P. Skov Olsen

Brunner's Glands of the Rat During Cysteamine Ulceration

Duodenal ulcers can be produced in rats by subcutaneous administration of cysteamine-HCl. The pathogenesis of these ulcers has not been fully explained. Increased acid secretion is necessary but not sufficient for ulcer production. In the present study we have observed pronounced alterations in the histologic appearance of the duodenal glands of Brunner during ulcer formation. The secretory cells became extremely flattened without mucus content and the lumina of the acini dilated. Changes became most pronounced between 4 and 8 h after administration of cysteamine. Repeated injections of pentagastrin in a dosage inducing an acid response equivalent to the one induced by cysteamine did not produce any histologic changes in Brunners glands or any ulcerations. When cysteamine was administered to rats with chronic gastric fistulas draining the gastric secretions, no duodenal ulcerations were produced, but Brunners glands still became depleted of mucus. These findings suggest that the histologic changes in Brunners glands are not secondary either to the increased acid secretion induced by cysteamine or to ulcer formation. Together with our previous demonstration of a marked reduction duodenal secretion in the first 10 h after cysteamine administration, the results of the present study suggest an inhibitory effect of cysteamine on the synthetic activity of Brunners glands rather than an impaired release mechanism. The effect of cysteamine on Brunners glands may be an important factor in the pathogenesis of cysteamine-induced duodenal ulceration.

Calcium and stimulus-secretion coupling in gastric fundic mucosa. Effect of inhibition of calcium transport by verapamil on gastric acid secretion in the isolated guinea pig fundic mucosa and in healthy subjects.

The effect on gastric acid secretion of blocking transmembrane Ca2+ influx into the parietal cells has been studied in the isolated guinea pig fundic mucosa and in healthy volunteers. Verapamil inhibited in a dose-related manner histamine-stimulated acid secretion in the guinea pig mucosa, whereas stimulation with theophylline and dibutyryl cyclic-AMP was unaffected. The effect of verapamil (Isoptin, 2.0 mg/h) on acid secretion stimulated by increasing doses (50, 200, 500 ng/kg-h) of 15-leucine synthetic human gastric I was studied in seven healthy volunteers, alone and in combination with infusion of calcium gluconate (1.0 meq Ca2+/kg-h). Verapamil inhibited the acid response to the lowest dose of gastrin, resulting in a significant increase of D50 of 15-leucine synthetic human gastrin I. This effect was partly reversed by calcium infusion. It is concluded that one of the mechanisms by which extracellular calcium concentration influences acid secretion is by transmembrane influx of Ca2+ during stimulation.

Role of delayed gastric emptying in the pathogenesis of cysteamine-induced duodenal ulcer in the rat.

Cysteamine is a potent duodenal ulcerogen in rats. It has been demonstrated to inhibit gastric empyting, whose role in ulcer formation is unknown. In the present study the effect of cysteamine on gastric motility and emptying rate in rats was studied by direct fluoroscopic observation. The delayed gastric empyting was due to a pronounced relaxation of the stomach and a complete blocking of gastric peristalsis. These effects have their maximum within the first 4 h after administration of cysteamine. Thereafter peristalsis and gastric empyting slowly return. In controls contrast medium administered intragastrically was completely discharged from the stomach within 30 min. After cysteamine the first small amounts of contrast medium were discharged into the duodenum after 4 h, and contrast medium remained in the stomach for at least 12 h after administration. The size of the stomach reached a maximum after 3 h and approached normal values again after 12 h. Because of complete gastric retention the acid gastric secretions provoked by cysteamine probably accumulate in the stomach during the first 4 h after cysteamine administration, and because of the absence of peristalsis they are not mixed with gastric contents. After 4 h this pool of undiluted gastric secretions gradually is emptied into the duodenum, where the mucosal resistance is reduced by inhibition of the secretory activity of Brunners glands, and ulceration rapidly develops. The time relationship is supported by histopathologic findings and measurements of gastric acid secretions after cysteamine. Vagotomy augmented the inhibitory effect of cysteamine on gastric motility. The relaxation was even more pronounced, and contrast medium was not discharged from the stomach within 24 h. In these rats cysteamine induced ulcerations in the stomach.

Effect of secretin and glucagon on Brunner's gland secretion in the rat.

Brunners gland secretion in response to infusion of secretin and glucagon was studied in the rat. Secretin was infused in doses of 15, 150 and 1500 ng/kg/h. All dose significantly increased bicarbonate and protein output and depleted Brunners glands of PAS-positive mucin. Bicarbonate secretion was related to plasma secretin concentration, and a marked stimulatory effect of secretin was found in very low, probably physiological, plasma concentrations. Maximal bicarbonate output was obtained at a plasma concentration of secretin about 20 pmol/l. Glucagon was infused at a rate of 1.0 micrograms/kg/h and did not influence secretion rate or cell morphology. Also large doses of 5.0 and 50.0 micrograms/kg/h had no effect on Brunners gland secretion. It is concluded that secretin in very low plasma concentrations stimulates secretion of bicarbonate, protein and mucus from Brunners glands in the rat, while glucagon has no effect, and it is suggested that secretin may be involved in the physiological regulation of Brunners gland secretion.

Neurotensin inhibits meal-stimulated gastric acid secretion in man.

