Histamine metabolism in human gastric mucosa. Effect of pentagastrin stimulation

The metabolism of histamine in the human gastric mucosa was studied in the basal state and during pentagastrin stimulation. Studies were made in healthy volunteers and in patients with peptic ulcer disease. Mucosal biopsies were taken from antral and oxyntic gland areas whereupon histamine content, histidine decarboxylase activity, and histamine methyltransferase activity were simultaneously assayed. Histamine content of the oxyntic gland mucosa was decreased as a consequence of pentagastrin administration in all groups studied, and this decrease was numerically largest in patients with duodenal ulcer disease. Pentagastrin induced a significant increase in histidine decarboxylase activity of the oxyntic gland mucosa with the most profound increase seen in patients with duodenal ulcer. The highest rates of histamine formation were present in the oxyntic mucosa of patients with Zollinger-Ellison syndrome. The activity of histamine methyltransferase was the same in all groups studied and was not changed by pentagastrin. In conclusion, pentagastrin administration in humans is followed by a significant mobilization of histamine only from the oxyntic gland mucosa, an effect that is more pronounced in patients with duodenal ulcer disease.     

Effects of proximal gastric vagotomy and antrectomy on parietal cell function in humans

Both proximal gastric vagotomy and antrectomy reduce maximal gastric acid secretion in vivo by about 60%. The combination of vagotomy and antrectomy reduces the maximal acid secretion by about 80%. This additive effect indicates that these surgical procedures differ in their mode of action. The function of isolated human oxyntic glands was studied before and after vagotomy and antrectomy, respectively, using radioactively labeled aminopyrine as a marker of parietal cell response. The basal accumulation increased after vagotomy, suggesting a vagally controlled inhibitory component. The carbachol response disappeared and the maximal response induced by histamine or dibutyryl-cyclic adenosine monophosphate was reduced by 60% (p less than 0.01) after vagotomy. This reduction could not be overcome by increasing the dose of dibutyryl-cyclic adenosine monophosphate. This indicates an intracellular effect of vagotomy peripheral to dibutyryl-cyclic adenosine monophosphate point of action. Antrectomy did not induce any statistically significant change at the glandular level, indicating that the reduced gastric acid secretion in vivo may be caused by a reduction in the number of oxyntic glands due to a removal of a trophic effect of antral gastrin.     

Effect of bilateral nephrectomy on serum gastrin concentration, gastric histamine content, histidine decarboxylase activity, and acid secretion in the rat.

Nephrectomy caused a marked increase in the concentration of circulating gastrin immunoreactivity but did not increase basal acid secretion. In normal rats, both histamine and pentagastrin stimulated gastric acid output, but after nephrectomy only histamine was effective. Histidine decarboxylase in the oxyntic mucosa was greatly activated following nephrectomy. Thus, in the nephrectomized rat gastrin (and pentagastrin) no longer evoked acid secretion, whereas it retained its ability to activate gastric histidine decarboxylase. The results suggest that the kidney is important for metabolism and excretion not only of gastrin but of humoral antagonists of gastrin-induced acid secretion as well.     

Growth of pancreas and gastrointestinal mucosa in antrectomized and gastrin-treated rats.

Growth responses to endogenous and exogenous gastrin were examined in the pancreas and gastrointestinal tract mucosa. Rats were either antrectomized to remove the primary source of endogenous gastrin or subjected to a sham operation. Three weeks after surgery, half of the antrectomized animals were injected ip with pentagastrin (250 microgram/day) four times per day. Injections were carried out for a week. Antrectomy resulted in serum gastrin levels approximately one third of normal. DNA synthesis and DNA and RNA content of the pancreas and oxyntic gland, duodenal, and colonic mucosa were significantly reduced by antrectomy. In each case, pentagastrin treatment restored DNA synthesis and RNA and DNA levels to normal. Significant decreases in pancreatic and colonic weights in antrectomized animals were also completely prevented by pentagastrin injection. These results indicate that endogenous gastrin has an important role in the regulation of pancreatic and colonic mucosal growth, in addition to its already established similar function in oxyntic gland mucosa.     

