H. Koop

Effect of cholestyramine on plasma cholecystokinin and pancreatic polypeptide levels, and exocrine pancreatic secretion

Abstract The effect of acute and long‐term administration of cholestyramine, a non‐absorbable bile salt binding resin, on exocrine pancreatic secretion, plasma‐cholecystokinin (CCK) and plasma‐pancreatic polypeptide (PP) was investigated in 10 healthy volunteers. Oral ingestion of 12 g cholestyramine augmented the stimulatory effect of a liquid test meal on plasma‐CCK (3·5‐fold) and plasma‐PP (2‐fold). During prolonged treatment with 3 times 12 g cholestyramine daily for 4 weeks, the most pronounced increase in basal hormone levels was observed after 1 day, but progressively decreased during treatment and had normalized after 4 weeks. However, the stimulated plasma‐CCK output was still significantly elevated after cessation of treatment, compared with pretreatment values. After acute and chronic cholestyramine administration only stimulated lipase secretion was elevated, whereas trypsin and amylase remained unchanged. It is suggested that removal of bile salts enhances CCK and thereby PP release and pancreatic lipase secretion.

Plasma CCK Levels in Patients with Pancreatic Insufficiency

After stimulation with a Lundh test meal, plasma concentrations of cholecystokinin (CCK) and pancreatic polypeptide (PP) and output of pancreatic enzymes were measured in 33 patients with exocrine pancreatic insufficiency and 26 healthy subjects. Patients with impairment of pancreatic function were subdivided into those with moderate and severe insufficiency. Plasma CCK and PP were measured by radioimmunoassay. Fasting plasma CCK in patients with pancreatic insufficiency (5.8±1.1 pmol/liter) did not differ significantly from controls (4.2±0.6 pmol/liter). After endogenous stimulation with a Lundh meal, plasma CCK increased in both groups without significant differences over 2 hr. Basal and stimulated plasma levels of pancreatic polypeptide (PP) were markedly decreased only in patients with severe pancreatic insufficiency. Our results demonstrate that basal and meal-stimulated CCK levels in patients with pancreatic insufficiency do not differ from controls. Furthermore the extent of functional impairment of the exocrine pancreas did not influence basal and postprandial CCK release.

Dissociation of cholecystokinin and pancreaticobiliary response to intraduodenal bile acids and cholestyramine in humans

The role of intraduodenal bile acids in the regulation of cholecystokinin (CCK), pancreatic polypeptide (PP), and secretin as well as exocrine pancreatic and biliary secretion was investigated by means of a duodenal marker perfusion technique in volunteers. The following solutions were perfused: (1) liquid test meal, (2) test meal with 6 g cholestyramine, (3) test meal with 2 g chenodeoxycholic acid (CDC), (4) test meal with 6 g cholestyramine and 2 g CDC, (5) 6 g cholestyramine alone, and (6) 2 g CDC alone. The test meal caused an immediate increase in CCK and PP plasma levels, whereas secretin was not significantly altered. CCK release was further enhanced by addition of cholestyramine, whereas CDC inhibited release. The stimulatory effect of cholestyramine was abolished by CDC. CDC alone and in combination with the test meal stimulated secretin release. The response of PP to the test meal was not altered by addition of either compound. Cholestyramine and CDC alone caused only a very small increase in CCK levels, whereas PP was stimulated to nearly postprandial values. Meal-stimulated pancreatic and biliary secretion was significantly enhanced by cholestyramine, CDC, and the combination of both. CDC and cholestyramine alone each stimulated enzyme and bile secretion to a greater extent than the test meal. We conclude that intraduodenal bile salts are a modulator of postprandial CCK release. Changes in exocrine pancreatic and biliary and PP secretion do not necessarily parallel CCK concentrations, suggesting that different mediators are involved in the observed bile acid-induced changes in humans.

Serotoninergic control of somatostatin and gastrin release from the isolated rat stomach

The influence of exogenous serotonin on the secretion of gastric somatostatin and gastrin was investigated under in vitro conditions using an isolated, vascularly perfused rat stomach preparation. Serotonin stimulated gastrin release, maximal effects were observed at 10(-6) M which increased gastrin levels by 78%; on the contrary, somatostatin secretion was inhibited (maximal inhibition of 56% at 10(-6) M). Changes in hormone secretion in response to serotonin were reversed by combined blockade of 5-HT1 and 5-HT2 receptors by methysergide and blockade of 5-HT2 receptors by ketanserin (10(-5) and 10(-6) M, respectively), and of cholinoreceptors by atropine (10(-5) M). It is concluded that in rats in vitro serotonin inhibits release of gastric somatostatin and stimulates gastrin secretion via specific serotonin receptors but muscarinic cholinergic receptors are also involved.

Antral Helicobacter pylori-like organisms in different states of gastric acid secretion

The frequency of Helicobacter pylori (H.p.) infestation in antral mucosa and the presence of gastritis were investigated in different states of gastric acid secretion. Biopsies were stained by the Warthin-Starry technique and hematoxylin-eosin. Antral H.p. was found in similar frequencies in Zollinger-Ellison syndrome (n = 17; profound acid hypersecretion, associated with duodenal ulcer disease in most cases) and the same number of age-matched controls (35% in each group) whereas H.p. could be detected in 31 out of 33 duodenal ulcer patients (94%). The incidence of H.p. infestation in H2-blocker refractory reflux oesophagitis was low (24%). Treatment of peptic lesions with omeprazole (drug-induced hypochlorhydria) led to a reduction or disappearance of H.p. in 7 out of 10 H.p.-positive patients whereas none of 19 primarily H.p.-negative patients became infected with H.p. during prolonged omeprazole therapy. It is concluded that (1) development of duodenal ulcers (as in gastrinomas) does not necessarily require H.p., and (2) at least in some patients H.p. is reduced in antral mucosa by omeprazole.

