Jan Axelson

Gastrin stimulates the self-replication rate of enterochromaffinlike cells in the rat stomach: Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats

The enterochromaffinlike cells in the rat stomach are rich in histamine and are thought to be under the influence of gastrin. The effect of sustained endogenous and exogenous hypergastrinemia on the activity and proliferation rate of the enterochromaffinlike cells was studied by determining the histidine decarboxylase activity and histamine concentration and by combining histamine immunocytochemistry and autoradiography after in vivo labeling with [3H]thymidine. The proliferation rate of the stem cells in the oxyntic mucosal progenitor zone was also studied. Exogenous hypergastrinemia was induced by infusion of rat gastrin-17 (60 nmol.kg-1.day-1). Endogenous hypergastrinemia was induced by inhibition of gastric acid secretion with omeprazole (80 mumol.kg-1.day-1) or ranitidine (1200 mumol.kg-1.day-1). The effect of omeprazole was also studied in antrectomized rats. In intact rats, all treatments resulted in elevated plasma gastrin levels and were accompanied by an increase in the histidine decarboxylase activity and the histamine content of the oxyntic mucosa. This resulted in an increase in the enterochromaffinlike cell proliferation rate, leading to enterochromaffinlike cell hyperplasia. The number of labeled stem cells was increased, but this effect was not as pronounced as in the enterochromaffinlike cells. In antrectomized rats, the inhibition of acid secretion by omeprazole did not result in elevated plasma gastrin or in an increase in the activity or number of enterochromaffinlike cells, indicating that omeprazole per se had no effect on these cells. These data support the view that gastrin stimulates the proliferation rate of both enterochromaffinlike cells and stem cells. Gastrin also stimulates the activity of the enterochromaffinlike cells.

Trophic effects of continuous infusion of [Leu15]-gastrin-17 in the rat

This report describes the trophic effects of exogenous gastrin on the digestive tract and pancreas and the effect on the density of enterochromaffinlike cells in the oxyntic mucosa of the stomach. Female rats were given 1.2 or 2.4 nmol/kg.h of synthetic human [Leu15]-gastrin-17 for 28 days (via osmotic minipumps implanted subcutaneously). As a result, measurable plasma gastrin increased from about 230 pg/ml in the controls to about 500 and 800 pg/ml in the low- and high-dose groups, respectively. The trophic effects of gastrin were reflected in increased stomach weight and oxyntic mucosal mass. Gastrin also increased the enterochromaffinlike cell density and associated parameters (histamine concentration and histidine decarboxylase activity) but was without demonstrable effects on other parts of the digestive tract and pancreas. The results show that continuous infusion of exogenous gastrin for 28 days induces trophic changes similar to those seen after a period of hypergastrinemia induced by treatment with effective inhibitors of acid secretion.

Gastrectomy Causes Bone Loss in the Rat: Is Lack of Gastric Acid Responsible?

Total gastrectomy or resection of the acid-producing part of the stomach (fundectomy) in the rat induced a marked and rapid reduction in bone wet weight, ash weight, and density (expressed as ash weight in mg/mm3 bone). Bone volumes were also affected but not as much. The radius, sternum, tibia, and femur were studied. Three weeks after gastrectomy the bone ash weight was reduced by almost 30% and the density by more than 25%. Maximum bone loss (approximately 40%) occurred about 6 weeks after the operation. The bone loss after gastrectomy was somewhat greater than that after fundectomy, whereas antrectomy had a marginal effect only. The percentage trabecular bone volume, calculated from morphometric analysis of histologic sections of the tibia, was greatly reduced by gastrectomy (approximately 50%), somewhat less so by fundectomy, whereas antrectomy had little effect. We set out to study whether calcium malabsorption could explain the bone loss after gastrectomy. Gastric acid is thought to facilitate the intestinal absorption of ingested calcium by mobilizing calcium from insoluble complexes in the diet. The possibility that lack of acid might contribute to the bone loss after gastrectomy was examined in experiments in which the proton pump inhibitor omeprazole was given for 4-8 weeks at such a dose (400 mumol/kg/day) that acid secretion was blocked almost completely during the period of study. This treatment was without effect on bone. However, the possibility could not be excluded that gastrectomized rats develop calcium deficiency for some reason other than lack of acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Endogenous and Exogenous Cholecystokinin and of Infusion with the Cholecystokinin Antagonist L-364,718 on Pancreatic and Gastrointestinal Growth