Antrectomy Does Not Accelerate Reversal of Omeprazole-Induced Trophic Effects in the Rat Stomach

The oxyntic mucosa in the rat stomach is under the influence of circulating gastrin. The histamine-producing enterochromaffin-like (ECL) cells constitute the major endocrine cell population in the oxyntic mucosa. They are notably sensitive to changes in the serum gastrin concentration and respond to long-term hypergastrinemia with hyperplasia, whereas hypogastrinemia induces hypoplasia. In the present study long-term, sustained hypergastrinemia was induced by daily treatment with a high dose of the proton pump inhibitor omeprazole. After 10 weeks omeprazoie-treated and control rats were antrectomized, resulting in prompt hypogastrinemia. Antrectomy was followed by a rapid reduction of the thickness of the oxyntic mucosa and a somewhat slower reduction of the ECL cell number in both omeprazoie-treated and control rats. The percentage decrease in the ECL cell number with time was similar in both groups; after 2-3 weeks the ECL cell number was half of that before antrectomy in both groups. Interestingly, however, 12 weeks after antrectomy the ECL cell number in the omeprazole-pretreated rats remained elevated compared with untreated rats. The histamine concentration of the oxyntic mucosa was markedly lowered within a week after antrectomy in both omeprazoie-treated and control rats. Although antrectomy induces hypogastrinemia and although atrophy develops rapidly in the oxyntic mucosa, the omeprazole-induced ECL cell hyperplasia was not completely reversed by antrectomy during the 12 weeks of examination.     

Antrectomy does not accelerate reversal of omeprazole-induced trophic effects in the rat stomach.

The oxyntic mucosa in the rat stomach is under the influence of circulating gastrin. The histamine-producing enterochromaffin-like (ECL) cells constitute the major endocrine cell population in the oxyntic mucosa. They are notably sensitive to changes in the serum gastrin concentration and respond to long-term hypergastrinemia with hyperplasia, whereas hypogastrinemia induces hypoplasia. In the present study long-term, sustained hypergastrinemia was induced by daily treatment with a high dose of the proton pump inhibitor omeprazole. After 10 weeks omeprazole-treated and control rats were antrectomized, resulting in prompt hypogastrinemia. Antrectomy was followed by a rapid reduction of the thickness of the oxyntic mucosa and a somewhat slower reduction of the ECL cell number in both omeprazole-treated and control rats. The percentage decrease in the ECL cell number with time was similar in both groups; after 2-3 weeks the ECL cell number was half of that before antrectomy in both groups. Interestingly, however, 12 weeks after antrectomy the ECL cell number in the omeprazole-pretreated rats remained elevated compared with untreated rats. The histamine concentration of the oxyntic mucosa was markedly lowered within a week after antrectomy in both omeprazole-treated and control rats. Although antrectomy induces hypogastrinemia and although atrophy develops rapidly in the oxyntic mucosa, the omeprazole-induced ECL cell hyperplasia was not completely reversed by antrectomy during the 12 weeks of examination.     

Studies of the release of gastrin from the human duodenum induced by gastrin-releasing peptide

In the present study the influence of duodenal exclusion and vagotomy on basal release of gastrin from extra-antral stores has been investigated in addition to the consequences of these procedures on the gastrin response to gastrin-releasing peptide (GRP) infusion. Basal gastrin concentrations and the response to GRP were measured in seven patients after a Whipple operation, in seven patients after antrectomy combined with selective gastric vagotomy and B I reconstruction, in seven patients operated on with antrectomy, selective gastric vagotomy, and Roux-en-Y reconstruction, and finally in seven patients after antrectomy, truncal vagotomy, and Roux-en-Y reconstruction. Gastrin was measured by a highly specific radioimmunoassay. Very low concentrations were obtained after a Whipple operation, and no increase followed GRP infusion. The basal gastrin concentrations were slightly higher in antrectomized patients, irrespective of whether a selective gastric vagotomy had been added. However, in these patients a significant gastrin response followed GRP infusion. Duodenal exclusion seemed not to influence the response to GRP. On the other hand, extragastric vagotomy was followed by low gastrin concentrations in the basal state and only a marginal response to GRP administration. These results strongly suggest that GRP releases gastrin from the human duodenal mucosa and that duodenal exclusion does not alter the response of the duodenal gastrin cells to GRP stimulation. Vagal denervation of the duodenal mucosa seems to suppress the gastrin response to GRP, indicating an excitatory influence of the vagus nerve.     

The vagus exerts trophic control of the stomach in the rat

Bilateral subdiaphragmatic truncal vagotomy results in great functional changes in the stomach although the changes in the gastric mucosal architecture are small. A trophic effect of the vagus on the stomach is revealed after unilateral vagal sectioning, taking advantage of the fact that, in the rat, each vagal trunk innervates only one side of the stomach, and that denervation of one side does not impair the functional capacity of the other. The denervated side of the stomach displayed atrophy that was reflected in reduced weight and height of the oxyntic mucosa and a reduced density of argyrophil cells. The lack of atrophy after bilateral vagotomy can be explained by counteracting forces, in that the subsequent rise in gastrin secretion (due to lack of acid feedback inhibition of gastrin release) probably masks antitrophic effects of the vagotomy per se. Interestingly, the number of somatostatin cells in the oxyntic mucosa was not reduced after unilateral vagotomy, nor was the weight of the antral mucosa or the density of enterochromaffin and gastrin cells in the antrum on the denervated side.     

