Guanosine negatively modulates the gastric motor function in mouse

Abstract

The aim of the present study was to evaluate if guanine-based purines may affect the gastric motor function in mouse. Thus, the influence of guanosine on the gastric emptying rate in vivo was determined and its effects on spontaneous gastric mechanical activity, detected as changes of the intraluminal pressure, were analyzed in vitro before and after different treatments. Gastric gavage of guanosine (1.75-10 mg/kg) delayed the gastric emptying. Guanosine (30 μM-1 mM) induced a concentration-dependent relaxation of isolated stomach, which was not affected by the inhibition of the purine nucleoside phosphorylase enzyme by 4′-deaza-1′-aza-2′-deoxy-1′-(9-methylene)-immucillin-H. The inhibitory response was antagonized by S-(4-nitrobenzyl)-6-thioinosine, a membrane nucleoside transporter inhibitor, but not affected by 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, a nonselective adenosine receptor antagonist, or by tetrodotoxin, a blocker of neuronal voltagedependent Na + channels. Moreover, guanosine-induced effects persisted in the presence of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylyl cyclase or tetraethylammonium, a nonselective potassium channel blocker, but they were progressively reduced by increasing concentrations of 2′5′dideoxyadenosine, an adenylyl cyclase inhibitor. Lastly, the levels of cyclic adenosine monophosphate (cAMP), measured by ELISA, in gastric full thickness preparations were increased by guanosine. In conclusion, our data indicate that, in mouse, guanosine is able to modulate negatively the gastric motor function, reducing gastric emptying and inducing muscular relaxation. The latter is dependent by its cellular uptake and involves adenylyl cyclase activation and increase in cAMP intracellular levels, while it is independent on neural action potentials, adenosine receptors, and K + channel activation.

Effects of Electroacupuncture on Interstitial Cells of Cajal (ICC) Ultrastructure and Connexin 43 Protein Expression in the Gastrointestinal Tract of Functional Dyspepsia (FD) Rats

“…Gastric remainder and small intestinal propulsion rate assessments were conducted as previously described to evaluate gastric and intestinal motility [ 23 , 24 ]. Before the experiments, rats were deprived of food for 24 h with free access to water.…”

Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease

“…As previously reported, guanine-based purines (guanosine and guanine) are able to modulate negatively the excitatory cholinergic control of mouse intestine (Zizzo et al, 2013, 2011). Guanine (1 mM) is still able to reduce by the same extent the neurally-evoked cholinergic contractile responses also in HGprt − mice (from 612.0 ± 10.6 mg to 373.5 ± 21.2 mg in control and from 306.5 ± 7.82 mg to 189.7 ± 19.7 mg ± 11.2 mg in HGprt − mice, in the presence of 1 mM guanine n = 5 each).…”

“…Recently, we have reported that guanine-based purines (guanosine and guanine) are able to modulate negatively gastrointestinal contractility in mouse, regulating the release of acetylcholine from the enteric excitatory cholinergic pathways intestine leading to a decrease in contractility (Zizzo et al, 2013, 2011). Data from the present work indicate that also in HGprt − mice exogenous administered guanine is still to modulate the prejuctional release of ACh by enteric nerves, indicating that cholinergic system is sensitive to guanine-based purines also in HGprt − mice, and then raising the possibility that cholinergic dysfunctions may derived from an increased effects of guanine-based purines on neural target.…”

“…Nearly every mediator/modulator neurotransmitter found in the central nervous system is also found in ENS, making the enteric nervous system a good model of nervous system, simpler and more accessible than the central nervous system. Since, among the different neurotransmitters/modulator that are involved in the control of intestinal contractility, acetylcholine (ACh) is thought to be the principal neurotransmitter involved in intestinal smooth muscle contraction, via activation of muscarinic receptors, we aimed to investigate the involvement of enteric excitatory cholinergic pathways on intestinal contractility in HGprt − mice, also in consideration that, we have previously reported that guanine-based purines (guanosine and guanine) are able to modulate negatively the excitatory cholinergic control of mouse intestine leading to a decrease in contractility (Zizzo et al, 2013, 2011). Since HPRT-deficient cells fail to recycle hypoxanthine and guanine, resulting in an accumulation of the purines, we hypothesized that an increased effect of guanine-based purines on neural target could cause an alteration of neural function, in turn resulting in motor dysfunctions.…”

The Guanine-Based Purinergic System: The Tale of An Orphan Neuromodulation

“…Nevertheless, GBPs appear to interfere with prejunctional acethylcoline release in the circular muscle layer of mouse colon, and their effects are dependent on their cellular uptake and independent from ABP receptors ( Zizzo et al, 2011 ). Furthermore, GUO is able to induce muscular relaxation; this effect is dependent on GUO cellular uptake, adenylyl cyclase activation and increase in cAMP intracellular levels, while it is independent of neural action potentials, ARs and K + channel activation ( Zizzo et al, 2013 ). In several experimental conditions GBPs seem to modulate glutamatergic neurotransmission.…”