentyl-N(3)-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-xanthine (FSCPX)] caused a concentration-dependent augmentation of crypt cell secretion or contraction and acted at nanomolar concentrations. The A3 agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) abolished coordinated responses and the A3 antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) could restore and further augment responses. The IB-MECA effect was resistant to knockdown of adenosine A1 receptor with the irreversible antagonist FSCPX; the IC(50) for IB-MECA was 0.8 microM. MRS1191 alone could augment or unmask coordinated responses to dimaprit, and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex I(sc) responses. Adenosine deaminase mimicked actions of adenosine receptor antagonists. A3 receptor immunoreactivity was differentially expressed in enteric neurons of different parts of colon. After tetrodotoxin, IB-MECA caused circular muscle relaxation. The data support the novel concept that eADO acts at low-affinity A3 receptors in addition to high-affinity A1 receptors to suppress coordinated responses triggered by immune-histamine H2 receptor activation. The short interplexus circuit activated by histamine involves adenosine, acetylcholine, substance P, and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast cell and histamine release.
authors.affiliation: Dept. of Anesthesiology, The Ohio State Univ., Columbus, 43210, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Bozarov
authors.forename: Yu-Zhong
authors.initials: YZ
authors.lastname: Wang
authors.forename: Jun Ge
authors.initials: JG
authors.lastname: Yu
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wunderlich
authors.forename: Hamdy H
authors.initials: HH
authors.lastname: Hassanain
authors.forename: Mazin
authors.initials: M
authors.lastname: Alhaj
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Cooke
authors.forename: Iveta
authors.initials: I
authors.lastname: Grants
authors.forename: Tianhua
authors.initials: T
authors.lastname: Ren
authors.forename: Fievos L
authors.initials: FL
authors.lastname: Christofi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002712:Chlorides / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000294:innervation / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D017259:Dimaprit / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007419:Intestinal Secretions / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009119:Muscle Contraction; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000294:innervation / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects; D055496:Neurogenic Bowel / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D064729:Neurokinin-1 Receptor Antagonists; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000187:drug effects / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012018:Reflex; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D002712:Chlorides; D004095:Dihydropyridines; D017442:Histamine Agonists; D006635:Histamine H2 Antagonists; C107728:MRS 1191; D064729:Neurokinin-1 Receptor Antagonists; D018733:Nicotinic Antagonists; D010880:Piperidines; C475107:RS 39604; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D011970:Receptors, Histamine H2; D018040:Receptors, Neurokinin-1; D014970:Xanthines; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; C100640:8-cyclopentyl-3-(3-((4-(fluorosulfonyl)benzoyl)oxy)propyl)-1-propylxanthine; C053907:8-cyclopentyl-1,3-dimethylxanthine; C058394:2-chloro-N(6)cyclopentyladenosine; D008464:Mecamylamine; D002927:Cimetidine; D006632:Histamine; D013806:Theophylline; C046379:1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine; D000241:Adenosine; D011407:Propane; D017259:Dimaprit