Hypergastrinemia of antral origin in duodenal ulcer

A case of recurrent duodenal ulcer, basal gastric hypersecretion, and hypergastrinemia of antral origin is presented. The diagnosis was suggested preoperatively by stimulation tests with secretin and food. Billroth II antrectomy led to normalization of serum gastrin within half an hour. The gastrin content of the antral mucosa was not increased, neither was antral G-cell hyperplasia demonstrable. Postoperatively the basal gastric acid output and fasting serum gastrin levels were normal, without a postprandial increase in serum gastrin concentrations. The case does not support the existence of a specific disease called antral G-cell hyperplasia.     

Mechanism of gastric acid response to pylorus ligation: effects of nephrectomy

In the rat nephrectomy raises the serum gastrin concentration but makes the parietal cells refractory to gastrin. Pylorus ligation stimulates the gastric acid output by a long vago-vagal reflex in innervated animals and by an intramural reflex in chronically vagotomized animals. Nephrectomy reduced the acid response to pylorus ligation in vagally intact rats but enhanced it in vagotomized rats. The acid response to pylorus ligation in all the experimental groups was inhibited by a muscarinic blocker, atropine, and by an H2-antagonist, metiamide. The serum gastrin concentration was raised by nephrectomy and by vagal denervation. Histamine mobilization from gastric endocrine cells is reflected in the activity of gastric histidine decarboxylase. The enzyme activity in pylorus-ligated innervated rats was raised by pentagastrin, atropine, and metiamide. In nephrectomized rats the basal enzyme activity was high, and it was raised further, slightly but significantly, by pentagastrin. The basal enzyme activity in pylorus-ligated rats was also quite high after vagotomy, and it was raised further by pentagastrin. After vagotomy + nephrectomy the basal enzyme activity was very high; it was not raised further by pentagastrin. It appears that both vago-vagal and intramural reflexes involve a cholinergic and a histaminergic pathway, that gastrin is not important for the neurally mediated acid response elicited by pylorus ligation, and that the postulated histaminergic pathway does not involve histamine derived from the gastric endocrine-like cells.     

Adaptive duodenal endocrine cell changes after antrectomy. Experimental study in the rat

The known gastric endocrine relationship between "G" cells and "D" cells is altered after the loss of antral "G" cell population after antrectomy, leading to physiologic adaptative changes over the cell population producing gastrin and somatostatin in the duodenum, replacing thus the endocrine function of the resected gastric antrum. In this experimental study, Sprague-Dawley rats have been randomized in two groups, Control and Antrectomy with gastroduodenostomy, maintaining the alimentary stimulation of the duodenum. Endocrine "G" and "D" cell studies have been carried out by immunohistochemical staining with an Avidin-Biotin affinity technique. The statistical method used was the "t" test of Student. The results demonstrated a significant increase of the duodenal "G" cell population without changes of the duodenal "D" cell population after antrectomy and gastroduodenostomy. The endocrine cell ratio "G/D" in the duodenum increases due to the loss of antral gastrin release and the decrease of gastric acid output provoked by antrectomy.     

Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa.

The stimulation of acid secretion by gastrin may in the rat be explained solely by gastrin-induced histamine release. This study was done to examine whether histamine could mediate the general trophic effect of gastrin on the oxyntic mucosa, by using a long-acting selective histamine-1 antagonist (astemizole) alone or with omeprazole-induced hypergastrinaemia for 90 days in female Sprague-Dawley rats. At day 90, isolated vascularly perfused rat stomachs were prepared to study maximal gastrin- and histamine-stimulated acid and pepsinogen outputs and maximal gastrin-stimulated histamine release. Oxyntic mucosa morphometry, mucosal histamine and pepsinogen contents, and plasma gastrin and histamine levels were also determined. For the first time, omeprazole has been found to inhibit gastric emptying and to increase plasma histamine. As compared with controls, astemizole alone did not influence plasma gastrin, increased plasma histamine in only some rats, and gave a slight increase in all other variables. Together with omeprazole, it further increased variables already stimulated by omeprazole. Thus, mucosal thickness, histamine concentration, and chief-cell density in oxyntic mucosa were significantly higher in astemizole/omeprazole-treated rats than in omeprazole-treated rats. Gastrin-stimulated histamine release was increased in both astemizole- and omeprazole-treated rats. For all rats plasma histamine was significantly correlated with plasma gastrin and with numerical fundic argyrophil cell density. In conclusion, the present study confirms the trophic effect of gastrin and shows a slight trophic effect of astemizole on the oxyntic mucosa. It also shows that plasma histamine may reflect the argyrophil cell density in the oxyntic mucosa and that omeprazole inhibits gastric emptying.     

