tetrodotoxin and Esophageal-Achalasia

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.. 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.. 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 omega-nitro-L-arginine. Histology showed loss of myenteric neurons and increased cholinergic nerve bundles.. 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.

Topics: Analysis of Variance; Animals; Arginine; Atropine; Benzalkonium Compounds; Cholinergic Fibers; Denervation; Disease Models, Animal; Electric Stimulation; Electrophysiology; Esophageal Achalasia; Esophagogastric Junction; Female; In Vitro Techniques; Male; Manometry; Muscle Contraction; Muscle Relaxation; Myenteric Plexus; Neurons; Nitric Oxide; Opossums; Pressure; Tetrodotoxin

The functional postganglionic innervation of isolated smooth muscle strips from the oesophagogastric junction was examined in specimens taken from six achalasia patients and seven controls. Muscle strips representing either the longitudinal or the circular layer were prepared and mounted in organ baths and isometric tension was recorded. Electrical field stimulation, selectively exciting nerves, was applied. Strips from the circular layer from controls relaxed during field stimulation, an effect that was the result of stimulation of noncholinergic, non-adrenergic, inhibitory nerves. Circular muscle strips from achalasia patients contracted during field stimulation, an effect that was caused by muscarinic receptor activation. In one patient, atropine reversed the contraction to a relaxation. Longitudinal muscle strips contracted in response to stimulation in both controls and achalasia patients. This response was abolished by atropine. In conclusion the function of postganglionic inhibitory nerve fibres to the circular layer of the oesophagogastric junction is severely impaired in achalasia, while there is a conspicuous, functional cholinergic innervation.

Topics: Adolescent; Adult; Aged; Atropine; Electric Stimulation; Esophageal Achalasia; Esophagogastric Junction; Female; Humans; Male; Middle Aged; Models, Biological; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nerve Fibers; Organ Culture Techniques; Papaverine; Tetrodotoxin