Histamine metabolism of the gastric mucosa following antrectomy

1. Histamine metabolism of the gastric mucosa in rats subjected to antrectomy, antrectomy and substitution with pentagastrin and exclusion of the antrum has been investigated employing various in vivo and in vitro methods.2. Mucosal histamine formation after antrectomy fell to about one third, whereas after antrum exclusion histamine formation increased many-fold.3. After antrectomy, mucosal histamine content decreased, and increased after antrum exclusion.4. After total gastrectomy, (a) whole-body histamine formation was reduced to about half, as judged by determining histamine excretion, and (b) pentagastrin infusion did not increase histamine excretion, showing absence of histamine mobilization from extra-gastric sources. In rats with the stomach retained, infusion of pentagastrin induced a dose-dependent increase in histamine excretion.5. Kinetic studies in which [(14)C]histidine was injected and the resulting urinary [(14)C]histamine determined showed that on pentagastrin infusion after antrectomy newly formed histamine was initially mobilized to a larger extent than in the controls.6. Antrectomized rats were subjected to substitution treatment by three injections per day of pentagastrin. After 3 weeks of substitution, histamine excretion was considerably higher than without substitution. After 6 weeks of substitution, histamine excretion was about the same in the substituted antrectomized, non-substituted antrectomized and sham-operated groups. Neither time nor substitution could, however, normalize the excretion of histamine on pentagastrin stimulation after antrectomy.7. In non-substituted antrectomized rats, pentagastrin was less effective in elevating mucosal histamine formation than in the substituted and sham-operated groups.8. The indispensability of the rat in this kind of study is emphasized.     

The release of histamine during gastric acid secretion in conscious rats

1. Conscious gastric-cannulated rats were given [(3)H]histidine and aminoguanidine by dosage procedures intended to build up fast-turnover and slow-turnover pools of tissue [(3)H]histamine. Acid secretion was stimulated by I.V. infusion of pentagastrin, and the [(3)H]histamine content of gastric juice and excretion in urine were determined at 30 min intervals.2. The amount of [(3)H]histamine in gastric juice derived from either a slow-turnover or fast-turnover pool was very low in unstimulated animals, and was not altered during pentagastrin-stimulated acid secretion.3. From a slow-turnover pool pentagastrin caused increased urinary excretion of [(3)H]histamine. This was abolished by gastrectomy, so that the [(3)H]histamine liberated by pentagastrin from this pool appears to have been derived from the stomach. Evidence was not found for the existence of a slow-turnover histamine pool in the glandular mucosa of the stomach, and the source within the stomach of this pentagastrin-liberated histamine is thus uncertain.4. From a fast-turnover pool pentagastrin did not cause an increased urinary excretion of [(3)H]histamine. The amount of [(3)H]histamine excreted by gastrectomized rats was not different from that produced by gastric-cannulated animals. This suggests that a high proportion of urinary histamine derived from a fast-turnover pool was non-gastric in origin.5. Differences in the time scale of [(3)H]histamine release and acid secretion were not found. In some experiments the urinary output of [(3)H]histamine was prolonged beyond the end of pentagastrin administration and gastric acid secretion. However, the overall data do not suggest that urinary histamine output and gastric acid secretion take different time courses.     

Acid secretion and mobilization of gastric mucosal histamine on combined cholinergic and pentagastrin stimulation

Acid secretion and urinary excretion of histamine in response to vagus excitation, infusion of methacholine or pentagastrin and to various combinations of these stimuli, were concomitantly studied in rats with Pavlov pouches. Vagus excitation (2-deoxy-d-glucose) enhanced the secretory response to pentgastrin, the effect being most conspicuous with small doses of pentagastrin, probably corresponding to the physiological dose-range of gastrin. Vagus excitation marginally increased excretion of histamine but did not seemingly encreased excretion of histamine but did not seemingly enhance excretion of histamine in response to pentagastrin. Methacholine substantially enhanced the secretory response to all doses of pentagastrin studied, but did not further increase histamine excretion. The secretory effect of a maximal dose of pentagastrin or histamine was about the same when combined with methacholine. The site of interaction between cholinergic stimuli, pentagastrin and gastric mucosal histamine is discussed.     