The Type of Anastomosis after Selective Gastric Vagotomy and Precise Antrectomy Is of No Importance for Basal and Postprandial Serum Gastrin Concentration

Twenty-six patients were treated for duodenal or recurrent ulcer with selective gastric vagotomy plus precise antrectomy—that is, complete removal of the entire antrum. Sixteen had a gastroduodenal anastomosis and 10 a gastrojejunal anastomosis. Fasting and protein meal-stimulated serum gastrin concentration was measured in 10 patients before antrectomy and in all after the operation. Fasting serum gastrin concentration was reduced and food-stimulated gastrin response abolished irrespective of the type of the anastomosis. It is concluded that a postprandial gastrin rise means retained antral tissue in the gastric remnant and that neither protein nor mechanical stimulation of the passage of food through the duodenum stimulates the duodenal G-cells to gastrin release.     

Effect of epidermal growth factor on the development of rat gastric mucosa

Epidermal growth factor (EGF) has been shown to stimulate the growth of adult rat gastric mucosa and to increase DNA synthesis of mouse small and large intestinal mucosa. This study examines whether EGF affects the functional and structural development of the rat gastric mucosa. Rats were injected with 20 micrograms/kg EGF three times/day for 5 days beginning on the 10th day after birth. A control group of animals received saline injections of identical volume. All rats were killed on day 15. EGF significantly increased the weight of the whole stomach and the DNA, RNA, and protein content of the oxyntic gland mucosa, but had no effect on the RNA/DNA ratio, or antral and serum gastrin levels. Two groups of similarly treated rats, were anesthetized with ether, pylorus-ligated, and injected with either saline or pentagastrin (250 micrograms/kg) after they had recovered from anesthesia. EGF-treated rats had significantly higher rates of basal acid secretion and pentagastrin-stimulated acid secretion than the saline-treated controls. EGF, however, did not alter basal or pentagastrin-stimulated pepsin secretion nor did it change mucosal pepsinogen content. These results indicate that EGF stimulates oxyntic mucosal growth in unweaned rats but that it does not lead to precocious maturation or functional development.     

Sample taking problems in measuring actual histamine levels of human gastroduodenal mucosa: specific and general relevance in clinical trials on peptic ulcer pathogenesis and selective proximal vagotomy.

Changes in histamine storage in the oxyntic mucosa of duodenal ulcer patients and their reversal by vagotomy and the histamine H2-antagonist cimetidine supported the hypothesis that histamine could be a causal factor in peptic ulcer pathogenesis. The specificity of these findings was impaired by problems in biopsy taking, however, and in the preparative steps before measuring the actual histamine contents in all parts of the gastric mucosa and in the duodenum. A prospective trial was carried out in 190 patients to identify these sources of bias and to overcome them by appropriate study designs. Usually a direct correlation was found between weight of biopsy and mucosal histamine content. This problem was solved by selecting a biopsy forceps producing smaller variations in sample size, by limiting the time of cold ischaemia to four to five minutes only and by taking three biopsy specimens for each single histamine value. The actual histamine content of mucosal biopsies remained constant for about four to five minutes only. The 'disappearance' rate was faster in control subjects than in duodenal ulcer patients. Hence by variation of the cold ischaemia time any artefacts of differences between mucosal histamine levels in controls and duodenal ulcer patients could be produced. Using the optimised sample taking procedure mucosal histamine contents of several gastric regions and the duodenal bulb were measured in 24 patients with duodenal ulcer, after selective proximal vagotomy without drainage and in control subjects without any stomach disease (randomised controlled trial). The histamine content was lower in all parts of the upper gastrointestinal tract in duodenal ulcer patients than in controls and was raised again in all regions after selective proximal vagotomy. As the most likely hypothesis it is suggested that vagal reflexes with afferent fibres coming from the oxyntic mucosa stimulate histamine release in duodenal ulcer patients by efferent peptidergic neurones to all parts of the stomach and the duodenum where the ulcer lesion is situated.     

