Electrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum

doi:10.1016/0016-5085(95)90386-0

Gastroenterology

Volume 109, Issue 3, September 1995, Pages 789-799

https://doi.org/10.1016/0016-5085(95)90386-0 Get rights and content

Abstract

$Background & Aims$ : Achalasia is characterized by loss of myenteric neurons and incomplete relaxation of the lower esophageal sphincter (LES). The aim of this study was to develop an achalasia model in the opossum using the surfactant benzyldimethyltetradecylammonium chloride (BAC). This study further characterizes the achalasia model. $Methods$ : BAC or saline was injected circumferentially into the LES of 14 adult opossums. Eight months after injection, manometry, isolated muscle bath studies, electrical field stimulation, and histochemical analysis were performed. $Results$ : Manometrically, the LES of BAC-treated opossums showed higher pressures (38.7 ± 12 mm Hg vs. 17 ± 3.0 mm Hg) and reduced esophageal body contraction amplitudes (4.2 ± 3 mm Hg vs. 27.4 ± 12 mm Hg). Isolated muscle strips challenged with carbachol and sodium nitroprusside contracted and relaxed similarly to controls. Electrical field stimulation failed to induce relaxation in BAC-treated tissue but did induce contraction. Contractile responses were markedly reduced by tetrodotoxin and atropine in BAC-treated animals and controls. An altered nitric oxide system was shown by the lack of response to l-arginine and N^ω-nitro-l-arginine. Histology showed loss of myenteric neurons and increased cholinergic nerve bundles. $Conclusions$ : Loss of NO inhibitory myenteric neurons markedly reduces the relaxation of the LES, and histology and pharmacological responses suggest a proliferation of cholinergic nerves into the LES contributing to the static elevated pressures of the amyenteric LES.