Effects of vagotomy with and without pyloroplasty on weight and food intake in rats.

Bilateral truncal vagotomy performed in 13 rats reduced weight gain by 26% compared to controls, but also produced gastric distension. Addition of pyloroplasty was found to facilitate gastric drainage in vagotomized rats, and both procedures were then performed in 57 rats of both sexes and varying initial weights. When fed ad libitum, vagotomized animals maintained a weight 14-30% less than controls over periods of 30-300 days. When pair fed, normal rats and rats with vagotomy and pyloroplasty weighed the same. Various partial vagotomies had no effect on weight gain. It was concluded that vagotomy reduces weight gain in rats, that the reduction is the result of decreased food intake, and that the effect of vagotomy is probably not due to gastric distension.     

Elicidation by a H-2-receptor antagonist of the significance of mucosal histamine mobilization in exciting acid secretion.

1. The consequence of H-2-receptor blockade for the secretory responses of the gastric mucosa to hormonal or cholinergic stimulation was studied in conscious rats with Heindenhain pouches or Pavlov pouches with the antrum retained or resected. 2. Metiamide almost completely abolished acid secretion induced by pentagastrin without altering significantly the amount of histamine excreted in the urine. Histamine mobilization on pentagastrin infusion determined in vitro, seemed to be larger during H-2-receptor blockade than with pentagastrin alone. 3. CCK-PZ mobilized mucosal histamine to a considerable extent; the secretory response to this hormone was completely abolished by H-2-receptor blockade. 4. Acid secretion in response to 2-deoxy-D-glucose was inhibited by H-2-receptor blockade in the presence or absence of the antrum; however the inhibition was less complete than with hormone-induced secretion. 5. The acid secretory response to 100 mg/kg of 2-deoxy-D-glucose appeared to be less susceptible to H-2-receptor blockade than that of 50-mg/kg of 2-deoxy-D-glucose. 6. Feeding induced a secretory response in the Pavlov pouch which initially was more effectively inhibited by H-2-receptor blockade than the response to 2-deoxy-D-glucose. In the absence of antral gastrin secretion by either stimulus was equally inhibited. 7. Methacholine-induced acid secretion was inhibited by infusion of the H-2-receptor antagonist, an inhibition that was absent when pentagastrin was concomitantly infused. 8. Although acid secretion induced by cholinergic stimuli was readily inhibited by the H-2-receptor antagonist, slight or nor inhibition was noted on pepsin secretion. 9. The role of histamine as a physiological stimulus for the parietal cell is discussed in view of the fact that the secretory effect of natural stimuli, known or demonstrated to mobilize mucosal histamine, is restrained by H-2-receptor blockade.     

Histamine storage and formation in canine gastric mucosa--effect of pentagastrin stimulation

Histamine storage and formation in the dog gastric mucosa were studied during basal conditions and after pentagastrin stimulation. Histamine formation (histidine decarboxylase activity), histamine content as well as the density of mast cells of the oxyntic gland mucosa were evenly distributed. Histamine content of the mucosa was significantly correlated to the density of mucosal mast cells. In the basal secretory state, histamine formation and histamine content of the oxyntic gland mucosa were of the same magnitude as in the antral mucosa. Pentagastrin stimulation induced a small but significant decrease in histamine content of the oxyntic gland mucosa and a subsequent acceleration in the rate of amine formation. Neither histamine content nor histidine decarboxylase activity of the antral mucosa was affected by pentagastrin infusion.     

