Actions of the 5-Hydroxytryptamine 1 Receptor Agonist Sumatriptan
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36 Gut 1998;42:36–41 Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive Gut: first published as 10.1136/gut.42.1.36 on 1 January 1998. Downloaded from gastrointestinal motility in man J Tack, B Coulie, A Wilmer, T Peeters, J Janssens Abstract Evidence has accumulated that enteric neu- Background—Pharmacological studies of ronal 5-hydroxytryptamine (5HT) receptors the enteric nervous system have shown the are involved in regulation of the MMC in ani- presence of several subtypes of 5-hydroxy- mals and in man.3–7 In vitro studies in the tryptamine (5HT) receptor, which might guinea pig showed that 5HT4 receptors, 5HT3 be involved in control of the migrating receptors, 5HT1A receptors, and 5HT1P recep- motor complex. tors are present on myenteric neurones in the Aims—To study the eVect of sumatriptan, stomach and in the small intestine.8–11 Using an agonist of enteric neuronal 5HT1P the selective 5HT3 receptor antagonist on- receptors, on interdigestive motility in dansetron, we showed that 5HT3 receptors are man. involved in the initiation of gastric phase 3 12 Subjects and methods—In 12 healthy sub- motor activity in man. Lack of suitable jects, interdigestive motility was recorded ligands precluded a similar study for 5HT1 manometrically in the upper gastrointes- receptors and for 5HT4 receptors. Recently, tinal tract. In seven subjects blood sam- however, we showed that sumatriptan, a 5HT1 ples were drawn every 15 minutes for receptor agonist which is used in the treatment 13 radioimmunoassay of motilin and soma- of migraine in man, is an agonist of 5HT1P tostatin. After two phase 3s of the migrat- receptors on myenteric neurones in the 14 ing motor complex, 6 mg of sumatriptan stomach. was administered subcutaneously. Re- We have also shown that administration of cording continued until two more phase 3s sumatriptan in man causes a notable delay in 15 had occurred. gastric emptying of both solids and liquids. Results—Sumatriptan induced a prema- The present study was undertaken to investi- gate the eVect of sumatriptan on interdigestive ture phase 3 in the jejunum after a median http://gut.bmj.com/ of 10 (8) minutes. The duration of the gastrointestinal motility and on gastrointestinal migrating motor complex cycle was short- hormones in man. We recorded gastrointestinal ened at the expense of phase 2. After motor activity in healthy volunteers before and sumatriptan, plasma somatostatin con- after the administration of sumatriptan. Simul- centrations were reduced and gastric taneously, plasma immunoreactive motilin and phase 3s were suppressed, although me- somatostatin concentrations were monitored and, finally, the eVect of a low dose of the dian motilin concentrations and the oc- 16 currence of plasma motilin peaks were not motilin agonist erythromycin on gastrointesti- on September 28, 2021 by guest. Protected copyright. aVected. Phase 3s of the migrating motor nal motor activity in the presence of su- complex preceding sumatriptan were as- matriptan was also studied. sociated with motilin peaks, while phase 3s In the treatment of migraine, sumatriptan after sumatriptan were not. Furthermore, 6 mg is administered subcutaneously, with a pretreatment with sumatriptan prevented bioavailability of 96%. After subcutaneous the induction of a gastric phase 3 by the administration, a plasma peak is reached after motilin agonist erythromycin. 10 minutes, and the mean plasma half life is about two hours.13 Sumatriptan does not cross Conclusions—Administration of the the blood–brain barrier.13 In the present study, 5HT1P receptor agonist sumatriptan in- duces a premature intestinal phase 3, sup- we used the dose and route of administration of Department of presses gastric phase 3s, prevents induct- sumatriptan which is applied in the acute Internal Medicine, treatment of migraine. Division of ion of a gastric phase 3 by erythromycin, Gastroenterology, and reduces plasma somatostatin concen- University Hospital trations. Materials and methods Gasthuisberg, (Gut 1998;42:36–41) Herestraat 49, B-3000 STUDY SUBJECTS Leuven, Belgium Keywords: migrating motor complex; motilin; Twelve healthy volunteers (two women and 10 J Tack somatostatin; erythromycin; enteric nervous system men; mean age 25.9 (2.8) years) participated in B Coulie the sumatriptan study. None of the subjects A Wilmer T Peeters had symptoms or a history of gastrointestinal J Janssens The interdigestive state of the gastrointestinal disease or drug allergies, and none were taking tract in most mammalian species, including any medication. The control group consisted of Correspondence to: man, is characterised by the presence of a 22 sex and age matched healthy volunteers. Dr Tack. cyclical pattern of motor activity called the Informed consent was obtained from each par- 12 Accepted for publication migrating motor complex (MMC). The con- ticipant. The protocol was approved by the 8 August 1997 trol of the MMC is incompletely understood. Ethics Committee of