Gut 1997; 40: 575-581 575 PAPERS Cholecystokinin in transient lower oesophageal Gut: first published as 10.1136/gut.40.5.575 on 1 May 1997. Downloaded from sphincter relaxation due to gastric distension in humans J Boulant, S Mathieu, M D'Amato, A Abergel, M Dapoigny, G Bommelaer Abstract gastric mechanoreceptors mainly located in the Background and aims-Transient lower subcardiac region." In dogs, cholecystokinin oesophageal sphincter relaxations (CCK) is involved in the occurrence of (TLOSRs) has been found to be the main TLOSR induced by gastric distension through mechanism of gastro-oesophageal reflux. peripheral CCK-A receptors.12 In dogs, cholecystokinin (CCK) is involved In normal subjects, CCK-8 infusion and in their occurrence. The aim was to meals have been reported to reduce the lower evaluate the role of endogenous and oesophageal sphincter (LOS) pressure and exogenous CCK in the occurrence of both these effects were blocked by loxiglumide, TLOSRs induced by gastric distension at a CCK-A receptor antagonist.'3 constant pressure in humans. The aim of the present study was to evaluate Methods-Ten healthy volunteers were the role of CCK-8 and loxiglumide in the studied. Lower oesophageal sphincter occurrence of TLOSR induced by gastric pressure was monitored with a sleeve distension in humans. device and gastric distension was per- formed via an intragastric bag monitored by a barostat. During distensions, saline, Methods CCK (30 ng/kg/h) or the CCK-A receptor http://gut.bmj.com/ antagonist loxiglumide (10 mg/kg/h) was SUBJECTS perfused in a random double blind order. We studied 10 healthy volunteers (five women Results-There was no significant differ- and five men; age range 25-39 years). Subjects ence between the number of TLOSRs were free of any gastrointestinal symptoms during the different distensions with and had no history of upper gastrointestinal saline; CCK increased the number of surgery. They did not take any medication TLOSRs at a mean rate of 13-1 compared known to alter oesophageal motor function. on September 24, 2021 by guest. Protected copyright. with 9-1 with saline (p<0001). Loxi- Each volunteer gave written consent, and the glumide significantly decreased the study was approved by the human ethics number of relaxations to 5 3 versus 8-3 committee of Clermont-Ferrand Hospital, under paired saline infusion (p<0.001). France (Comite Consultatif et de Protection Conclusions-In humans, CCK-A recep- des Personnes dans la Recherche Biomedicale tor subtype is involved in the occurrence de la Region Auvergne). of transient lower oesophageal sphincter relaxations induced by gastric distension. Department of (Gut 1997; 40: 575-58 1) MATERIALS AND MEASUREMENTS Gastroenterology, Oesophageal manometry was performed with a Hotel-Dieu, Clermont-Ferrand, Keywords: lower oesophageal sphincter, transient multilumen assembly incorporating a 6 cm France relaxations, gastro-oesophageal reflux, cholecystokinin, sleeve device (ESM3DS Arndorfer Medical J Boulant loxiglumide. Specialities, Greendale, WI, USA).'4 The S Mathieu A Abergel sleeve sensor monitored LOS pressure. Side M Dapoigny hole catheters recorded pressure in the gastric G Bommelaer Transient lower oesophageal sphincter re- fundus and oesophageal body at 5, 10, and 15 Rotta Research laxation (TLOSR), unrelated to swallowing, cm above the LOS. Another side hole detected Laboratorium, has been found to be the main mechanism of pharyngeal pressure to monitor swallowing. Via Valosa di Sopra, gastro-oesophageal reflux both in healthy Catheters were perfused with gas free distilled 20052 Monza (MI), Italy subjects and in patients with gastro-oes- water by a low compliance capillary pneumo- M D'Amato ophageal reflux disease. 1-6 Research is now hydraulic pump (Arndorfer Medical Speciali- Correspondence to: directed toward identifying the mechanisms ties, Greendale, WI, USA). The perfusion Dr J Boulant, involved in the occurrence of TLOSR7 and rates were 0-1 ml/min for the pharyngeal Department of Gastroenterology, developing drugs to decrease its rate in patients catheter and 0 5 ml/min for the gastric and H6tel-Dieu, BP 69, with gastro-oesophageal reflux disease. oesophageal body catheters and for the sleeve 63003 Clermont-Ferrand, France. The frequency of TLOSR is greatly in- device. Output from the pressure transducers 0 Accepted for publication creased in humans8 9 and dogs' " by disten- was processed by an eight channel polygraph 23 December 1996 sion of the stomach, which probably triggers (Polygraph HR Synectics Medical, Stockholm, 576 Boulant, Mathieu, D'Amato, Abergel, Dapoigny, Bommelaer Sweden) connected to a computer (486 DX (Rotta Research Laboratorium SpA., Monza, 33, Data Jet Personal Computers). Italy), was studied. Due to the half life of Gastric distension was performed with air via loxiglumide (>six hours),'7 it was not possible an intragastric bag, using an electronic baro- to randomise its administration against placebo stat (Institut National de la Recherche on a single day. Therefore the experiment was