Histamine storage and formation in canine gastric mucosa - effect of pentagastrin stimulation

Histamine storage and formation in the dog gastric mucosa were studied during basal conditions and after pentagastrin stimulation. Histamine formation (histidine decarboxylase activity), histamine content as well as the density of mast cells of the oxyntic gland mucosa were evenly distributed. Histamine content of the mucosa was significantly correlated to the density of mucosal mast cells. In the basal secretory state, histamine formation and histamine content of the oxyntic gland mucosa were of the same magnitude as in the antral mucosa. Pentagastrin stimulation induced a small but significant decrease in histamine content of the oxyntic gland mucosa and a subsequent acceleration in the rate of amine formation. Neither histamine content nor histidine decarboxylase activity of the antral mucosa was affected by pentagastrin infusion.     

Gastric secretion and its facilitation as related to gastric mucosal histamine

1. In conscious rats provided with Pavlov or Heidenhain pouches the acid and pepsin responses to vagal stimulation, or infusions of gastrin, histamine, methacholine, and to various combinations of these stimulants have been established. The concomitant mobilization and increased formation of gastric mucosal histamine have also been examined.2. Histamine evoked graded acid responses in the Pavlov and Heidenhain pouches. The innervated pouch was more sensitive to histamine than the denervated. Stimulation of pepsin secretion was apparent only in the Heidenhain pouch.3. The acid response to vagal stimulation evoked by 2-deoxy-D-glucose was facilitated by infusion of histamine, but not that of pepsin, the secretion of which was depressed.4. Acid secretion in response to graded infusion of methacholine was enhanced by background infusions of histamine in subthreshold, sub-maximal and maximal dosages.5. The acid response to vagal stimulation was enhanced by a background infusion of gastrin, but not that of pepsin, the secretion of which was depressed.6. A background infusion of a large dose of histamine depressed the maximal acid response to gastrin in both types of pouches.7. Administration of histamine restrained the accelerating effect of gastrin on histidine decarboxylase activity, probably by a feed-back coupling.8. The increase in gastric mucosal histamine, as reflected in its urinary excretion, in response to gastrin infusion was enhanced by vagal stimulation.9. The amounts of histamine that can be mobilized and newly formed in the gastric mucosa have been evaluated and found to be fully adequate for efficient stimulation of the parietal cell.     

The possible mechanism for the 'fade' in acid gastric secretion during continuous infusions of pentagastrin.

1. The 'fade' phenomenon seen in acid gastric secretion in response to a continuous intravenous infusion of pentagastrin has been studied in anaesthetized cats. Whereas acid secretion to a continuous infusion of histamine steadily increased for 3 hr, that to pentagastrin infusion rose steeply to a maximum at 45 min and then decreased gradually to reach about 60% of maximum after 2 hr. 2. Pre-treatment of the cats with the 5-hydroxytryptamine (5-HT) blocking drugs, methysergide and cyproheptadine or with the 5-hydroxytryptamine-depleting drug reserpine completely altered the pattern of secretion to pentagastrin such that the response was similar to that seen during an infusion of histamine. These drugs did not affect secretion stimulated by histamine. 3. It is suggested from these results that pentagastrin releases 5-hydroxytryptamine which at first potentiates and then inhibits the resulting stimulated secretion.     

Vagotomy inhibits the effect of neurotensin on gastrointestinal transit in the rat

Neurotensin has previously been shown to delay gastric emptying, gastrointestinal transit and ileo-caecal emptying in the rat. To investigate the vagal influence on these effects of neurotensin, separate groups of rats were operated with combined vagotomy and pyloroplasty or with pyloroplasty alone and compared to a group of normal rats. All animals were supplied with a permanent gastrointestinal catheter and a venous catheter. After operation the rats were allowed to recover for 7 days, and were fasted for 24 h prior to the experiments. A radioactive marker of 1.0-0.5 ml Na2(51)CrO4 in isotonic polyethylene glycol 400 was instilled intraluminally in the stomach, proximal or distal the small intestine. Saline (control animals) or neurotensin (test animals) was given i.v. in each group studied. The animals were killed at 15, 30, 60, and 120 min after administration of the marker. The distribution of the marker in the gastrointestinal tract was registered with a scintillation detector and quantitative analysis of the amount of radioactivity retained in separate gastrointestinal segments was carried out. Gastric emptying was delayed by combined vagotomy and pyloroplasty (P less than 0.01) compared to pyloroplasty alone and normals. Neurotensin at doses of 6 (P less than 0.05) and 12 (P less than 0.01) pmol kg-1 min-1 retarded gastric emptying dose-dependently in normals and rats with pyloroplasty alone, but did not further slow the gastric emptying in rats with vagotomy and pyloroplasty. However, at a dose of 24 pmol kg-1 min-1 neurotensin delayed gastric emptying (P less than 0.01) compared to controls. Gastrointestinal transit was slowed down by neurotensin at a dose of 6 pmol kg-1 min-1 in normals (P less than 0.01) and rats with pyloroplasty alone (P less than 0.05). In rats with vagotomy and pyloroplasty, neurotensin at doses of 6 and 12 pmol kg-1 min-1 had no effect on gastrointestinal transit.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine metabolism of the guinea-pig gastric mucosa.

