P2 purinoceptor antagonists inhibit the non-adrenergic, non-cholinergic relaxation of the human colon in vitro

Benkó, Rita; Undi, Sarolta; Wolf, Matyas; Vereczkei, András; Illényi, L; Kassai, Miklós; Cseke, László; Kelemen, Dezső; Horváth, Örs Péter; Antal, A; Magyar, Klara; Barthó, L.

doi:10.1016/j.neuroscience.2007.04.016

Cited by 14 publications

(18 citation statements)

References 49 publications

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“…We cannot find any obvious reason for this discrepancy. Another surprising finding of the present series of experiments was that a combination of PPADS and suramin, a treatment that was effective in reducing the NANC relaxation in the human colonic circular muscle under similar conditions (Benko et al 2007), failed to inhibit that in the small intestine. Further studies are clearly needed to compare the purinoceptor antagonist spectra of MRS 2179 and the PPADS + suramin combination.…”

Section: Discussionmentioning

confidence: 55%

“…A combination of the P 2 purinoceptor antagonists PPADS (50 μM) and suramin (100 μM) was used in the experiments of Undi et al (2006) and Benko et al (2007) for studying a participation of purinergic mechanisms in the NANC relaxation of the CM of the human ileum and sigmoid colon, respectively. This combination of antagonists was more effective than either substance alone.…”

Section: Introductionmentioning

confidence: 99%

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The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

et al. 2009

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

et al. 2009

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“…(5,31). However, 2Ј-deoxy-N 6 -methyl adenosine 3Ј,5Ј-diphosphate tetraammonium salt (MRS 2179), which is the N 6 -methyl modification of 2Ј-deoxyadenosine 3Ј,5Ј-bisphosphate, is a potent P2Y 1 receptor antagonist (8) and is presently considered competitive and specific (1,19).…”

mentioning

confidence: 99%

Purinergic and nitrergic junction potential in the human colon

Gallego

Gil²,

Aleu³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

120

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The aim of the present work is to investigate a putative junction transmission [nitric oxide (NO) and ATP] in the human colon and to characterize the electrophysiological and mechanical responses that might explain different functions from both neurotransmitters. Muscle bath and microelectrode techniques were performed on human colonic circular muscle strips. The NO donor sodium nitroprusside (10 M), but not the P2Y receptor agonist adenosine 5Ј-O-2-thiodiphosphate (10 M), was able to cause a sustained relaxation. N G -nitro-L-arginine (L-NNA) (1 mM), a NO synthase inhibitor, but not 2Ј-deoxy-N 6 -methyl adenosine 3Ј,5Ј-diphosphate tetraammonium salt (MRS 2179) (10 M), a P2Y antagonist, increased spontaneous motility. Electrical field stimulation (EFS) at 1 Hz caused fast inhibitory junction potentials (fIJPs) and a relaxation sensitive to MRS 2179 (10 M). EFS at higher frequencies (5 Hz) showed biphasic IJP with fast hyperpolarization sensitive to MRS 2179 followed by sustained hyperpolarization sensitive to L-NNA; both drugs were needed to fully block the EFS relaxation at 2 and 5 Hz. Two consecutive single pulses induced MRS 2179-sensitive fIJPs that showed a rundown. The rundown mechanism was not dependent on the degree of hyperpolarization and was present after incubation with L-NNA (1 mM), hexamethonium (100 M), MRS 2179 (1 M), and NF023 (10 M). We concluded that single pulses elicit ATP release from enteric motor neurons that cause a fIJP and a transient relaxation that is difficult to maintain over time; also, NO is released at higher frequencies causing a sustained hyperpolarization and relaxation. These differences might be responsible for complementary mechanisms of relaxation being phasic (ATP) and tonic (NO).ATP; IJP; smooth muscle; rundown; purinergic receptors THE IDENTITY OF THE INHIBITORY neurotransmitter(s) involved in nonadrenergic, noncholinergic (NANC) inhibitory neurotransmission is still being debated, but ATP and nitric oxide (NO) are presently recognized as two of the major inhibitory mediators in the gastrointestinal (GI) tract. Nitrergic neurons mediate lower esophageal sphincter relaxation after swallowing (34), and vagally induced gastric (11) and pyloric (2) relaxation regulate colonic transit time (26) and mediate the rectoanal inhibitory reflex (28). Fewer studies have been published on the putative role of ATP as a neurotransmitter mediating these physiological functions. ATP and NO might participate in the regulation of gastroduodenal motility in rats, (17) and ATP might participate in vagally induced gastric relaxation (4) and intrinsic gastric adaptive relaxation in mice (12). These (and other) data suggest that these neurotransmitters have important physiological functions; however, smooth muscle relaxation might have different properties (i.e., tonic vs. phasic) that should be better characterized. The release of inhibitory neurotransmitter(s) at the neuromuscular junction is the final step for smooth muscle relaxation. Inhibitory junction potentials (IJPs) have been well c...