Continuous subcutaneous infusion of cholecystokinin (CCK-8; 5 micrograms/kg/h) to rats for 7 weeks raised the plasma CCK concentration almost fivefold and increased the pancreatic weight by about 50% but was without effect on the gastrointestinal tract. Continuous subcutaneous infusion of the CCK antagonist L-364,718 (200 micrograms/kg/h) for 7 weeks reduced the weight of the pancreas by about 30% but was without effect on the gastrointestinal tract. The effect of continuous subcutaneous infusion of CCK-8 and L-364,718 in combination was very similar to that of L-364,718 alone. Pancreaticobiliary diversion (PBD) induced a nearly 10-fold increase in the plasma CCK concentration 3 and 7 weeks after the operation. The serum gastrin values were unaffected. The weight of the pancreas was more than doubled after 7 weeks. At the same time the small intestine had gained weight, but the colon was unaffected. Continuous subcutaneous infusion of L-364,718 prevented the effect of PBD on the pancreas. On the basis of the assumption that L-364,718 is a specific antagonist of CCK, we conclude that endogenous CCK has a trophic effect on the pancreas but not on the gastrointestinal tract and that it is essential for normal pancreatic growth.

Hypergastrinaemia evoked by omeprazole stimulates growth of gastric mucosa but not of pancreas or intestines in hamster, guinea pig and chicken

Treatment of chickens, hamsters and guinea-pigs with the long-acting anti-secretagogue omeprazole resulted in elevated levels of serum gastrin. The chickens received 400 mumol/kg by i.m. injection once daily, the hamsters and guinea-pigs received the same dose by the oral route once daily. In all 3 species omeprazole raised the intragastric pH to 4, measured 12-14 h after the administration of the drug. After 10 weeks of treatment, trophic changes were observed in the stomach of hamster and guinea pig and in the proventriculus of chicken. The trophic changes were manifested in a greatly increased stomach weight and gastric mucosal mass. There were no trophic effects outside the stomach (or proventriculus). The results are in agreement with previous observations in the rat and support the view that long-lasting sustained hypergastrinaemia causes trophic changes in the stomach but not in the pancreas or in the intestines.

Evidence that gastrin enhances 45Ca uptake into bone through release of a gastric hormone

An acute challenge with gastrin-17 enhanced the uptake of 45Ca into sternum and several long bones in rats by about 10-30%; gastrectomy prevented this effect. Long-term treatment with (Leu15)-gastrin-17 (continuous infusion via osmotic minipumps for 4 weeks) enhanced the uptake of 45Ca into bone (examplified by radius and sternum) by 18-26% (tested on the last day of the infusion). Surgical removal of the acid-producing part of the stomach (fundectomy) or treatment with the anti-ulcer drugs, ranitidine (a histamine H2-receptor antagonist administered by continuous infusion) or omeprazole (an H+/K(+)-ATPase inhibitor administered daily by gastric tube for 4 weeks), induced sustained hypergastrinemia (through loss of acid feedback inhibition of gastrin release). The ranitidine- and omeprazole-evoked hypergastrinemia was associated with 32-62% enhancement of bone 45Ca uptake but the hypergastrinemia of fundectomized rats was not. Gastrectomy abolished the effect of omeprazole. We suggest that exogenous and endogenous gastrin influences calcium uptake into bone indirectly by releasing a calciotropic hormone (gastrocalcin) from the acid-producing part of the stomach. The bone ash weight was reduced by gastrectomy or fundectomy (4 weeks), but neither ranitidine nor omeprazole-evoked hypergastrinemia (4 weeks) raised the bone ash weight. The stimulated calcium uptake into bone of hypergastrinemic rats treated with ranitidine or omeprazole was associated with a 22-32% increase in the density of osteoclasts in the tibia. This finding is in line with the hypothesis that long-lasting hypergastrocalcinemia produces accelerated turn-over of bone rather than increased bone calcium content.