1. The mobilization of gastric mucosal histamine as reflected by changes in formation and content has been studied in guinea-pigs on feeding and after injections of pentagastrin or 2-deoxy-D-glucose. 2. Re-feeding fasting guinea-pigs as well as injections of pentagastrin or 2-deoxy-D-glucose raised the rate of mucosal histamine formation; pentagastrin induced a fourfold rise. 3. Some properties of the enzyme catalysing the formation of histamine were examined. The results indicated that this enzyme is histidine decarboxylase, L-histidine carboxy-lyase, E.C. 4.1.1. 22. 4. The enzyme imidazole-N-methyl transferase, E.C. 2.1.1.8, which carries out methylation of the imidazole ring to yield 1-methyl-4-(beta-aminoethyl)imidazole (methylhistamine), was found in high amounts in the mucosa. The enzyme did not change upon stimulation of the mucosa. 5. The metabolism of histamine within the gastric mucosa is discussed in relationship to a suggested role of the amine in exciting acid secretion.     

The adaptation of renal urea excretion after unilateral nephrectomy and after overloading with urea

Summary Urea and inulin clearances were measured in unanesthetized rats 5 and 50 h, and 2–3 weeks after unilateral nephrectomy. At identical i-v infusion rates, urine flow in the uninephrectomized animals was similar to that of sham-operated controls. In the low range of urine flow rates, fractional urea excretion was higher in recently uninephrectomized animals than in controls. The increase appeared to be the consequence of the increased fractional excretion of water. At higher rates of urine flow, and after large loads of urea, the single kidney excreted urea in a manner similar to that of control kidneys. Urea clearances were, in 148/150 clearance determinations, lower than the simultaneously measured inulin clearances. A large increase of GFR was observed in rats chronically loaded and acutely infused with urea.Supported by Fonds National Suisse de la Recherche Scientifique, Grant No. 3440.70.     

Studies on the excretion of [14C]histamine and its metabolites by the rabbit kidney

1. After intravenous administration of [(14)C]histamine in rabbits, the urinary excretion of [(14)C]histamine and [(14)C]histamine metabolites was examined over a period of 4 hr.2. It was found that [(14)C]histamine was excreted in the unchanged form only in small amounts (6-7%), while 54-71% was eliminated in the form of its metabolites.3. Under normal conditions, the percentage excretion of metabolites, but not of histamine, showed a dose dependence. With the higher [(14)C]histamine dose, a significantly smaller proportion of the dose given was excreted as metabolites than with the lower dose. The proportion of unchanged [(14)C]histamine excreted remained constant.4. Pre-treatment with histamine infusions, or with mepyramine maleate, caused an increase in the excretion of [(14)C]histamine metabolites while the excretion of [(14)C]histamine remained unchanged.5. Pre-treatment with a diuretic, a combination of mersalyl and theophylline, did not influence the excretion of [(14)C]histamine nor of its metabolites.     

