Gastric Histamine Content Research Articles

IL-18 mediates the formation of stress-induced, histamine-dependent gastric lesions

A role of IL-18 in the induction of gastric lesions by water immersion and restraint stress (WRS) was investigated. When wild-type BALB/c mice were exposed to WRS, levels of IL-18 in the serum and stomach increased rapidly with the development of acute gastric lesions. In IL-18-deficient mice [IL-18 knockout (KO) mice] similarly exposed to WRS, no gastric lesions were observed, but the administration of IL-18 before exposure to WRS resulted in the induction of WRS-induced gastric lesions. WRS enhanced gastric histidine decarboxylase (HDC) activity with concomitant increases in gastric histamine content. In IL-18 KO mice, the WRS-induced elevation of gastric HDC activity and histamine levels was much less than that in wild-type mice, but it was augmented by prior administration of IL-18. Treatment of wild-type mice with cimetidine, a histamine H2 receptor antagonist, inhibited the formation of WRS-induced gastric lesions with no effect on the induction of gastric IL-18 by WRS. Levels of corticosterone, one of the stress indicators, were lower in IL-18 KO mice than in wild-type mice. The glucocorticoid receptor antagonist mifepristone had no effect on gastric IL-18 and histamine levels but aggravated the stress-induced gastric lesions, indicating that corticosterone was not involved in the IL-18-mediated formation of stress-induced gastric lesions. These results indicate that IL-18 is involved in the induction of gastric lesions by WRS through augmentation of HDC activity and production of histamine in the stomach.

Gastroprotective effect of leptin on gastric mucosal injury induced by ischemia–reperfusion is related to gastric histamine content in rats

Leptin has cytoprotective effect to gastric mucosal injury in rats. We aimed to test the hypothesis that leptin induced histamine is involved in the prevention of ischemia–reperfusion (I/R) induced gastric mucosal injury in rats. At the end of the 30 min celiac artery occlusion and 12 h reperfusion process, serum and gastric tissue samples were taken from three group of rats to measure oxidative status, histamine levels and for histological examinations. Leptin decreased ulcer and polymorphonuclear leukocyte (PMNL) index, and serum malondialdehyde (MDA) and protein carbonyl content but increased gastric tissue histamine levels. We concluded that leptin exerts a protective effect on gastric mucosa to I/R induced gastric injury probably through increasing tissue histamine content which, in turn, maintain the gastric mucosal blood flow.

Role of gastric acid secretion in progression of acute gastric erosions induced by ischemia–reperfusion into gastric ulcers