Gut: first published as 10.1136/gut.40.5.575 on 1 May 1997. Downloaded from Agronomique, Toulouse, France) to maintain run on two separate days, saline being perfused constant intragastric pressure by an electronic during the first distension as a control and feedback mechanism. The principle of the loxiglumide or saline in a random double blind barostat is as follows: when the stomach order (loxiglumide and saline were delivered in contracts, the barostat aspirates air from the similar blinded ampoules) during the second bag to maintain constant pressure and the bag distension. Infusions of loxiglumide were volume decreases; when the stomach is started 20 minutes before gastric distension relaxed, air is injected and the bag volume with a bolus of 30 mg/kg/h during 10 minutes increases.'5 The highly compliant polyethylene and continued at a dose of 10 mg/kg/h until the bag had a maximal volume capacity of 1400 ml end of distension. and was connected to the barostat via a 12F diameter single lumen polyvinyl tube. The electronic barostat was connected to the DATA ANALYSIS computer via the same polygraph (Polygraph The reader was blinded as to whether CCK, HR Synectics Medical, Stockholm, Sweden). saline, or loxiglumide had been infused Manometric traces were analysed for basal LOS pressure, and for the occurrence of STUDY DESIGN TLOSRs. Mean end expiratory LOS pressure Each subject fasted for at least eight hours was estimated with reference to gastric before the study. Subjects initially underwent pressure at end expiration defined as zero. static oesophageal manometry to assess Based on the analysis and according to primary peristalsis and to determine the Holloway et al,8 TLOSR was defined as: (1) location of the upper oesophageal sphincter the absence of swallowing four seconds before and LOS. Then the folded bag was wound and two seconds after the onset ofTLOSR, (2) round the tube and introduced slowly into the a relaxation rate of 1 mm Hg/s, (3) time from stomach through a nostril. The bag was onset to complete relaxation of 10 seconds, unfolded by manually injecting 300 ml air and (4) nadir pressure of 2 mm Hg. Excluding and pulled into the fundus, completely de- TLOSR associated with multiple rapid flated, and connected to the barostat. The swallowing, falls in LOS pressure that fulfilled manometric probe was introduced into the the last three criteria but had a duration http://gut.bmj.com/ oesophagus through the other nostril, the > 10 s were also judged as TLOSR, irrespective sleeve sensor being positioned in the LOS of the timing of the onset of the fall in LOS zone. A 30 minute resting recording session pressure in relation to swallowing. was then run and served as a basal control The maximal distension volume was re- period. Thereafter the intragastric bag was ported for each distension and for each sub- inflated by stepwise 2 mm Hg increments every ject. five minutes until a constant pain threshold on September 24, 2021 by guest. Protected copyright. was reached. Distension steps were separated from each other by a five minute relaxation, the STATISTICAL ANALYSIS bag being entirely deflated. For further Data were compared using analysis of variance experiments and for each subject on each day, (ANOVA) and Student's t test for paired the constant intragastric pressure of distension values. Statistical significance was accepted if was defined as 75% of the gastric pain p<005. A statistical analysis of order and threshold pressure. The recording was made treatment effect was calculated. Values are while the subjects were seated. presented as means (SD). The study was performed in two ex- periments on three separate days for each subject, involving two gastric distensions on Results each day (Fig 1). The two distensions at the constant pressure defined on each day were OESOPHAGEAL MANOMETRY performed during 30 minutes separated by a As we always found the same LOS pressure or 90 minute washout period. The gastric bag was number of TLOSRs under saline whatever the deflated during this washout period. order or day (no order effect), data obtained In the first experiment, the effect of CCK with CCK or loxiglumide were compared with was studied. On the same day, saline (as a the paired saline infusion (Fig 2). control) or CCK-8s (Kinevac: sincalide; ER Squibb and Sons Ltd, Montreal, Canada)'6 at a dose of 30 ng/kg/h were perfused in random Transient lower oesophageal sphincter relaxations double blind order with a syringe pump (Robo- Without distension, at the basal state, TLOSRs medic 100, Gazui Electronic, France) during occurred at a rate of 1-4 (1-0)/30 min. each distension. Saline or CCK-8s infusions Gastric distension with the barostat increased started 10 minutes before gastric distension and the number of TLOSRs. This increase was continued until the end of distension. reproducible as the number of TLOSRs under In the second experiment, the effect of the saline infusion was similar during all series of CCK-A receptor antagonist loxiglumide distensions with saline (Fig 2).