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Origin of Gastrin Liberated by Gastrin Releasing Peptide in Man

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Origin of Gastrin Liberated by Gastrin Releasing Peptide in Man Gut: first published as 10.1136/gut.28.9.1128 on 1 September 1987. Downloaded from Gut, 1987, 28, 1128-1133 Origin of gastrin liberated by gastrin releasing peptide in man L LUNDELL, G LINDSTEDT, AND L OLBE From the Departments ofSurgery II and Clinical Chemistry, Sahlgren's Hospital, University ofGothenburg, Gothenburg, Sweden SUMMARY Gastrin release induced by gastrin releasing peptide (GRP) in man has been studied in patients before and after complete resection of the antrum and duodenal bulb, as well as after pancreaticoduodenectomy according to Whipple. Studies in healthy subjects showed that 400 pmol/kg an hour of GRP induced a maximal release of gastrin. Infusion of this dose of GRP after a complete resection of the antrum and duodenal bulb induced a small, but significant increase in gastrin concentrations. After pancreaticoduodenectomy, however, GRP infusion had no effect on serum gastrin concentrations. In patients previously subjected to an incomplete antrectomy, GRP infusion was followed by a gastrin response considerably higher than after a complete antrectomy. Our results would suggest that GRP is capable of releasing gastrin predominantly from the antrum and the duodenal bulb, but also a small amount of gastrin from the remaining part of the duodenum. Gastrin releasing peptide infusion and determination of gastrin release may be of clinical significance in showing remaining significant gastrin pools in patients with recurrent ulceration after previous gastric resections. http://gut.bmj.com/ The tetradecapeptide bombesin originally isolated biological effects in mammals including stimulation from the frog skin has been found to have counter- of gastric acid secretion (probably secondary to the parts in mammalian stomach and intestine.' Bom- gastrin release), pancreatic enzyme secretion, gall besin like immunoreactive material has been found in bladder and intestinal smooth muscle contraction high concentrations in the human gastric mucosa as and release of several gastrointestinal regulatory on October 2, 2021 by guest. Protected copyright. well as in the muscle layers of the stomach both in the peptides.'2 Gastrin releasing peptide administration fundus and in the antrum.23 Bombesin is a potent in man is followed by substantial gastrin release. stimulant for gastrin release in all species studied and There are, however, divergent results as to the has been shown to induce a dose dependent gastrin release of other gastrointestinal peptides.""'4 release also in man.4" From the porcine non-antral It has been suggested that bombesin and conse- gastric tissue a 27-aminoacid peptide hormone with a quently GRP as well might be of clinical usefulness to striking sequence homology with the frog's skin pep- reveal remaining gastrin sources in patients with tide bombesin has been isolated and termed gastrin recurrent peptic ulcerations after previous gastric releasing peptide.' Gastrin releasing peptide (GRP) resections. Results have been presented indicating has recently been shown to be equipotent with both an antral and extra antral release of gastrin by bombesin in raising plasma concentrations of some bombesin. '"t The aim of the present study was to gastroenteropancreatic hormones.7' Gastrin releas- investigate the dose response relationship between ing peptide has been suggested to play a role in the infused dose of GRP and the amount of gastrin neuroregulation of gastrin secretion from the antrum released and also to investigate the origin of gastrin but the peptide seems to produce a wide variety of released by GRP by carrying out studies on patients Address for correspondencc: Lars L,undell, MD, PhD, Department of Surgery before and after histologically complete antrectomy 11, Sahigren's Hospital. S-413 45 Gothenburg. Sweden. and duodenal bulb resection as well as after a Received for publication 12 February 1987. pancreaticoduodenectomy according to Whipple. 1128 Gut: first published as 10.1136/gut.28.9.1128 on 1 September 1987. Downloaded from Gastrin release by GRP 1129) Methods 250- PATIENTS Studies were carried out on six healthy volunteers age years, range (mean 56 36-68) and eight patients 200- (mean age 46 years, range 30-63) before and at least three months after a histologically complete antrum- z bulb resection, six of whom also had a selective cn gastric vagotomy. The preoperative investigation was 150 01 carried out after any ulcer drug treatment had been postponed for at least 48 hours. All eight patients had a gastroduodenostomy according to Billroth I. The operative specimens were subjected to routine histo- E 100 pathological investigation with haematoxylin and eosin staining. Six patients (mean age 67 years, range 61-75) were investigated six months after a pancre- aticoduodenectomy according to Whipple because of 50: pancreatic carcinoma. At the time of investigation no sign of remaining or recurrent