Cholecystokinin Is Responsible for Growth of the Pancreas after Pancreaticobiliary Diversion in Rats

Pancreaticobiliary diversion (PBD) caused a more than twofold increase in pancreatic weight after 10 days, with no further increase after 15 or 20 days or 7 weeks. Although the weight gain after PBD to a minor extent (10%) reflected increased water content, the main cause was hypertrophy and hyperplasia with increased pancreatic protein and DNA content. The cholecystokinin (CCK) concentrations in plasma were increased 10-fold from the 5th postoperative day. The trophic effects on the pancreas were completely abolished by the CCK antagonist L-364,718. Further, the antagonist caused a significant reduction in pancreatic weight, protein, and DNA in otherwise untreated controls. We conclude that PBD in rats induces trophic effects on the pancreas by increasing circulating CCK concentrations and that CCK is important for normal pancreatic growth.

Preoperative ropivacaine infiltration in breast surgery

The aim of the study was to investigate whether preoperative infiltration with ropivacaine in conjunction with breast surgery improves postoperative pain management and attenuates postoperative nausea and vomiting.

Hypergastrinaemia induced by acid blockade evokes enterochromaffin-like (ECL) cell hyperplasia in chicken, hamster and guinea-pig stomach.

SummaryTreatment of chickens, hamsters and guinea-pigs with large doses of the long-acting antisecretory agent omeprazole for 10 weeks resulted in elevated serum gastrin levels and in increased stomach weight and mass of oxyntic mucosa. Also the antral gastrin cell density was increased. Another striking effect was the hyperplasia of the histamine-producing enterochromaffin-like (ECL) cells — a prominent endocrine cell population with unknown function — in the oxyntic mucosa. Accordingly, the gastric mucosal histamine concentration and rate of histamine formation were increased in all three species. The results suggest that marked and long-lasting suppression of acid secretion leads to elevated serum gastrin levels and diffuse ECL cell hyperplasia not only in the rat, as previously seen, but also in the chicken, hamster and guinea-pig; this hyperplasia is associated with accelerated histamine formation in all three species. The following sequence of events is suggested to occur in mammalian as well as submammalian vertebrates: suppression of acid secretion — hypergastrinaemia — ECL cell hyperplasia.

Gastrin and the vagus interact in the trophic control of the rat oxyntic mucosa.

Gastrin is a trophic hormone for the stomach, and permanent reduction of circulating gastrin by antrectomy leads to atrophy of the oxyntic mucosa, including a reduced density of histamine-storing endocrine cells (so-called ECL cells). Recently, it was proposed that also the vagal nerve has a trophic influence on the stomach. The two vagal trunks innervate the anterior and posterior side of the gastric wall, respectively. This arrangement makes it possible to denervate one side of the stomach selectively. The objective of the present study was to examine the consequences of combined antrectomy and vagotomy (unilateral or bilateral). Male Sprague-Dawley rats were subjected to unilateral or bilateral subdiaphragmatic truncal vagotomy with or without antrectomy. Control rats were sham-operated. The rats were killed 8 weeks after the operation. Bilateral vagotomy raised the basal serum gastrin concentration (fasting level). The thickness of the oxyntic mucosa and the density of ECL cells were not significantly different from age-matched vagally intact controls. Unilateral vagotomy induced no change in the basal serum gastrin concentration, nor did it affect the mucosa on the intact side. On the denervated side, however, there was reduced mucosal thickness and a greatly reduced ECL cell density. With a combination of antrectomy and vagal denervation the decrease in ECL cell density was exaggerated compared to the effect of antrectomy or unilateral vagotomy alone.(ABSTRACT TRUNCATED AT 250 WORDS)