A1 receptors mediate adenosine inhibitory effects in mouse ileum via activation of potassium channels

Zizzo, Maria Grazia; Bonomo, Alessandra; Belluardo, Natale; Mulè, Flavia; Serio, Rosa

doi:10.1016/j.lfs.2009.03.006

Cited by 17 publications

(12 citation statements)

References 32 publications

(41 reference statements)

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“…In spite of a large body of published studies, the physiological function of adenosine remains to be fully clarified. This is an important point, considering that adenosine-mediated effects have been mainly studied on intestinal preparations pre-contracted with a muscarinic agonist or with electric field stimulation-evoked acetylcholine release rather than on ileal spontaneous basal tone [17], [21]–[24]. Moreover, difficulties in dissecting adenosine-mediated responses arise from concurrent activation of different adenosine receptor subtypes, each leading to opposing (i.e.…”

Section: Discussionmentioning

confidence: 99%

Adenosine-Mediated Enteric Neuromuscular Function Is Affected during Herpes Simplex Virus Type 1 Infection of Rat Enteric Nervous System

et al. 2013

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Adenosine plays an important role in regulating intestinal motility and inflammatory processes. Previous studies in rodent models have demonstrated that adenosine metabolism and signalling are altered during chronic intestinal inflammatory diseases. However, the involvement of the adenosinergic system in the pathophysiology of gut dysmotility associated to a primary neurodysfunction is still unclear. Recently, we showed that the neurotropic Herpes simplex virus type-1 (HSV-1), orally inoculated to rodents, infects the rat enteric nervous system (ENS) and affects gut motor function without signs of systemic infection. In this study we examined whether changes in purinergic metabolism and signaling occur during permanent HSV-1 infection of rat ENS. Using isolated organ bath assays, we found that contraction mediated by adenosine engagement of A1 or A2A receptors was impaired at 1 and 6 weeks post-viral administration. Immunofluorescence studies revealed that viral infection of ENS led to a marked redistribution of adenosine receptors: A1 and A2B receptors were confined to the muscle layers whereas A2A and A3 receptors were expressed mainly in the myenteric plexus. Viral-induced ENS neurodysfunction influenced adenosine metabolism by increasing adenosine deaminase and CD73 levels in longitudinal muscle-myenteric plexus with no sign of frank inflammation. This study provides the first evidence for involvement of the adenosinergic system during HSV-1 infection of the ENS. As such, this may represent a valid therapeutic target for modulating gut contractility associated to a primary neurodysfunction.

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Section: Discussionmentioning

confidence: 99%

Adenosine-Mediated Enteric Neuromuscular Function Is Affected during Herpes Simplex Virus Type 1 Infection of Rat Enteric Nervous System

et al. 2013

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“…Due to the scarce information on the physiological function of the pyrimidines as modulators of gastrointestinal motor activity and in consideration that extracellular nucleotides and their receptors have been implicated in the pathogenesis of inflammatory bowel disease [17], we aimed to investigate the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), and the P2Y receptor subtype(s) involved, using as model the murine small intestine, in which the functionality of the adenine nucleotidepreferring receptors has been established [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Zizzo

Mastropaolo

Grählert

et al. 2011

Purinergic Signalling

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We investigated the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), using as model the murine small intestine. Contractile activity of a mouse ileum longitudinal muscle was examined in vitro as changes in isometric tension. Transcripts encoding for uracil-sensitive receptors was investigated by RT-PCR. UDP induced muscular contractions, sensitive to PPADS, suramin, or MRS 2578, P2Y 6 receptor antagonist, and mimicked by PSB 0474, P2Y 6 -receptor agonist. UTP induced biphasic effects characterized by an early inhibition of the spontaneous contractile activity followed by muscular contraction. UTP excitatory effects were antagonized by PPADS, suramin, but not by MRS 2578, whilst the inhibitory effects were antagonized by PPADS but not by suramin or MRS 2578. UTPγS, P2Y 2 / 4 receptor agonist but not 2-thio-UTP, P2Y 2 receptor agonist, mimicked UTP effects. The inhibitory effects induced by UTP was abolished by ATP desensitization and increased by extracellular acidification. UDP or UTP responses were insensitive to TTX, atropine, or L-NAME antagonized by U-73122, inhibitor of phospholipase C (PLC) and preserved in the presence of nifedipine or low Ca 2+ solution.

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“…In addition, it has been demonstrated that some effects of guanosine could occur via activation of K + channels [39] and increase of the K + conductance plays a central role in the muscular relaxation, being target also of cAMP [40]. However in our preparations, pretreatment with TEA, a widely used nonselective K + channel blockers, was ineffective on the guanosineinduced relaxation, indicating that, in contrast to the effects of other purinergic compound in mouse gastrointestinal smooth muscle as ATP or adenosine [41][42][43], guanosine in gastric preparations did not enhance the K + channel open probability. Therefore, there will be required further investigations to define the action mechanism by which guanosine induces muscular relaxation.…”

Section: Discussionmentioning

confidence: 54%

Guanosine negatively modulates the gastric motor function in mouse

Zizzo

Mulè

Amato

et al. 2013

Purinergic Signalling

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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.

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A1 receptors mediate adenosine inhibitory effects in mouse ileum via activation of potassium channels

Cited by 17 publications

References 32 publications

Adenosine-Mediated Enteric Neuromuscular Function Is Affected during Herpes Simplex Virus Type 1 Infection of Rat Enteric Nervous System

Adenosine-Mediated Enteric Neuromuscular Function Is Affected during Herpes Simplex Virus Type 1 Infection of Rat Enteric Nervous System

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Guanosine negatively modulates the gastric motor function in mouse

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