Electrophysiological Properties of Inhibitory Junction Potential in Murine Lower Oesophageal Sphincter.

Imaeda, Kazuo; Cunnane, T.C.

doi:10.1540/jsmr.39.119

Cited by 12 publications

(13 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results on pigs show that maximal EFS relaxation was inhibited to the same degree by L-NAME and ODQ (by 60%) and that apamin fully blocked the EFS induced relaxation resistant to nitric oxide inhibition in both series of experiments. The apamin-sensitive component has been indirectly attributed to ATP in previous studies (Imaeda and Cunnane, 2003). We found that the apamin-sensitive component of EFS relaxation is strongly inhibited by MRS 2179, showing that a purine mediates this component by acting on P2Y 1 receptors; it is slightly but consistently inhibited by NF 279, also suggesting the involvement of P2X 1,2,3 receptors; and it is slightly inhibited by the peptidase chymotrypsin, suggesting that PACAP (an apamin-sensitive peptidergic neurotransmitters) also has a minor role in EFS-induced relaxation.…”

Section: Discussionmentioning

confidence: 91%

“…Colocalization of these neurotransmitters and/or their synthesizing enzymes on inhibitory enteric motor neurons of the upper gastrointestinal tract including LES has been described by immunohistological and other morphological studies (Ny et al, 1994(Ny et al, , 1995aUc et al, 1997;Werkstrom et al, 1997). Physiological and pharmacological studies have demonstrated the direct effects or characterized the actions of these neurotransmitters after stimulation of inhibitory LES motor neurons (Ny et al, 1995bUc et al, 1997;Yuan et al, 1998;Imaeda and Cunnane, 2003). However, evidence suggests that nitric oxide from neural sources is the major contributor to LES relaxation (Murray et al, 1991;Tottrup et al, 1991;Gonzalez et al, 2004), and the relative physiological contribution of other neurotransmitters remains unclear.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacologic Characterization of Intrinsic Mechanisms Controlling Tone and Relaxation of Porcine Lower Esophageal Sphincter

Farré

Aulí

Lecea

et al. 2005

J Pharmacol Exp Ther

104

View full text Add to dashboard Cite

The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 M), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 M), ATP (10 M-30 mM), and tricarbonyldichlororuthenum dimer (1 M-1 mM) was unaffected by tetrodotoxin (1 M) or L-N G -nitroarginine methyl ester (L-NAME; 100 M). Calcitonin gene-related peptide (CGRP; 1 nM-1 M) did not affect LES tone. ATP relaxation was blocked by 1 M apamin and the P2Y 1 antagonist MRS 2179 (N 6 -methyl 2Ј-deoxyadenosine 3Ј,5Ј-bisphosphate; 10 M). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml ␣-chymotrypsin. L-NAME (Ϫ62.52 Ϯ 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-␣]quinoxalin-1-one (ODQ; 10 M, Ϫ67.67 Ϯ 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 M) was inhibited by L-NAME (Ϫ60.37 Ϯ 10.8%) and ODQ (Ϫ41.90 Ϯ 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by ␣-chymotrypsin and the P2X 1,2,3 receptor antagonist NF 279 (8,8¢-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 M), and unaffected by tin protoporphyrin IX (100 M). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y 1 receptors and a minor contribution of purinergic P2X 1,2,3 receptors and PACAP. Nitrergic and purinergic cotransmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.The lower esophageal sphincter (LES) acts as a barrier at the gastroesophageal junction (GEJ). Basal tone of LES is primarily myogenic in origin and is modulated by a combination of hormonal factors and neurogenic mechanisms that involve local enteric motor neurons and extrinsic nerves and are not yet fully understood. Nonadrenergic, noncholinergic enteric motor neurons are the final step in the inhibitory vagal pathway to LES, allowing swallowing-induced and transient LES relaxation that causes physiologic gastroesophageal reflux and belching (Chang et al., 2003). Vasoactive intestinal peptide (VIP), nitric oxide, ATP, pituitary adenylate cyclase-activating peptide (PACAP), carbon monoxide, and calcitonin gene-related peptide (CGRP) have been

show abstract

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Pharmacologic Characterization of Intrinsic Mechanisms Controlling Tone and Relaxation of Porcine Lower Esophageal Sphincter

Farré

Aulí

Lecea

et al. 2005

J Pharmacol Exp Ther

104

View full text Add to dashboard Cite

show abstract

“…The fast component presents a rundown, whereas the slow component can be sustained (10). In the clasp region of the mouse (14,41), IJP also has a fast component partly antagonized by apamin, followed by a slow sustained nitrergic component. In the present study, we could not record a biphasic IJP, and the response in strips obtained from both the EB and the clasp and sling regions in the LES showed only a slow component with a small amplitude (5-6 mV), which was L-NNA sensitive and could be sustained under repetitive stimulation.…”

Section: Discussionmentioning

confidence: 98%

Regional functional specialization and inhibitory nitrergic and nonnitrergic coneurotransmission in the human esophagus

