ABSTRACT
To compare the gastroesophageal junction of the human with the pig, M(2) and M(3) receptor densities and the potencies of M(2) and M(3) muscarinic receptor subtype selective antagonists were determined in gastric clasp and sling smooth muscle fibers. Total muscarinic and M(2) receptors are higher in pig than human clasp and sling fibers. M(3) receptors are higher in human compared with pig sling fibers but lower in human compared with pig clasp fibers. Clasp fibers have fewer M(3) receptors than sling fibers in both humans and pigs. Similar to human clasp fibers, pig clasp fibers contract significantly less than pig sling fibers. Analysis of the methoctramine Schild plot suggests that M(2) receptors are involved in mediating contraction in pig clasp and sling fibers. Darifenacin potency suggests that M(3) receptors mediate contraction in pig sling fibers and that M(2) and M(3) receptors mediate contraction in pig clasp fibers. Taken together, the data suggest that both M(2) and M(3) muscarinic receptors mediate the contraction in both pig clasp and sling fibers similar to human clasp and sling fibers.
Subject(s)
Esophagogastric Junction/physiology , Muscle Contraction/physiology , Muscle, Smooth/physiology , Receptor, Muscarinic M2/metabolism , Receptor, Muscarinic M3/metabolism , Animals , Benzofurans/pharmacology , Carbachol/pharmacology , Diamines/pharmacology , Dose-Response Relationship, Drug , Esophagogastric Junction/drug effects , Humans , Isometric Contraction/drug effects , Isometric Contraction/physiology , Muscarinic Antagonists/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Pyrrolidines/pharmacology , Receptor, Muscarinic M2/antagonists & inhibitors , Receptor, Muscarinic M3/antagonists & inhibitors , Sus scrofaABSTRACT
BACKGROUND: There is no simple method to measure intravariceal pressure in patients with esophageal varices. OBJECTIVE: Our purpose was to develop a new noninvasive technique to measure resting intravariceal pressure and wall tension. DESIGN: A model was developed. A long balloon (varix) was fitted inside an airtight cylinder (esophagus). Fluid ran through the model varices to maintain 5 different constant pressures. An endoscope was placed in the model esophagus, and pressure was increased by air insufflation. The endoscopy and pressure readings from the esophagus and varix were recorded continuously until variceal collapse. SETTING: Patient studies were done in an endoscopy suite with the patient under fentanyl and midazolam sedation. PATIENTS: Esophageal pressure was measured during air insufflation in patients with varices until the varices collapsed. EUS was used to measure radius and wall thickness to calculate wall tension. RESULTS: In the varix model, the mean (SD) intraluminal esophageal pressures at variceal flattening for the model varices at 5, 10, 15, 20, and 25 mm Hg were 5.69 (0.34), 11 (0.32), 15.72 (0.51), 21.55 (0.63), and 25.8 (0.14) mm Hg. The correlation between actual and measured variceal pressure in the model at variceal flattening was r = 0.98. In the patients, a total of 10 varices in 3 patients were evaluated. The mean (SD) for the varices in each subject was 12.16 (2.4), 23.2 (1.3), and 6.5 (2.2) mm Hg for subjects 1, 2, and 3, respectively. CONCLUSION: Standard endoscopy with air insufflation and manometry can be used as an accurate, simple, and reproducible method to measure intravariceal pressure.
Subject(s)
Esophageal and Gastric Varices/diagnosis , Esophagoscopy/methods , Manometry/methods , Signal Processing, Computer-Assisted , Endosonography/methods , Esophageal and Gastric Varices/complications , Esophagus/blood supply , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/prevention & control , Humans , Insufflation , Male , Middle Aged , Models, Theoretical , Muscle, Smooth, Vascular/physiology , Pressure , Risk Assessment , Sensitivity and Specificity , Tensile Strength , Video RecordingABSTRACT
Although muscarinic receptors are known to mediate tonic contraction of human gastrointestinal tract smooth muscle, the receptor subtypes that mediate the tonic contractions are not entirely clear. Whole human stomachs with attached esophagus were procured from organ transplant donors. Cholinergic contractile responses of clasp, sling, lower esophageal circular (LEC), midesophageal circular (MEC), and midesophageal longitudinal (MEL) muscle strips were determined. Sling fibers contracted greater than the other fibers. Total, M(2) and M(3) muscarinic receptor density was determined for each of these dissections by immunoprecipitation. M(2) receptor density is greatest in the sling fibers, followed by clasp, LEC, MEC, and then MEL, whereas M(3) density is greatest in LEC, followed by MEL, MEC, sling, and then clasp. The potency of subtype-selective antagonists to inhibit bethanechol-induced contraction was calculated by Schild analysis to determine which muscarinic receptor subtypes contribute to contraction. The results suggest both M(2) and M(3) receptors mediate contraction in clasp and sling fibers. Thus, this type of analysis in which multiple receptors mediate the contractile response is inappropriate, and an analysis method relating dual occupation of M(2) and M(3) receptors to contraction is presented. Using this new method of analysis, it was found that the M(2) muscarinic receptor plays a greater role in mediating contraction of clasp and sling fibers than in LEC, MEC, and MEL muscles in which the M(3) receptor predominantly mediates contraction.