tumour growth was 0 100 200 300 400 apparent. Six patients (mean age 59 years, range GRP (pmol /kgxh ) 49-70) were also investigated at different time inter- vals after a histologically incomplete antrectomy. All Fig. 1 Gastrin response to stepwise increasing doses of subjects gave their informed consent to take part in GRP in healthy volunteers. Mean and SE are given. the investigation, which was approved by the local ethical committee. In four subjects (mean age 49 nanogram of the calibrator corresponds to 0 95 mU years, range 42-67), two healthy volunteers and two and 0-48 pmol. The stated cross-reactivity with non- patients previously operated on with proximal gastric sulphated gastrin-34 (an 80% pure preparation) vagotomy, one test was carried out without naso- 62-73% depending on the concentration - that is, the gastric intubation and one test at least three weeks assay does not discriminate between the major afterwards were carried out by perfusion of the species of serum gastrin. The precision of the assays stomach with a buffer solution (Sorensens buffer) in during the present study period was similar to that http://gut.bmj.com/ order to obtain a stable pH of 7 in the gastric lumen reported previously.2" For cross-reactivity data with (for technical details see '9). cholecystokinin see the foot note.* Each subject was studied in the morning after an In studying the dose response relationship overnight fast. If not otherwise stated no nasogastric between infused dose of GRP and gastrin release, tube was inserted. A cannula was inserted into an each dose of GRP was infused for 45 minutes. The arm vein for infusion of GRP and another in a vein in gastrin response to each dose of GRP was calculated the other arm for blood as sampling. the mean of the two last 15 minute samples. The on October 2, 2021 by guest. Protected copyright. The GRP used was synthetic preparation of the dose of GRP was stepwise increased. porcine peptide (Cambridge Research Biochemical Statistical evaluation of the data was carried out by Ltd, UK). For infusion, the peptide was dissolved in application of the Student's t test. sterile aqueous 0 15 mol/l sodium chloride solution containing 5 g/l of human albumin, the latter to Results reduce absorption of the peptide to the plastic syringe and tubing of the infusion equipment. DOSE RESPONSE REL ATIONSHIP For was gastrin determination, 10 ml of blood The mean basal serum concentration in the six drawn at 15 minute intervals into gastrin glass tubes without healthy volunteers was 63 (SE 9.2) ng/l. On infusing anticoagulant or other additive and, after centrifuga- GRP in a dose of 10 pmol/kg/h, the serum gastrin tion serum was removed and stored at -20°C until increased to 106 ng/l. A dose response relationship time of assay. Gastrin was determined"' using a was obtained between infused dose of GRP and double antibody polyethylene glycol assisted radio- release A maximal immunoassay (Diagnostic Products Corporation, gastrin (Fig. 1). gastrin releasing Los Angeles, California, USA) using human non- sulphated gastrin-17 for calibration. The method is *The manufaicturer gives the following cross-reaictivity daita for chotecystokinin: standardised Research Standard A CCK27- 3 added I tgll - 97'%. CCK-4+3 aidded I [pg/l - 0(7%. CCK2t-A3 (non- against (68-439, sulphated) atdded I Lg/l - 29-4% aind CCK,A39 (sulphated) atdded I pg/l gives a synthetic human non-sulphated gastrin-17). One per cent cross-reaictivity of 19-4. Gut: first published as 10.1136/gut.28.9.1128 on 1 September 1987. Downloaded from 1130 Lundell, Lindstedt, and Olbe Buffer perfusion (220ml/15min) Intact stomach Afterlintrum-bulb resection Saline GRP (400pmol /kg xh) Saline Soline ,-- GRP (400 pmol/ kg x h ) Saline 600- * Buffer perfusion 300- , 500- 01 C- 400- c c~ c~20O- -2WC 0 300- E a 01cn 200- E 7 100- n3lo 0 15 30 45 60 75 90 105 120 Time (min) 6 15 30 45 60 75 9) 105 12V Time ( min) Fig. 2 Gastrin response to GRP infusion infourpatients with or without bufferperfusion ofthe gastric lumen (see Fig. 3 Gastrin response to GRP infusion before and after Methods). Mean and SE are given. complete resection ofthe antrum and duodenal bulb. Mean and SE are given. effect seemed to follow infusion of 400 pmol of GRP/kg/h. GASTRIN RESPONSE AFTER PANCREATICODUODENECTOMY INFLUENCE OF LUMINAL pH ON GASTRIN Investigations on six patients carried out after RELEASE pancreaticoduodenectomy revealed no increase in In four subjects, a GRP infusion (400 pmol/kg/h) was serum gastrin during infusion of 400 pmol/kg/h of done either without nasogastric intubation or during GRP (Fig. 4). perfusion of the stomach with Sorensens buffer solution. The initial gastrin response did not differ INCOMPLETE ANTRECTOMY between the two investigations (Fig. 2), but the Six patients were investigated because of recurrent response to GRP infusion during buffer perfusion ulcers after a previous gastric resection and were http://gut.bmj.com/ seemed to be more prolonged than without naso- found either on a retrospective analysis of the opera- gastric intubation.
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