Lecea

Gallego

Farré

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Lecea B, Gallego D, Farré R, Opazo A, Aulí M, Jiménez M, Clavé P. Regional functional specialization and inhibitory nitrergic and nonnitrergic coneurotransmission in the human esophagus. Am J Physiol Gastrointest Liver Physiol 300: G782-G794, 2011. First published February 17, 2011 doi:10.1152/ajpgi.00514.2009.-The aim of this study was to explore the myenteric mechanisms of control of human esophageal motility and the effect of nitrergic and nonnitrergic neurotransmitters. Human circular esophageal strips were studied in organ baths and with microelectrodes. Responses following electrical field stimulation (EFS) of enteric motoneurons (EMNs) or through nicotinic acetylcholine receptors were compared in the esophageal body (EB) and in clasp and sling regions in the lower esophageal sphincter (LES). In clasp LES strips: 1) sodium nitroprusside (1 nM to 100 M), adenosine-5=-[␤-thio]diphosphate trilithium salt (1-100 M), and vasoactive intestinal peptide (1 nM to 1 M) caused a relaxation; 2) 1 mM N -nitro-L-arginine (L-NNA) shifted the EFS "on"-relaxation to an "off"-relaxation, partly antagonized by 10 M 2=-deoxy-N 6 -methyladenosine 3=,5=-bisphosphate tetrasodium salt (MRS2179) or 10 U/ml ␣-chymotrypsin; and 3) nicotine-relaxation (100 M) was mainly antagonized by L-NNA, and only partly by MRS2179 or ␣-chymotrypsin. In sling LES fibers, EFS and nicotine relaxation was abolished by L-NNA. In the EB, L-NNA blocked the latency period, and MRS2179 reduced "off"-contraction. The amplitude of cholinergic contraction decreased from the EB to both LES sides. EFS induced a monophasic inhibitory junction potential in clasp, sling, and EB fibers abolished by L-NNA. Our study shows a regional specialization to stimulation of EMNs in the human esophagus, with stronger inhibitory responses in clasp LES fibers and stronger cholinergic excitatory responses in the EB. Inhibitory responses are mainly triggered by nitrergic EMNs mediating the inhibitory junction potentials in the LES and EB, EFS on-relaxation in clasp and sling LES sides, and latency in the EB. We also found a minor role for purines (through P2Y1 receptors) and vasoactive intestinal peptide-mediating part of nonnitrergic clasp LES relaxation. lower esophageal sphincter; esophageal body; inhibitory motoneurons; inhibitory coneurotransmission THE MAIN PHYSIOLOGICAL FUNCTION of the lower esophageal sphincter (LES) is to generate a zone of high pressure that prevents the reflux of acid gastric content into the esophagus. LES relaxations occur briefly after swallowing, and transient LES relaxations cause physiological gastroesophageal reflux and allow belching. Enteric motoneurons (EMNs) are the final step in the inhibitory vagal pathway to the LES, mediating swallow-induced and transient LES relaxation (3). Nitric oxide (NO) released from these inhibitory EMNs is the major contributor to LES relaxation in humans (12) and opossums (20, 33). However, vasoactive intestinal peptide (VIP) and ATP are putative inhibitory neurotransmitters in animal studies (14, 21-24, 34, ...

show abstract

“…Furthermore, these two muscles demonstrate differences in resting membrane potential, voltage-gated K ϩ and Ca 2ϩ channel current densities, and calcium handling (28, 29, 43). These differences provide for the likelihood that neural mediation of relaxation as well as maintenance of resting tone would also differ in sling and circular muscles.The inhibitory neurotransmitter nitric oxide (NO) relaxes the circular muscle in virtually all species studied (7,16,31,39,48,(52)(53)(54). There is little or no evidence that the sling muscle is innervated by or responsive to nitrergic influence.…”

mentioning

confidence: 99%

“…The inhibitory neurotransmitter nitric oxide (NO) relaxes the circular muscle in virtually all species studied (7,16,31,39,48,(52)(53)(54). There is little or no evidence that the sling muscle is innervated by or responsive to nitrergic influence.…”

mentioning

confidence: 99%

Feline lower esophageal sphincter sling and circular muscles have different functional inhibitory neuronal responses

L’Heureux¹,

Muinuddin²,

Gaisano³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

The lower esophageal sphincter (LES) has a circular muscle component exhibiting spontaneous tone that is relaxed by nitric oxide (NO) and a low-tone sling muscle that contracts vigorously to cholinergic stimulation but with little or no evidence of NO responsiveness. This study dissected the responses of the sling muscle to nitrergic innervation in relationship to its cholinergic innervation and circular muscle responses. Motor responses were induced by electrical field stimulation (EFS; 1-30 Hz) of muscle strips from sling and circular regions of the feline LES in the presence of cholinergic receptor inhibition (atropine) or NO synthase inhibition [NG-nitro-L-arginine (L-NNA)+/-atropine]. This study showed the following. First, sling muscle developed less intrinsic resting tone compared with circular muscle. Second, with EFS, sling muscle contracted (most at 50% by 5 Hz. Third, on neural blockade with atropine or L-NNA+/-atropine, 1) sling muscle, although predominantly influenced by excitatory cholinergic stimulation, had a small neural NO-mediated inhibition, with no significant non-NO-mediated inhibition and 2) circular muscle, although little affected by cholinergic influence, underwent relaxation predominantly by neural release of NO and some non-NO inhibitory influence (at higher EFS frequency). Fourth, the sling, precontracted with bethanecol, could relax with NO and some non-NO inhibition. Finally, the tension range of both muscles is similar. In conclusion, sling muscle has limited NO-mediated inhibition to potentially augment or replace sling relaxation effected by switching off its cholinergic excitation. Differences within the LES sling and circular muscles could provide new directions for therapy of LES disorders.

show abstract

Electrophysiological Properties of Inhibitory Junction Potential in Murine Lower Oesophageal Sphincter.

Cited by 12 publications

References 23 publications

Pharmacologic Characterization of Intrinsic Mechanisms Controlling Tone and Relaxation of Porcine Lower Esophageal Sphincter

Pharmacologic Characterization of Intrinsic Mechanisms Controlling Tone and Relaxation of Porcine Lower Esophageal Sphincter

Regional functional specialization and inhibitory nitrergic and nonnitrergic coneurotransmission in the human esophagus

Feline lower esophageal sphincter sling and circular muscles have different functional inhibitory neuronal responses

Contact Info

Product

Resources

About