The effect of physiological doses of exogenous neurotensin on meal-stimulated gastric acid secretion and serum gastrin concentration was investigated in six healthy subjects. Acid secretion was reduced by 32% during intravenous infusion of neurotensin, the plasma neurotensin concentration being within physiological range. Serum gastrin concentration was unchanged during infusion of neurotensin. The results strongly suggest that neurotensin participates in the regulation of gastric acid secretion and support the theory that neurotensin may play a role in the intestinal phase of gastric acid secretion in man.

The mechanism of gastrin release in cysteamine-induced duodenal ulcer.

Duodenal ulcer can be induced in rats by a single dose of cysteamine. The ulcer formation is accompanied by acid hypersecretion and elevated serum gastrin levels. This study was performed to elucidate the mechanisms of gastrin release after an ulcerogenic dose of cysteamine. Cysteamine induced a rise in serum gastrin from 29 +/- 5 pg/ml to a maximum of 203 +/- 62 pg/ml after 3 h in unoperated rats, whereas no rise was seen in vagotomized or antrectomized rats. The beta-adrenergic blocking agent propranolol strongly inhibited cysteamine-induced gastrin release, whereas atropine dependent on an intact vagus and may be mediated by beta-adrenergic receptors.

Stimulatory Effect of Epidermal Growth Factor on Liver Regeneration after Partial Hepatectomy in Rats

The effect of epidermal growth factor (EGF) on liver regeneration was investigated in rats subjected to partial hepatectomy. In a dose-response study EGF in doses of 6 and 24 nmol/kg x day increased liver regeneration after treatment for 48 h compared with controls, whereas a dose of 48 nmol/kg x day had no effect. In a subsequent study EGF, 6 nmol/kg x day, accelerated liver regeneration significantly after 36, 48, and 72 h of treatment. A possible influence of EGF on other hepatotrophic factors was investigated. No changes in the concentration of gastrin, insulin, or glucagon was found in portal venous blood. This study has shown that EGF in small doses can stimulate liver regeneration, whereas higher doses are ineffective. The study suggests that EGF should be regarded as a hepatotrophic factor.

Effect of neurotensin and neurotensin fragments on gastric acid secretion in man.

The effect of intravenous infusion of neurotensin (NT) and NT-fragments on pentagastrin stimulated gastric acid secretion was investigated in healthy subjects. Neurotensin was infused in three doses (72, 144 and 288 pmol/kg per h). An N-terminal fragment (NT 1-8), a C-terminal fragment (NT 8-13) and an NT-analogue, substituted at the C-terminal tyrosine residue (Phe11-NT) were infused in two doses (72 and 144 pmol/kg per h). Concentrations of the infused peptides were measured in peripheral venous blood by radioimmunoassay. Plasma levels of NT 1-13, NT 1-8 and Phe11-NT increased in a dose-dependent manner; NT 1-13 to 50 (34-69), 78 (54-113) and 143 (112-242) pmol/l (medians and range) at 72, 144 and 288 pmol/kg per h, NT 1-8 to 405 (340-465) and 1215 (915-1300) pmol/l, and Phe11-NT to 200 (110-245) and 390 (250-410) pmol/l at 72 and 144 pmol/kg per h, respectively. Increases in plasma levels of NT 8-13 could not be detected during the infusion, suggesting that the fragment is rapidly metabolized in man. Neurotensin 1-13 inhibited gastric acid secretion in a dose-dependent manner and the decrease in gastric acid secretion was linearly related to plasma levels of NT 1-13. Neurotensin 1-8 and NT 8-13 inhibited gastric acid secretion only at 144 pmol/kg per h, while the analogue Phe11-NT had no effect. The results showed that the inhibition of gastric acid secretion produced by NT was dose-dependent and linearly related to circulating levels of NT, and that under physiological conditions this effect presumably is elicited by the C-terminal part of the peptide.

The Effect of Vasoactive Intestinal Polypeptide on Meal-Stimulated Gastric Acid Secretion in Man

The effect of vasoactive intestinal polypeptide (VIP) on meal-stimulated gastric acid secretion was studied in six healthy volunteers. Acid secretion was stimulated by instillation of a 10% solution of peptone, which was adjusted to pH 5.5, circulated through the stomach via a double-lumen gastric tube by a peristaltic pump. The acid secretion was estimated by continuous titration by a pH-stat. The subjects were studied twice on separate days, receiving an intravenous infusion of either VIP (1 microgram/kg/h) or saline. No effect on acid secretion was found. Mean serum gastrin concentration rose from 42 pmol/l to 150 pmol/l during meal stimulation and was unaffected by infusion of VIP. Plasma VIP concentration during infusion of saline was 6.8 pmol/l and during VIP infusion, 82.8 pmol/l. Plasma VIP concentration was unaffected by the peptone meal.

The Effect of a Synthetic Met-Enkephalin Analogue (Fk 33–824) On Gastric Acid Secretion and Serum Gastrin in Man

A synthetic met-enkephalin analogue was infused into seven healthy human subjects on a background infusion of pentagastrin to study the effect on gastric acid secretion and serum gastrin concentration. Gastric acid secretion rose from 4.2 meq H+/15 min to 7.8 meq H+/15 min during infusion of met-enkephalin, 0.1 micrograms/h. Met-enkephalin in a dose of 1 microgram/kg/h had no effect on pentagastrin-stimulated acid secretion. Serum gastrin concentration remained unchanged throughout the study. It is suggested that met-enkephalin could be a partial agonist on the parietal cell. The possible role of met-enkephalin in the cephalic phase of gastric acid secretion is discussed.