the University Hospital. Sumatriptan and interdigestive motility 37 RECORDING TECHNIQUE ANALYSIS Recordings of antroduodenojejunal intralumi- Analysis of the recordings of gastroduodenoje- nal pressures were performed using an eight junal motor activity was performed by two of lumen polyvinyl catheter (outer diameter 6 the authors (JT and AW) independently. Visual Gut: first published as 10.1136/gut.42.1.36 on 1 January 1998. Downloaded from mm) with a latex bag at its end that could be inspection allowed continuous identification of filled with mercury. The probe was introduced the most distal antral recording site as the via the mouth and positioned under fluoro- catheter that recorded up to three pressure scopic control in such a way that the most dis- waves per minute (antral waves) just proximal tal of the three proximal sensors, which were 3 to the catheter that recorded up to 12 contrac- cm apart, was located in the antrum at the level tions per minute (duodenal waves) or to the of the pylorus or just distal to it. The three catheter that exhibited a mixture of antral and other sensors were located in the horizontal duodenal waves. The diVerent phases of the part of the duodenum and in the proximal migrating motor complex were identified as jejunum, respectively at 17, 42, and 67 cm dis- described previously.21216 Whenever possible, tal to the antropyloric recording sites. The two the propagation velocity of phase 3 was remaining catheters were used for filling and assessed from the gastric to the duodenal sen- emptying the mercury bag. This catheter sor and from the first to the second jejunal sen- assembly allowed at least one recording orifice sor. to be kept in the distal antrum during the entire Plasma motilin and somatostatin concentra- experiment and thus the migrating motor tions were determined by radioimmunoassay complex was adequately monitored simultane- as previously described.17 18 To determine ously in the distal antrum, the duodenum, and whether sumatriptan aVects basal concentra- the upper jejunum. The recording catheters tions of somatostatin or motilin, all concentra- were continuously perfused with water by tions of each hormone before sumatriptan were means of a low compliance pneumohydraulic compared against all concentrations of each infusion pump (Arndorfer Medical Specialties hormone after sumatriptan. In addition, the Inc., Greendale, Wisconsin, USA) at a flow rate average hormone concentrations for each of 0.4 ml/min, and were connected to external MMC cycle were assessed for possible diVer- pressure transducers (Siemens Elema 746, Sie- ences between each other. In addition, the mens, Iselin, New Jersey, USA). Pressures were maximum motilin concentration before su- recorded on a polygraph (Elema Mingograph matriptan was compared with the maximum 82, Siemens) using a paper speed of 5 mm/s. motilin concentration after sumatriptan. The motilin concentration associated with phase 3 STUDY DESIGN was defined as the motilin concentration meas- Following an overnight fast of at least 12 hours, ured during phase 3 at its segment of onset or the recording probe was introduced as de- just prior to the onset of phase 3 if no sample scribed above and secured to the subject’s chin was taken during the phase 3.16 17 To test http://gut.bmj.com/ with adhesive tape. In 12 volunteers, gastroin- whether motilin peaks were present at the onset testinal motility was recorded until the passage of a phase 3, the motilin concentrations associ- of two phase 3s of the MMC. Ten minutes after ated with each phase 3 were compared with the the second phase 3 passed at the most distal average of all motilin concentrations over the recording site, 6 mg of sumatriptan (Imitrex, whole recording time and to the average moti- Glaxo Belgium) was administered subcutane- lin concentrations of each MMC cycle preced- ously. This dose has been shown to be safe and ing (or following) the phase 3. on September 28, 2021 by guest. Protected copyright. eVective in the control of migraine.13 In nine of The two tailed paired t test was used to the 12 volunteers, motility was recorded until determine significant diVerences between cycle two consecutive phase 3s of the MMC had lengths, the velocity of propagation, and the occurred after the administration of su- duration of the phase 3. A one population matriptan. In seven of these nine volunteers, model with repeated measurements on cat- blood samples were also drawn at 15 minute egorical data for time and treatment main intervals throughout the study to determine eVect (Catmod procedure, SAS software) was motilin and somatostatin concentrations. In used to determine whether there was a signifi- the remaining three volunteers, 15 minutes cant diVerence between the number of phase after the administration of sumatriptan, 40 mg 3s of MMC starting in the stomach before and of erythromycin lactobionate (Abbott Labs), after sumatriptan. The unpaired t test was used dissolved in 100 ml normal saline, was infused to compare the number of phase 3s originating over 20 minutes via a second intravenous line.