Cell proliferation in the post-surgical stomach, dietary salt, and the effect of H pylori eradication

AIMS: To study the epithelial kinetics of the post-surgical stomach with reference to dietary salt intake and H pylori. METHODS: Endoscopic biopsies of the antrum/anastomosis and corpus were taken for histology and MIB-1 immunostaining. The labelling index (LI%) was determined in the three zones of the gastric glands (zone 1 = surface + gastric pit; zone 2 = isthmus; zone 3 = gland base) in patients with vagotomy and pyloroplasty (n = 12), gastroenterostomy + vagotomy (n = 4), partial gastrectomy (n = 3), and Billroth I operation (n = 3). Dietary salt was determined by urinary sodium/creatinine ratio. Twelve patients were H pylori positive (10 vagotomy and pyloroplasty; 2 partial gastrectomy) and had a repeat biopsy three months after antihelicobacter treatment (10 were H pylori negative after treatment). RESULTS: There was no correlation between salt intake and antrum/anastomosis (r = -0.34; p = 0.2) or corpus (r = -0.16; p = 0.2) labelling indices. Gastric mucosal proliferation is increased in the antrum/ anastomosis compared to the corpus in H pylori positive (p = 0.014) but not H pylori negative subjects (p = 0.084). This may reflect the different types of post-surgical stomach in each group. Gastric mucosal proliferation is reduced in antrum/anastomosis (p = 0.002) and corpus (p = 0.016) following H pylori eradication. CONCLUSIONS: Dietary salt does not influence gastric mucosal proliferation in the post-surgical stomach but H pylori may have a role in gastric stump carcinogenesis.     

Pancreatic and intestinal growth-promoting effect of truncal vagotomy in the rat

The effect of chronic subdiaphragmatic truncal vagotomy was investigated on body weight gain, food intake pattern, and also on intestinal and pancreatic growth, in adult rats. Two sham-operated groups, the one fed ad libitum, the other pair-fed with the vagotomized rats, served as controls. Body weight of vagotomized rats decreased in the first 5 postoperative days, due to hypophagia. Then, body weight increased as food intake reached the presurgery level. The rats were killed after 34 days of vagotomy. A moderate pancreatic and intestinal hypertrophy was observed in the vagotomized rats, while the tissue weight of and the DNA and protein contents in the colon and the oxyntic and antral areas of the stomach did not change compared to controls. The mechanism of the intestinal and pancreatic hypertrophy is unknown; several humoral and nervous factors may be involved in it.     

Long-term changes in the rat gastric mucosa after truncal vagotomy and pyloroplasty

In 40 male mature albino Wistar rats histological changes of gastric mucosa were analyzed, parietal and chief cells were counted and gastric juice pH was determined 120, 240 and 365 days after truncal vagotomy and pyloroplasty. In all the groups gastric mucosa was attenuated and morphological signs of preatrophic gastritis (decline in parietal cells number, a certain mucoidization of fundal glands without changes in surface epithelium, alteration of mucosal lamina propria) were present. On the background of atrophic changes compensatory and adaptive processes (increase of mitotic activity of epitheliocytes--precursors of differentiating cells, normalization of parietal cells differentiation along the stem line, i.e. of ratio of differentiating, mature functioning and degenerating cell forms) were noted, that lead to repair of histo-structure and function on the whole, although at a lower level. Following long-term intervals after vagotomy glandular gastric epithelium acquires its histo-typical form with parietal secretory activity decreased to some extent.     

Mechanism of inhibition of gastric acid secretion by vagal denervation in the rat

Acute bilateral subdiaphragmatic vagotomy in the conscious fistula rat greatly reduced gastric acid secretion, stimulated by the combined intravenous infusion of pentagastrin (10 μg/kg/h), histamine dihydrochloride (3 mg/kg/h) and carbachol (50 μg/kg/h). The reduction of acid output was immediate (within 15 min after vagotomy). The greatly reduced acid response to these secretagogues persisted for at least 8 weeks after vagal denervation (longest time studied). The sudden and dramatic effect of vagotomy on acid secretion is not related to a possible deficiency of either acetylcholine or histamine at the respective receptor site since the combined infusion of gastrin, histamine and carbachol did not prevent the suppression of acid secretion. Since the decline in acid output following vagal denervation was immediate, it probably reflects a sudden inaccessibility rather than loss of muscarinic or H₂-receptors. The acid output obviously depends upon intramural “transducer” systems that respond to and transmit the vagal input. It is likely that the intramural ganglia represent such “transducer” systems. In the absence of a vagal drive these neuronal “transducers” cease to fire and as a result the parietal cells become almost unresponsive to stimuli.     

