Site of action of GABAB receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats

McDermott, Catherine; Abrahams, T.; Partosoedarso, Elita R.; Hyland, Niall P.; Ekstrand, J.; Monroe, Michael J; Hornby, Pamela J.

doi:10.1053/gast.2001.24849

Cited by 50 publications

(40 citation statements)

References 34 publications

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“…The involvement of GABA B R in the inhibition of transient LES relaxations is attributed to activation of GABA B R present in the dorsal vagal complex (10,11), vagal mechanosensitive afferent neurons (11 -13), and vagal motor neurons innervating LES (14). In ferret LES, baclofen has been shown to reduce vagal output at two peripheral sites, presynapti- Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the compound has been proposed to be useful as a therapeutic agent for the management of reflux disease (9). The mechanism underlying the effect of GABA B R agonist has been proposed based on functional studies showing that involvement of GABA B R in transient LES relaxations is attributed to the presence of GABA B R in the dorsal vagal complex (10,11), vagal mechanosensitive afferent neurons (11 -13), and vagal motor neurons innervating the LES (14). However, it is not known if GABA B R is present in the LES itself; therefore it remains to be determined whether the GABA B R agonists act at the central nervous system and/or the level of the periphery.…”

Section: Introductionmentioning

confidence: 99%

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Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

et al. 2009

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Abstract. Baclofen, a GABA B -receptor (GABA B R) agonist has been proposed to be useful as therapeutic agent for the management of gastro-esophageal reflux disease, but whether the compound acts directly at the lower esophageal sphincter (LES) remains to be elucidated. We performed the present study to assess the presence of GABA B R in human LES. Western blot analysis showed that both proteins of GABA B1(a) /GABA B1(b) and GABA B2 subunits were present in the muscle layer of LES. Immunohistochemical findings showed that both GABA B1 -and GABA B2 -subunit proteins were located on the neurons within the myenteric plexus, and furthermore, both proteins were observed in the same neurons. Reverse transcriptase-polymerase chain reaction analysis also revealed the presence of mRNAs for both subunits of GABA B R and also mRNAs for 6 isoforms of GABA B1 subunits, from GABA B1(a) to GABA B1(g) , except GABA B1(d) , in human LES. Thus, the functional GABA B R-forming heterodimers with subunits of GABA B1 and GABA B2 are located on the myenteric neurons in human LES, suggesting that GABA B R agonists and antagonists act at least, at the level of the peripheral nervous system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

et al. 2009

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“…It inhibits the gastric distension-mediated mechanoreceptor activity and vagal afferent discharge (25). GABA B receptors are present in the DMV complex and may have a central site of action, thus influencing the efferent discharges to the LES (19,26). GABA B may also reduce the peripheral preganglionic discharges that mediate LES relaxation (4).…”

Section: Discussionmentioning

confidence: 99%

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats

Liu

Pehlivanov

Mittal

2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Recent studies indicate that baclofen decreases the frequency of TLESR; however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of their EMG activity, respectively. One week after the surgery, animals were lightly sedated and recordings were performed using a manometry catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 mol/kg iv) on the graded esophageal distension and gastric distension-induced LES and crural diaphragm responses were studied. Distension of the esophagus and stomach induces relaxation of the LES and inhibition of the crural diaphragm, simultaneously. Baclofen blocks both the esophageal and the gastric distension-induced relaxation of the LES and inhibition of the crural diaphragm. The magnitude of response to baclofen was significantly larger for the crural diaphragm inhibition than for the LES relaxation. Baclofen, a GABAB receptor agonist, blocks the reflex inhibitory pathway to the LES and crural diaphragm. The reflex inhibitory pathway to the crural diaphragm is more sensitive to blockade by baclofen than the reflex LES inhibitory pathway. transient lower esophageal sphincter relaxation; gastroesophageal reflux; crural diaphragm; GABAB agonist TRANSIENT LOWER ESOPHAGEAL sphincter (LES) relaxation (TLESR) is the major mechanism of gastroesophageal reflux in normal subjects and patients with reflux disease (8, 23). Recent studies in animals and humans reveal that baclofen, a GABA B agonist, inhibits TLESR (3,11,13,28). Studies (10) documenting the blockade of TLESR by baclofen used the LES relaxation criteria to identify TLESR. During TLESR, along with LES, there is also inhibition of the other major component of the antireflux barrier, i.e., the crural diaphragm (21). Distension of the stomach in dogs induces TLESR, which is also associated with inhibition of the crural diaphragm (17). Simultaneous relaxation of the LES and inhibition of crural diaphragm also occurs during distension of the esophagus in cats (1). The effect of baclofen on the crural diaphragm inhibition during TLESR and esophageal distension is not known. The goals of our study were twofold: 1) to determine the effects of baclofen on the gastric distension-mediated LES relaxation and crural diaphragm inhibition, the two important components of the TLESR, and 2) to determine the effects of baclofen on the esophageal distension-mediated relaxation of the LES and inhibition of the crural diaphragm. MATERIALS AND METHODS Diaphragm electrodes implantation.These studies were conducted in five female adult cats, weighing between 3 and 3.7 kg. The protocol for the study was approved by The Animal Ethics Committee of the University of California, San Diego, and San Diego Veterans Affairs Hospital. Under general anesthesia induced by xylazine (1.5 m...

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“…1 GABA B receptors are present in the nucleus tractus solitarius and in the dorsal motor nucleus of the vagus, which are known as centres that integrate the afferent preganglionic signal arising from gastric tension mechanoreceptors 2 and the lower oesophageal sphincter (LOS). 3 Physiology and pharmacology studies in animals have shown that activation of GABA receptors with the GABA B agonist baclofen inhibits transient LOS relaxation, gastro-oesophageal reflux, 4 5 and gastric secretion. 6 In normal human subjects and in patients with gastro-oesophageal reflux disease (GORD), recent studies have shown that baclofen reduces the rate of transient lower oesophageal sphincter relaxations (TLOSR), the rate of gastro-oesophageal acid reflux episodes, and increases basal LOS pressure.…”

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confidence: 99%

Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

Ciccaglione

2003

Gut

151

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Site of action of GABAB receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats

Cited by 50 publications

References 34 publications

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats

Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

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