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Citation Excerpt :
Physiologically, this likely equates inflammatory compromise or apoptosis of the postganglionic neurons controlling the LES. Herein lies the most fundamental heterogeneity among patients with achalasia; in many cases, the LES contracts vigorously after a swallow, suggesting total loss of inhibitory input with preserved cholinergic excitatory innervation, quite likely from hypertrophy of the extrinsic vagal fibers controlling the LES.98,99 In other cases, there is partial EGJ relaxation followed by contraction, suggesting an imbalance between inhibitory and excitatory modulation, and in still other cases there is no apparent deglutitive response, excitatory or inhibitory.
High-resolution manometry and recently described analysis algorithms, summarized in the Chicago Classification, have increased the recognition of achalasia. It has become apparent that the cardinal feature of achalasia, impaired lower esophageal sphincter relaxation, can occur in several disease phenotypes: without peristalsis, with premature (spastic) distal esophageal contractions, with panesophageal pressurization, or with peristalsis. Any of these phenotypes could indicate achalasia; however, without a disease-specific biomarker, no manometric pattern is absolutely specific. Laboratory studies indicate that achalasia is an autoimmune disease in which esophageal myenteric neurons are attacked in a cell-mediated and antibody-mediated immune response against an uncertain antigen. This autoimmune response could be related to infection of genetically predisposed subjects with herpes simplex virus 1, although there is substantial heterogeneity among patients. At one end of the spectrum is complete aganglionosis in patients with end-stage or fulminant disease. At the opposite extreme is type III (spastic) achalasia, which has no demonstrated neuronal loss but only impaired inhibitory postganglionic neuron function; it is often associated with accentuated contractility and could be mediated by cytokine-induced alterations in gene expression. Distinct from these extremes is progressive plexopathy, which likely arises from achalasia with preserved peristalsis and then develops into type II achalasia and then type I achalasia. Variations in its extent and rate of progression are likely related to the intensity of the cytotoxic T-cell assault on the myenteric plexus. Moving forward, we need to integrate the knowledge we have gained into treatment paradigms that are specific for individual phenotypes of achalasia and away from the one-size-fits-all approach.
Application of the newly developed stents in the treatment of benign cardia stricture: An experimental comparative study
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Citation Excerpt :
All protocols were approved by the animal research committee of our institution and were conducted in accordance with the guidelines of the International Council on Animal Care. Forty-eight beagle dogs of both sexes that were 8 months old and weighed between 14 and 20 kg had benzyl-dimethyltetradecylammonium chloride (BAC, 4 mmol/L, 12 mL) injected circumferentially into the LES to cause a benign cardia stricture.12,13 The dogs were randomized into a control group (n = 12), a pneumatic dilation group (PDG, n = 12), a standard esophageal stent group (SESG, n = 12), and a novel cardia stent group (NCSG, n = 12).
Retrievable temporary stent placement has recently been suggested as a potential treatment for benign esophageal stricture.
To assess the efficacy of a newly designed cardia stent for the treatment of benign cardia stricture in a canine model compared with groups that received pneumatic dilation or standard esophageal stent insertion.
Basic experimental study.
GI interventional center.
Forty-eight dog models were randomly divided into a control group (no stent insertion) (n = 12), a pneumatic dilation group (PDG) (n = 12), a standard esophageal stent group (SESG) (n = 12), and a novel cardia stent group (NCSG) (n = 12).
Pneumatic dilation, standard esophagus stent, cardia stent.
Lower esophageal sphincter pressures and the 5-minute barium height were assessed before and immediately after the procedure, after 1 week, and at 1-, 3-, and 6-month follow-up. Three dogs in each group were killed for histological examination.
Stent insertion was tolerated by all dogs, with a lower migration rate in the NCSG (0% vs 41.7% in the SESG; P = .0373). At the 6-month follow-up, the lower esophageal sphincter pressure and 5-minute barium height values in the NCSG were still stable compared with those in the PDG and SESG (P < .05). Immunohistochemistry for mouse anti–proliferating cell nuclear antigen and α-smooth muscle actin revealed a stronger inflammatory reaction peak in the PDG than in the SESG and NCSG (P < .05). Collagen proliferation was most severe after 6 months in the PDG (P < .05).
Longer follow-up studies are required to assess whether the recurrence rate is lower because of less inflammation and scarring.
The novel cardia stent was more effective than pneumatic dilation or a standard stent in this canine model.
Etiology and pathogenesis of achalasia
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The primary pathophysiologic abnormality in achalasia is loss of intrinsic inhibitory innervation of the lower esophageal sphincter and smooth muscle segment of the esophageal body. Disease of the extrinsic (vagal) nervous system and esophageal musculature may also be present, but these are less consistent findings and could represent secondary phenomena. Inflammation within the esophageal myenteric plexus is pathognomonic of the disease, but the cause of this inflammation is uncertain. Autoimmunity and previous viral infection have been hypothesized, but remain unproven.
Lower esophageal sphincter is achalasic in nNOS<sup>-/-</sup> and hypotensive in W/W<sup>v</sup> mutant mice
2001, Gastroenterology
$Background & Aims:$ It has been proposed that nitrergic nerves mediate lower esophageal sphincter (LES) relaxation with intramuscular interstitial cells of Cajal (ICC-IM) as an intermediary. Dysfunction of the nitrergic pathway has been shown to cause LES hypertension and impaired relaxation in achalasia. We determined whether mice with neuronal nitric oxide synthase gene disruption (nNOS^−/−) and W/W^v mice lacking ICC-IM have achalasia-like LES dysfunction. $Methods:$ Intraluminal manometry using a customized micro-sized catheter assembly was performed in anesthetized mice. Basal LES pressure and swallow- and vagal-evoked LES relaxations were quantified in wild-type, Nω-nitro-l-arginine methyl ester HCl salt (l-NAME)-treated, nNOS^−/−, and W/W^v mice. $Results:$ Wild-type mouse LES maintained a basal pressure (24 ± 3 mm Hg; N = 8) and relaxed normally to swallow (87% ± 3%; N = 8) and vagal stimulation (91% ± 4% mm Hg; N = 6). Pretreatment with l-NAME (100 mg/kg, intravenously) attenuated LES relaxation to both stimuli (P < 0.05). The LES in nNOS^−/− was significantly hypertensive (36 ± 5 mm Hg; N = 10; P < 0.05) with a markedly impaired relaxation (P < 0.05). In contrast, W/W^v mouse LES was significantly hypotensive (11 ± 2 mm Hg; N = 6; P < 0.05) with normal relaxation that was blocked by l-NAME. $Conclusions:$ nNOS^−/− mice have LES hypertension with impaired relaxation resembling achalasia. In contrast, W/W^v mice have hypotensive LES with unimpaired relaxation, suggesting that ICC-IM do not play a role in nitrergic neurotransmission.
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2019, Canadian Journal of Gastroenterology and Hepatology
Achalasia: from diagnosis to management
2016, Annals of the New York Academy of Sciences

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^☆: Supported by the VA Merit Award; American Federation for Aging Research; Madison VA Geriatric Research, Education and Clinical Center; and National Institutes of Health-Binational Science Foundation.

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Alimentary tractElectrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum☆

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Fundam Appl Toxicol

Gastroenterology

Gastroenterology

Gastroenterology

Esophageal motility

Motor functions of the pharynx and esophagus

Nitric oxide as a mediator of nonadrenergic noncholinergic neurotransmission

Am J Physiol

Neuromedin B receptor in esophagus: evidence for subtypes of bombesin receptors

Am J Physiol

Nitric oxide as a putative nonadrenergic noncholinergic inhibitory transmitter in the canine pylorus in vivo

Am J Physiol

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by nonadrenergic inhibitory nerves in the gut

Br J Pharmacol

What's new in the esophagus

Dig Dis Sci

The spectrum of manometric abnormalities in achalasia

Endosc Rev

Gastroesophageal sphincter pressure and histological changes in distal esophagus in patients with achalasia of the esophagus

Dig Dis Sci

Achalasia of the esophagus: pathologic and etiologic considerations

Ann Surg

Fine-structure changes in achalsia of the esophagus: II. Esophageal smooth muscle

Am J Pathol

Selective loss of nitrinergic and CGRP innervation in esophageal achalasia

J Gastrointest Motil

Alimentary tract
Electrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum☆