Renal function in sheep during infusion of alkali metal ions into the renal artery.

1. The effect on renal function of 1 M solutions of LiCl, NaCl, KCl, RbCl and CsCl and 3 M-NaCl infused close-arterially to the kidney for 10 min at 0-7ml./min has been studied in nine experiments on four unilaterally nephrectomized sheep. The levels of flow, electrolyte concentration and electrolyte excretion in the urine were measured before, during and for 50 min after the infusions. 2. The infusion of 1-M-NaCl produced little change in urine flow and composition whereas 3 M-NaCl resulted in relatively small increases in urine flow and sodium excretion. 3. The infusion of lithium, potassium, rubidium and caesium resulted in marked increases in urine flow, urinary sodium concentration and excretion, urinary potassium excretion and osmolal clearance while the urinary potassium concentration decreased. 4. Changes in urine flow and urinary pH during the infusions of all the alkali ions except sodium were consistent with increased urinary bicarbonate excretion. 5. The osmolal clearance was increased by the infusion of lithium, potassium, rubidium and caesium, but equivalent increases in the rate of solutefree water reabsorption did not occur. 6. The infusion of caesium resulted in a depression of the glomerular filtration rate (G.F.R.) which was not observed when the other alkali ions were infused. 7. The effects of lithium, potassium and rubidium on urine flow and composition were rapid in onset and the residual effects on these ions, on cessation of infusion, were relatively short. The effects on caesium were slow in onset and prolonged in duration. 8. It was concluded that lithium, potassium, rubidium, and caesium altered urine flow and electrolyte excretion by acting upon common mechanisms which were predominantly intra-renal and located in the proximal segment of the nephron.     

Effect of parathyroid hormone on urinary acidification.

The effect of parathyroid hormone (PTH) administration on urinary acidification was studied in intact and thyroparathyroidectomized dogs. PTH administration resulted in a significant increase in urine pH and HCO3 excretion. In dogs with maximally acid urine caused by Na2SO4 infusion PTH administration also led to a significant increase in urine pH and to a decrease in ammonium excretion. To examine the effect of PTH on H+ secretion in the distal nephron we measured the urine-blood (U-B) PCO2 gradient in dogs with maximally alkaline urine (urine pH greater than 7.8) before and after PTH administration. After infusion of the hormone, HCO3 excretion increased significantly but the U-B PCO2 gradient remained unchanged. The effects of PTH infusion on urinary acidification in animals with distal renal tubular acidosis caused by LiCl administration were also studied. PTH administration to these dogs increased HCO3 excretion to the same level seen in normal dogs. These data suggest that PTH does not inhibit distal H+ secretion but increases HCO3 excretion by depressing proximal HCO3 reabsorption.     

Increased urinary excretion of 1.4-methyl-imidazoleacetic acid in patients with atopic dermatitis

To investigate whether the overall histamine turnover is increased in patients with atopic dermatitis, without respiratory disease, the urinary excretion of the main histamine metabolite 1,4-methyl-imidazoleacetic acid (MIAA) was examined in 23 patients and in 23 age- and sex-matched non-atopic controls. The patients excreted significantly more MIAA than the controls. One third of the patients however, showed MIAA excretion within or below normal range. The MIAA excretion was neither correlated to the severity of the eczema nor to the total serum IgE. It was concluded that histamine does not play a significant role in the pathophysiology of atopic dermatitis, and that the great variation in MIAA excretion, and hence the histamine turnover, reflected the spectrum of histamine releasability in the patients.