Key points• Neural-mediated relaxation occurs in the gastrointestinal tract. To accomplish this function, two neurotransmitters, ATP or a related purine and nitric oxide, are released by inhibitory motorneurons.• The type of purinergic receptor is still under debate but previous data using a classical pharmacological approach (receptor agonists and antagonists) suggested that P2Y 1 receptors are responsible for purinergic neurotransmission in the gastrointestinal tract.• In the present study we used a genetically modified mouse in which P2Y 1 receptors had been knocked out.• P2Y 1 -deficient mice had functional nitrergic neurotransmission but purinergic neurotransmission was absent.• The present work confirms the hypothesis demonstrating that P2Y 1 receptors mediate the purinergic component of the smooth muscle relaxation in the gastrointestinal tract.Abstract Purinergic and nitrergic co-transmission is the dominant mechanism responsible for neural-mediated smooth muscle relaxation in the gastrointestinal tract. The aim of the present paper was to test whether or not P2Y 1 receptors are involved in purinergic neurotransmission using P2Y 1 −/− knock-out mice. Tension and microelectrode recordings were performed on colonic strips. In wild type (WT) animals, electrical field stimulation (EFS) caused an inhibitory junction potential (IJP) that consisted of a fast IJP (MRS2500 sensitive, 1 μM) followed by a sustained IJP (N ω -nitro-L-arginine (L-NNA) sensitive, 1 mM). The fast component of the IJP was absent in P2Y 1 −/− mice whereas the sustained IJP (L-NNA sensitive) was recorded. In WT animals, EFS-induced inhibition of spontaneous motility was blocked by the consecutive addition of L-NNA and MRS2500. In P2Y 1 −/− mice, EFS responses were completely blocked by L-NNA. In WT and P2Y 1 −/− animals, L-NNA induced a smooth muscle depolarization but 'spontaneous' IJP (MRS2500 sensitive) could be recorded in WT but not in P2Y 1 −/− animals. Finally, in WT animals, 1 μM MRS2365 caused a smooth muscle hyperpolarization that was blocked by 1 μM MRS2500. In contrast, 1 μM MRS2365 did not modify smooth muscle resting membrane potential in P2Y 1 −/− mice. β-Nicotinamide adenine dinucleotide (β-NAD, 1 mM) partially mimicked the effect of MRS2365. We conclude that P2Y 1 receptors mediate purinergic neurotransmission in the gastrointestinal tract and β-NAD partially fulfils the criteria to participate in rodent purinergic neurotransmission. The P2Y 1 −/− mouse is a useful animal model to study the selective loss of purinergic neurotransmission.

1- P2Y(1) receptor is the general mechanism of purinergic inhibition in the gastrointestinal tract, 2- P2Y(1)(-/-) mouse is a useful animal model to study selective impairment of purinergic neurotransmission and 3- P2Y(1)(-/-) mouse might help in the identification of purinergic neurotransmitter(s).

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Otilonium bromide causes inhibition of L-/T-type calcium channels, muscarinic, and tachykininergic responses that acting together explain the pharmacological properties of the compound.

The biology of H S is a still developing area of research and several biological functions have been recently attributed to this gaseous molecule in many physiological systems, including the cardiovascular, urogenital, respiratory, digestive and central nervous system (CNS). H S exerts anti-inflammatory effects and can be considered an endogenous mediator with potential effects on gastrointestinal motility. During the last few years, we have investigated the role of H S as a regulator of gastrointestinal motility using both animal and human tissues. The aim of the present work is to review published data regarding the potential role of H S as a signalling molecule regulating physiopathological processes in gastrointestinal motor function. H S is endogenously produced by defined enzymic pathways in different cell types of the intestinal wall including neurons and smooth muscle. Inhibition of H S biosynthesis increases motility and H S donors cause smooth muscle relaxation and inhibition of propulsive motor patterns. Impaired H S production has been described in animal models with gastrointestinal motor dysfunction. The mechanism(s) of action underlying these effects may include several ion channels, although no specific receptor has been identified. At this time, even though there is much experimental evidence for H S as a modulator of gastrointestinal motility, we still do not have conclusive experimental evidence to definitively propose H S as an inhibitory neurotransmitter in the gastrointestinal tract, causing nerve-mediated relaxation.