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

Abstract

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, ...

Dysphagia: current reality and scope of the problem

“…Advances in this area found specific myenteric mechanisms of control of LES relaxation and oesophageal body peristalsis. 75,76 The main neurotransmitter mediating up to 75% of human LES relaxation in in vitro studies is nitric oxide, with a minor role for purines (through P2Y1 receptors) and vasoactive intestinal peptide 75,77 (Figure 3). In addition, circular strips from the oesophageal body respond to stimulation of enteric motor neurons with an 'on' contraction at the beginning of the stimulus and an 'off ' contraction after a latency period.…”

“…Stimulation of inhibitory neurons releasing nitric oxide modulates timing of 'on' and 'off ' contractions and controls the velocity of oesophageal body peristalsis. 75 Amplitude of these contractions is mainly mediated by acetylcholine (Ach) released from excitatory enteric motor neurons 75 and tachykinins acting on NK2 receptors. 78 Therefore, primary peristaltic contractions in the oesophageal body are always preceded by deglutitive inhibition caused by stimulation of inhibitory neurons.…”

“…81 However, our knowledge of the relationship between abnormal motor function and oesophageal dysphagia symptoms is limited, as is our understanding of the intrinsic mechanisms and neurotransmitters involved in the control of oesophageal peristalsis and LES relaxation. 75,76,82 Research into these two aspects will be critical to understand the pathophysiology of symptoms of oesophageal dysphagia and develop effective pharmacologic treatments for patients.…”

“…[96][97][98] The cause of initial injury in these The main neurotransmitter mediating 75% of LES relaxation in human in vitro studies is NO through the GC signalling pathway. 74,75,82 Studies exploring the neurotransmitters involved in the non-nitrergic relaxation of the LES also found a minor role for purines (acting through P2Y1R) responsible for 15% of this relaxation and VIP for 10%. 75 LES contraction following stimulation of motor neurons is mainly mediated by ACh acting on mA3ChR.…”

Interstitial cells of Cajal mediate nitrergic inhibitory neurotransmission in the murine gastrointestinal tract

“…In a first approach, we used murine fundus tissue, based on its mainly nitrergic inhibitory neurotransmission seen under our conditions; furthermore, the electrophysiological responses of murine fundus resemble those observed in human esophagus and lower esophageal sphincter (28). Second, colon tissue showing purinergic and nitrergic cotransmission was used for the study of more complex neuroeffector interactions.…”