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“…Inhibitory neuromuscular transmitters in the enteric nervous system (ENS) include nitric oxide (NO)(He et al, 1993; Osthaus and Galligan, 1992; Sanders et al, 1992; Smits and Lefebvre, 1996) and one or more purinergic neurotransmitters (Burnstock, 2008; Crist et al, 1992; Durin et al, 2014; Huang et al, 2001; Mutafova-Yambolieva and Durin, 2014; Mutafova-Yambolieva et al, 2007; Smits and Lefebvre, 1996). The purinergic neurotransmitter acts at P2Y 1 receptors on GI smooth muscle (Benko et al, 2007; De Man et al, 2003; Gallego et al, 2006; Wang et al, 2007) and PDGF-α positive fibroblast-like cells (Kurashi et al, 2011, 2014). P2Y 1 receptors link to Ca 2+ release from intracellular stores and P2Y 1 receptor activation causes fast inhibitory junction potentials (IJPs) and relaxation (Benko et al, 2007; Gallego et al, 2006; Wang et al, 2007; Zhang et al, 2010).…”

mentioning

confidence: 99%

“…The purinergic neurotransmitter acts at P2Y 1 receptors on GI smooth muscle (Benko et al, 2007; De Man et al, 2003; Gallego et al, 2006; Wang et al, 2007) and PDGF-α positive fibroblast-like cells (Kurashi et al, 2011, 2014). P2Y 1 receptors link to Ca 2+ release from intracellular stores and P2Y 1 receptor activation causes fast inhibitory junction potentials (IJPs) and relaxation (Benko et al, 2007; Gallego et al, 2006; Wang et al, 2007; Zhang et al, 2010). IJPs result from Ca 2+ -induced activation of apamin-sensitive small-conductance Ca 2+ -dependent K + channels (SK channels)(Crist et al, 1992; Pascuad et al, 1996; Wang et al, 2007; Zhang et al, 2010).…”

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confidence: 99%

R‐Type Ca²⁺ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea‐pig ileum

Rodriguez‐Tapia

Naidoo

DeVries

et al. 2017

Experimental Physiology

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There is evidence that R-type Ca2+ channels contribute to synaptic transmission in the myenteric plexus. It is unknown if R-type Ca2+ channels contribute to neuromuscular transmission. We measured the effects of the nitric oxide synthase (NOS) inhibitor, nitro L-arginine (NLA), Ca2+ channel blockers and apamin (SK channel blocker) on neurogenic relaxations and contractions of the guinea pig ileum longitudinal muscle-myenteric plexus (LMMP) in vitro. We used intracellular recordings to measure inhibitory junction potentials (IJPs). Immunohistochemical and western blot techniques localized R-type Ca2+ channel protein in the LMMP and circular muscle. CdCl2 (pan Ca2+ channel blocker) blocked and NLA and NiCl2 (R-type Ca2+ channel blocker) reduced neurogenic relaxations in a non-additive manner. NiCl2 did not alter neurogenic cholinergic contractions but it potentiated neurogenic non-cholinergic contractions. Relaxations were inhibited by apamin, NiCl2 and NLA and were blocked by combined application of these drugs. Relaxations were reduced by NiCl2 or ω-conotoxin (ω-CTX, N-type Ca2+ channel blocker) and were blocked by combined application of these drugs. Longitudinal muscle IJPs were inhibited by NiCl2, but not MRS 2179 (P2Y1 receptor antagonist). Circular muscle IJPs were blocked by apamin, MRS 2179, ω-CTX and CdCl2 but not NiCl2. We conclude that neuronal R-type Ca2+ channels contribute to inhibitory neurotransmission to longitudinal muscle but less so or not all in the circular muscle of the guinea pig ileum.

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P2 purinoceptor antagonists inhibit the non-adrenergic, non-cholinergic relaxation of the human colon in vitro

Cited by 14 publications

References 49 publications

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

Purinergic and nitrergic junction potential in the human colon

R‐Type Ca²⁺ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea‐pig ileum

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P2 purinoceptor antagonists inhibit the non-adrenergic, non-cholinergic relaxation of the human colon in vitro

Cited by 14 publications

References 49 publications

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

Purinergic and nitrergic junction potential in the human colon

R‐Type Ca2+ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea‐pig ileum

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R‐Type Ca²⁺ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea‐pig ileum