| Title | ACTIVATION OF ADENOSINE LOW AFFINITY A3 RECEPTORS INHIBITS THE ENTERIC SHORT INTER-PLEXUS NEURAL CIRCUIT TRIGGERED BY HISTAMINE. | | Author(s) | Bozarov A, Wang YZ, Yu JG, Wunderlich J, Hassanain HH, Alhaj M, Cooke HJ, Grants I, Ren T, Christofi FL | | Institution | 1. | | Source | Am J Physiol Gastrointest Liver Physiol 2009 Oct 1. | | Abstract | We tested the novel hypothesis that endogenous (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 intra-crystal distance) simultaneously with short-circuit current (Isc, Cl(-) secretion). The short-inter-plexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5HT4 (RS39604), NK1R (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 (CPT, PACPX or 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 knock-down of ADOA1R with the irreversible antagonist FSCPX; the IC(50) for IB-MECA was 0.8microM. MRS1191 alone could augment or unmask coordinated responses to dimaprit and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex Isc responses. Adenosine deaminase mimicked actions of ADO 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 ADO, acetylcholine, substance P and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast-cell / histamine release. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19808660 |
|