Early or Late Operation in the Treatment of Crohn's Disease

The present report describes the long-term effects of antrectomy, antrum exclusion, portacaval shunt, omeprazole treatment, or the combination of omeprazole treatment and portacaval shunt on the number and density of somatostatin cells in the oxyntic mucosa of the rat. Antrectomy, which is associated with hypogastrinemia, raised the number and density of the somatostatin cells, whereas antrum exclusion and omeprazole treatment, which are associated with hypergastrinemia, reduced the number and density of the somatostatin cells. Portacaval shunt, which is associated with hypogastrinemia, increased both the number and the density. Omeprazole treatment of portacava-shunted rats suppressed or even reversed the somatostatin cell hyperplasia after portacaval shunt alone. From these findings it is unlikely that gastrin stimulates the proliferation of somatostatin cells in the oxyntic mucosa. In fact, there seems to be an inverse relationship between the serum gastrin concentration and the somatostatin cell number.     

Somatostatin cells in the oxyntic mucosa of hypo- or hypergastrinemic rats.

The present report describes the long-term effects of antrectomy, antrum exclusion, portacaval shunt, omeprazole treatment, or the combination of omeprazole treatment and portacaval shunt on the number and density of somatostatin cells in the oxyntic mucosa of the rat. Antrectomy, which is associated with hypogastrinemia, raised the number and density of the somatostatin cells, whereas antrum exclusion and omeprazole treatment, which are associated with hypergastrinemia, reduced the number and density of the somatostatin cells. Portacaval shunt, which is associated with hypogastrinemia, increased both the number and the density. Omeprazole treatment of portacaval--shunted rats suppressed or even reversed the somatostatin cell hyperplasia after portacaval shunt alone. From these findings it is unlikely that gastrin stimulates the proliferation of somatostatin cells in the oxyntic mucosa. In fact, there seems to be an inverse relationship between the serum gastrin concentration and the somatostatin cell number.     

Neural pathways for the release of gastrin,cholecystokinin, and pancreatic polypeptide after a meal in dogs

We have measured gastrin, cholecystokinin (CCK), and pancreatic polypeptide (PP) release after a meal in normal dogs under basal conditions and during atropine infusion, and after various neural sections. Denervation of the gastric antrum (antral vagotomy) abolished the early part of the gastrin response to food. Truncal vagotomy, celiac ganglionectomy, and atropine reduced the early release of CCK, which occurred before the start of gastric emptying, suggesting that a neural, cholinergic mechanism may release CCK immediately after a meal. PP release was abolished by truncal vagotomy, and also by antral vagotomy. As no direct pathways are known between the antrum and the pancreas, this suggests either that antral afferents are essential for this response or that vagally mediated hormone release from the antrum mediates PP release.     

Gastrin, antral g cells, and gastric acid in secretagogue-induced and antihistamine-inhibited duodenal ulcers.

In fasting control rats there was continuous basal gastric acid secretion, with a low plasma gastrin and antral G-cells full or immunofluroescent gastrin. After subcutaneous infusion of the gastric secretagogues, pentagastrin + carbachol, there was a six-hour period of gastric hypersecretion, but no change in plasma and G-cell gastrin. Pretreatment with the antihistamine derivative, Pfizer UK-9040, decreased both basal and stimulated acid secretion, whereas plasma gastrin levels increased and the antral G-cells were emptied of gastrin. These results suggest that this antihistamine derivative decreases gastric acid secretion by a direct action on the parietal cells and not by reducing gastrin release from the G-cells. The increased release of gastrin from the G-cells may be secondary to decreased gastric acid production, or more probably by a direct stimulation of the antral G-cells.     

Role of antral histamine and gastrin in gastric acid secretion: experimental facts and hypotheses

Histamine isolated from the gastric antral mucosa probably potentiates the secretory activity of gastrin by suppression of the inhibitory effect of somatostatin on gastrin. In dogs with gastric fistula and Heindenhain pouch, acid secretion was obtained in response to exogenous gastrin, antral histamine or various combinations of both stimulants. Acid output was expressed by graphic representation: the administered doses of gastrin and antral histamine were reported respectively, on the X and Y axis, the acid output values were plotted on the intersection of the stimulant dosages used, and curves of equal acid outputs were drawn. This representation was used to approach the physiological and physiopathological mechanisms of gastric secretion, considering that gastrin and antral histamine could be the main parameters. It also seems possible that an histaminic factor could be involved in secretion processes. Excess or lack of one of the other stimulants could be responsible for an increased or a decreased secretory response: these facts can be related to the curves of high acid output or low acid output observed in the animal. Thus, histamine, especially of antral origin, might be an important component of the secretion mechanism, by modulation of gastrin activity; both substances could be the main mediators of somatostatin-induced inhibition.