Effect of Food Deprivation on the Function of the Intestinal Cholecystokinin-Producing Cell in the Rat

The influence of fasting and refeeding on storage and secretion of cholecystokinin (CCK) was investigated in the rat. Groups of rats deprived of food for 12 and 96 h were studied. Animals of each group received 0.75 g of long-chain triglycerides or water via an orogastric tube after the fasting period 15 min prior to exsanguination. Rats fed ad libitum served as controls. Duodenal, jejunal and ileal segments were dissected for tissue extraction and immunohistochemical staining of CCK-containing cells. Fasting over 96 h resulted in a significant reduction of plasma CCK, duodenal CCK concentrations and number of duodenal CCK-containing cells. Changes were less pronounced in the more distal parts of the small bowel. Refeeding caused an increase in plasma and tissue CCK concentrations, thus abolishing all significant differences that occurred during fasting. Gel chromatography of tissue extracts showed a shift towards the bigger molecular forms after 96 h of fasting. We conclude that storage and secretion of gut CCK are reduced during food deprivation in rats. The reduction of tissue CCK appeared at the expense of the lower molecular forms. However, the functional responsiveness of the CCK cell as indicated by the postprandial rise in plasma CCK seems to be maintained after a 4-day fast.

Effect of starvation on endocrine cells in the rat stomach

The influence of food deprivation on gastric G- and D-cells and on parietal cells was studied in the rat. In fed controls and groups of rats fasted for 12 and 96 h G-, D- and parietal cell densities, somatostatin and gastrin concentration in antral and fundic specimens and serum gastrin were compared. Gastrin in antral mucosa, serum gastrin, G-cell density as well as antral D-cell density decreased in long-term fasted rats by 52%, 90%, 58% and 42%, respectively. Fundic D-cell density remained unchanged. After 96 h starvation somatostatin concentration slightly increased in antral mucosa (+35%; P less than 0.05), but decreased in fundic mucosa (-40%; P less than 0.05). Parietal cell density was not influenced by prolonged fasting. These findings demonstrate that changes in D-cell morphology and mucosal somatostatin content are not parallel and that the rat gastric D-cell is less dependent on food in the gastric lumen than the G-cell. The unaltered fundic D-cell density reflects the functional activity of gastric D-cell which has also been shown to be independent of the presence or absence of food.

Effect of Gastrin Receptor Antagonists on Gastric Acid Secretion and Gastrin and Somatostatin Release in the Rat Stomach

The effects of two recently developed gastrin receptor antagonists, PD 136450 and L-365,260, on pentagastrin-stimulated acid secretion were investigated in rats. PD 136450 at a dose of 6 mg/kg s.c. (9.6 mumol) completely abolished acid secretion induced by pentagastrin. The inhibition of 18 mg/kg PD 136450 s.c. lasted for at least 8 h and was still effective after 14 days of treatment (18 mg/kg s.c. every 8 h). Acute application of L-365,260 at a dose of 3.8 mg/kg, which is equimolar (9.6 mumol) to 6 mg/kg PD 136450 reduced acid responses slightly. However, when L-365,260 was administered intravenously at a dose of 3 mg/kg, this antagonist completely abolished the pentagastrin-stimulated acid secretion. Furthermore, the effect of PD 136450 on endogenous gastric somatostatin and gastrin releases was tested in the isolated, vascularly perfused rat stomach. PD 136450 perfused at a concentration of 1 microM slightly increased somatostatin secretion after stimulation with a high dose of isoproterenol (10(-7) M). There was no effect of PD 136450 on basal or acetylcholine-stimulated gastrin secretion.

Role of cholecystokinin in the control of gastric somatostatin in the rat: in vivo and in vitro studies

Cholecystokinin (CCK) has been shown to be a powerful stimulus for somatostatin release from isolated canine fundic D-cells in short-term culture. The influence of the CCK analogue caerulein on the secretory activity of the D-cell in the intact stomach in vitro and the effect of elevated plasma levels of endogenous CCK on gastric somatostatin stores in vivo were investigated in the rat. Basal somatostatin secretion from the isolated, vascularly perfused rat stomach preparation was not affected by various doses of caerulein. Slight stimulation of somatostatin-like immunoreactivity (SLI) release by epinephrine was significantly inhibited by caerulein, whereas caerulein did not alter half-maximal stimulation of SLI secretion by isoproterenol. Rats with chronically elevated plasma CCK levels induced by experimental exocrine pancreatic insufficiency did not show any change in tissue concentrations of SLI or in D-cell number, both in the antrum and corpus. These data suggest that CCK--in contrast to dogs--is not an important modulator of gastric somatostatin in the rat.

Trophic Effect of Truncal Vagotomy on the Rat Pancreas

The trophic effect of truncal vagotomy was studied in rats. Three months after vagotomy and pyloroplasty pancreatic weight was significantly increased by 40% (p less than 0.001). Gastric stasis and consecutive distension of the stomach was observed in the majority of vagotomized animals despite pyloroplasty; the trophic effect of vagotomy on the pancreas was most pronounced in animals with severe stomach distension. Basal gastrin levels were increased after truncal vagotomy but did not correlate to gastric stasis and to the hypertrophy and hyperplasia of the exocrine pancreas. Basal pancreatic polypeptide hexapeptide levels were not altered after vagotomy. Morphometric studies on the endocrine pancreatic tissue showed that the relative volume density decreased due to the increase in exocrine tissue. However, the total islet cell mass remained constant. It is concluded that chronic truncal vagotomy has a trophic effect on the exocrine but not on the endocrine pancreas; additional factors besides gastrin seem to be responsible for this.