P2Y1 receptors mediate inhibitory neuromuscular transmission in the rat colon

Background and purpose: Inhibitory junction potentials (IJP) are responsible for smooth muscle relaxation in the gastrointestinal tract. The aim of this study was to pharmacologically characterize the neurotransmitters [nitric oxide (NO) and adenosine triphosphate (ATP)] and receptors involved at the inhibitory neuromuscular junctions in the rat colon using newly available P2Y(1) antagonists. Experimental approach: Organ bath and microelectrode recordings were used to evaluate the effect of drugs on spontaneous mechanical activity and resting membrane potential. IJP and mechanical relaxation were studied using electrical field stimulation (EFS). Key results: N omega-nitro-L-arginine (L-NNA) inhibited the slow component of the IJP and partially inhibited the mechanical relaxation induced by EFS. MRS2179, MRS2500 and MRS2279, all selective P2Y(1) receptor antagonists, inhibited the fast component of the IJP without having a major effect on the relaxation induced by EFS. The combination of both L-NNA and P2Y(1) antagonists inhibited the fast and the slow components of the IJP and completely blocked the mechanical relaxation induced by EFS. Sodium nitroprusside caused smooth muscle hyperpolarization and cessation of spontaneous motility that was prevented by oxadiazolo[4,3-alpha]quinoxalin-1-one. Adenosine 5'-O-2-thiodiphosphate, a preferential P2Y agonist, hyperpolarized smooth muscle cells and decreased spontaneous motility. This effect was inhibited by P2Y(1) antagonists. Conclusions and implications: The co-transmission process in the rat colon involves ATP and NO. P2Y(1) receptors mediate the fast IJP and NO the slow IJP. The rank order of potency of the P2Y(1) receptor antagonists is MRS2500 greater than MRS2279 greater than MRS2179. P2Y(1) receptors might be potential pharmacological targets for the regulation of gastrointestinal motility.