Gut 1993; 34: 321-328 321 Cholecystokinin in the control of gastric acid secretion in man Gut: first published as 10.1136/gut.34.3.321 on 1 March 1993. Downloaded from J W Konturek, R Stoll, S J Konturek, W Domschke Abstract alone in fasted humans or in dogs` caused partial This study was designed to determine the role stimulation of gastric acid secretion but when of cholecystokinin in the control gastric acid combined with gastrin it inhibited gastrin in- secretion in men using loxiglumide, a specific duced secretion. The inhibitory action of chole- cholecystokinin receptor blocker. Three cystokinin could not be, however, confirmed on groups of healthy subjects (A, B, and C) were the isolated canine parietal cells which respond to used; group A - for studies with postprandial gastrin and cholecystokinin with equal stimula- gastric secretion, group B - for studies with tion of acid production.6 This discrepancy exogenous gastric secretagogues and group C - between the in vivo inhibition and in vitro for 12 hour intragastric pH-metry. Cephalic stimulation by cholecystokinin of acid secretion phase stimulated by modified sham feeding in has been explained that cholecystokinin in vivo group A subjects increased gastric acid secre- may release a local inhibitor of parietal cells such tion to about 50% of pentagastrin maximum as somatostatin." Indeed, using a highly selec- and the treatment with loxiglumide in a stan- tive and potent cholecystokinin receptor blocker dard dose (20 [tmolIkg iv loading dose plus such as L-364,718, it was recently found in infusion of 20 iumol/kg/h afterwards) failed to dogs9 '° that cholecystokinin released by a protein affect this secretion. Gastric acid response to a or fat meal exerts a tonic inhibitory influence on 5% peptone meal instilled intragastrically gastric acid secretion and this effect may be greatly enhanced gastric acid secretion and mediated, at least in part, by somatostatin."' plasma gastrin concentration but the addition This study was designed to use the selec- of loxiglumide in the standard dose resulted in tive antagonist of type A cholecystokinin further increase in both gastric acid and plasma receptors, loxiglumide," 12 to evaluate the role of gastrin responses to peptone meal. Infusion of cholecystokinin in the control ofgastric secretion caerulein in gradually increasing doses (15-120 and gastrin release in man under physiological pmollkg/h) and gastrin releasing peptide conditions such as cephalic or gastrointestinal (25-200 pmol/kg/h) resulted in a dose depen- phase of this secretion as well as following http://gut.bmj.com/ dent stimulation of gastric acid secretion stimulation with exogenous secretagogues reaching about 35% and 25% of maximum including pentagastrin, caerulein or gastrin attained with pentagastrin. When loxiglumide releasing peptide. was added in a standard dose, the acid responses to caerulein and gastrin releasing peptide were further increased two to three Methods fold attaining the peak reaching, respectively, on October 2, 2021 by guest. Protected copyright. about 100% and 50% ofpentagastrin maximum. SUBJECTS In group C subjects, 12 hour pH-metry Studies were carried out on three groups (A, B, revealed the usual increase in gastric pH after and C) ofyoung healthy men (mean age 22 years, each meal in tests with placebo. Loxiglumide range 19-37; mean weight 71 kg, range 59-76). (1200 mg tablets tid, po) resulted in signifi- Group A subjects underwent modified sham cantly lower pH after each meal and this was feeding and peptone meal tests with or without accompanied by significantly higher gastrin administration of loxiglumide. Group B subjects responses than in placebo tests. We conclude were used in tests with the infusion of penta- that cholecystokinin released by peptone meal, gastrin, caerulein or gastrin releasing peptide ordinary meals or gastrin releasing peptide with or without addition ofloxiglumide. Group C exerts a potent inhibitory influence on gastric subjects were used for the intragastric recording acid secretion and gastrin release in men ofpH during 12 hours ofnormal activities with or and this inhibition involves subtype A without oral administration of loxiglumide. This Institute of Physiology, cholecystokinin receptors. study was approved by the Human Research University Medical (Gut 1993; 34: 321-328) Review Committee and informed consent was School, Krakow, Poland, and obtained from each subject. Department of Medicine, University of Munster, Gastric acid secretion depends upon the interplay Munster, Germany J W Konturek of many stimulatory and inhibitory influences STUDIES ON THE EFFECTS OF LOXIGLUMIDE ON R Stoll that arise within the central nervous system and MODIFIED SHAM FEEDING AND PEPTONE MEAL S J Konturek the gastrointestinal tract resulting in the INDUCED GASTRIC SECRETION W Domschke cephalic, gastric, and intestinal phases of this In group A (eight subjects), modified sham Correspondence to: Prof Dr S J Konturek, secretion.' feeding and intragastric peptone meal were used Institute of Physiology, Cholecystokinin is one ofmajor gut hormones2 to induce, respectively, cephalic vagal and 31-531 Krakow, ul. Grzegorzecka 16, Poland. that has also been implicated in the control of gastrointestinal phases of gastric secretion as Accepted for publication gastric secretion. Exogenous cholecystokinin or described before.'" '" Briefly, for modified sham 14 July 1992 its natural analogue, caerulein, administered feeding, a double lumen Dreiling tube was 322 Konturek, Stoll, Konturek, Domschke 100* MSF gastrointestinal phase of gastric secretion) per- formed alone or in combination with loxiglumide. On the first test day, 5% peptone solution (Bactoprotone, Difco Labs, Detroit, Michigan, to 5-5 (with 1 M NaOH) and USA) adjusted pH Gut: first published as 10.1136/gut.34.3.321 on 1 March 1993. Downloaded from L- osmolarity ofabout 300 mOsm/l (with 1 M NaCl) C: 50 - T was administered during six consecutive 30 U) minute meals. On a second test day, loxiglumide (.9 was administered iv in a loading dose of 20 itmol/ kg followed by a constant dose of 20 [tmol/kg/h starting with the fourth 30 minute peptone meal. All tests with peptone meal started after an --T-- -T-- --v- 5 overnight fast. A double lumen tube was intro- duced into the stomach and basal gastric acid secretion was quantified by suction aspiration for 15fl a 30 minute period. Peptone meal was introduced into the stomach in the volume of 300 ml at the start ofeach ofsix consecutive 30 minute periods. The stomach was emptied completely before the administration of the next 300 ml meal. Gastric was -E content continuously mixed with the aspira- 10* tion and the meal stimulated c)0 MSF + LOX perfusion system 0 acid secretion was measured by intragastric titra- E tion with the end point of pH 5-5 using 50 mM E u Na(OH) as described previously.'4 IS .2 5. U, o STUDIES ON THE EFFECTS OF LOXIGLUMIDE ON (.9 CAERULEIN, PENTAGASTRIN AND GASTRIN RELEASING PEPTIDE INDUCED GASTRIC SECRETION Group B subjects were also intubated with a M double lumen Dreiling tube and gastric acid secretion was stimulated using caerulein (Farm- 1I 6 italia, Milano, Italy) infused iv in gradually increasing doses (15-120 pmol/kg/h), each dose 30 Minute periods being infused for 30 minutes and then doubled http://gut.bmj.com/ Figure 1: Plasma gastrin concentrations and gastric acid outputs under basal conditions and with or without addition of loxiglumide (20 after modified sham feeding in group A subjects with or without administration ofloxiglumidte. mol/kg in a loading dose at the start of the study Mean (SEM) ofeight tests on eight subjects. followed by 20 [tmol/kg/h) given throughout the periods of caerulein administration. After with- passed under fluoroscopic control for the aspirai- drawal ofinfusion ofcaerulein, the gastric aspira- tion of gastric juice as described previously. 14 tion was continued for 60 minutes and then Residual gastric contents were discarded and thLe pentagastrin (2 6 nmol/kg/h) was infused for 60 on October 2, 2021 by guest. Protected copyright. gastric aspirates were collected by a suctioIn minutes with or without administration of loxi- pump in 15 minute periods. After 45 minutes glumide (20 [tmol/kg/h) to achieve maximal basal period, the subjects were served an appetiss- secretory response to this peptide. In six group B ing meal of 250 g beef steak, 150 g french subjects, pentagastrin was also infused in sepa- potatoes, with about 250 ml water to drink th.e rate test day in a constant dose (0 65 [tmol/kg/h) food was tested, chewed and spat out for 1 5 to elicit submaximal secretory response. When minutes. The aspiration of gastric juice wais gastric acid output in response to pentagastrin carried out during modified sham feeding and reached a well sustained plateau, caerulein was during consecutive 105 minute period. Then added to iv infusion in a constant dose of 30 pentagastrin (2 nmol/kg/h) was infused for 6.0 pmol/kg/h with or without addition of loxi- minutes and the aspiration of gastric juice wa1S glumide (20 Rmol/kg/h). In control tests, penta- continued to determine maximal acid output in gastrin alone was administered for the entire 150 these subjects. All meals were prepared in a minutes. separate room so that subjects could not see )r The same six subjects of group B were also smell the food until the time of modified sharm used in different occasions in tests with iv feeding and each subject was trained in a prn infusion of gradually increasing doses (25-200 liminary study not to swallow food during cheuv- pmol/kg/h) of gastrin releasing peptide (gift of ing. In different test day the modified sharm Professor N Yanaihara, Shizuoka, Japan) with or feeding was performed while loxiglumide (kindlIy without the administration of loxiglumide in a provided by Dr L Rovati, Rotta Labs, Milanc , standard dose as used in the feeding experiments.