Ischemia followed by reperfusion is known to produce gastric lesions due to oxidative stress, but the role of gastric H + secretion in the formation of this mucosal injury remains unknown. We studied alterations in gastric acid secretion and gastric histamine content, as well as the expression of histidine-decarboxylase and interleukin-1β during the mucosal recovery from ischemia–reperfusion erosions. Gastric secretion was studied in rats (series A) with gastric fistula before, during and after the ischemia induced by clamping of celiac artery for 0.5 h followed by reperfusion in animals pretreated with vehicle (saline), omeprazole, a proton pump inhibitor, or ranitidine, a histamine (H 2) receptor antagonist. In series B, the animals were submitted to 0.5 h of ischemia followed by 1 h of reperfusion and then anesthetized at 0, 3, 12 and 24 h or 3, 5, 10 or 15 days after the end of ischemia–reperfusion to determine gastric blood flow by H 2-gas clearance technique, area of gastric lesions, plasma gastrin and interleukin-1β levels, histamine content by radioimmunoassay (RIA) and expression of histidine-decarboxylase and interleukin-1β mRNA by reverse transcription polymerase chain reaction. Clamping of celiac artery caused cessation of gastric blood flow and almost complete suppression of basal gastric acid secretion (series A) that returned gradually to the control value at day 3 after ischemia–reperfusion, accompanied by the rise in plasma gastrin levels, pronounced expression of histidine-decarboxylase mRNA and increased mucosal histamine content. Ischemia, followed by 1 h of reperfusion, produced gastric erosions (series B) that reached maximum at 12 h, but then declined at 24 h. These erosions progressed at day 3 into deeper ulcers whose area declined progressively within the next 5–15 days. The gastric blood ceased to flow (series B) during 30 min of clamping and was reduced throughout the period of healing of acute erosions, being accompanied by a gradual rise in mucosal interleukin-1β mRNA content and in plasma interleukin-1β levels. Treatment with omeprazole or ranitidine, which completely suppressed gastric acid secretion and significantly raised plasma gastrin level, greatly reduced the formation of erosive lesions preventing the progression of these lesions to chronic gastric ulcers, and this was accompanied by the rise in gastric blood flow and plasma gastrin levels and the significant attenuation of plasma interleukin-1β levels. The ranitidine and omeprazole-induced suppression of ischemia–reperfusion erosions were abolished by the instillation of exogenous 0.2 N HCl into the stomach of these rats. The histidine-decarboxylase was faintly expressed in the intact gastric mucosa, but strongly upregulated during mucosal recovery from the damage induced by ischemia–reperfusion. We conclude that following ischemia–reperfusion: (1) gastric acid secretion, gastric microcirculation and histamine production markedly decline, while interleukin-1β release significantly increases, probably playing an important role in the progression of acute lesions into chronic gastric ulcerations; (2) the suppression of gastric acid secretion by omeprazole and ranitidine, that induces hypergastrinemia, prevents the progression of gastric erosions into ulcers; and (3) the addition of exogenous acid restores the progression of the acute lesions into gastric ulcers, indicating that gastric acid plays a key role in ulcerogenesis induced by ischemia–reperfusion.

Gastric histamine content and ulcer formation in rats with ethanol-induced injury. Effects of cinnarizine and flunarizine

The effects of the calcium antagonists cinnarizine and flunarizine on gastric histamine content and ulcer formation in rats with ethanol-induced injury were studied. Gastric ulcers were inflicted by oral application of 50% or 100% ethanol solution. Cinnarizine (20 mg/kg), flunarizine (10 mg/kg) and cimetidine (100 mg/kg) were administered orally 1 h before ethanol. Histamine was assayed fluorometrically. No effect of the tested drugs on 50% ethanol-induced gastric damage was observed. Cinnarizine and flunarizine inhibited 100% ethanol-induced lesion formation by 71% (p < 0.01) and 20% (p > 0.05), respectively. The inhibition exerted by cimetidine was 54% (p < 0.05). Gastric histamine content was not affected by 50% ethanol, while 100% ethanol decreased it two-fold. None of the tested drugs induced significant changes in gastric histamine levels. No correlation was obtained between the ulceroprotective effect of the used calcium antagonists and the gastric histamine content in ethanol-induced injury.

Gastric histamine content and gastric ulcer formation in cold/restraint stressed rats: Effects of cinnarizine and flunarizine

The effects of the calcium channel blockers cinnarizine (20 mg/kg p.o.) and flunarizine (10 mg/kg p.o.) on gastric and small intestine histamine content and ulcer formation were determined in cold/restraint stressed rats (4°C for 3 h). The effects of cimetidine (100 mg/kg p.o.) were studied for comparison. After the stress, a significant increase (+27%) in gastric histamine content concomitant with gastric ulceration was observed. Pretreatment with cinnarizine or flunarizine restored histamine to the control value and reduced both the incidence (−22% and −44% respectively) and the severity (-nearly 35%) of gastric ulcers. Neither marked changes in histamine content nor mucosal lesions were detected in the small intestine. The effects of cinnarizine and flunarizine resembled those of cimetidine. The obtained data suggest a possible relation between the decrease in the elevated histamine content in stressed rats and the protection against ulcer formation exerted by cinnarizine and flunarizine.

Effect of His-Phe, a competitive inhibitor of histidine decarboxylase, on gastric acid secretion in chronic gastric fistula rats: Delay in acid secretion response to pentagastrin

The dipeptide His-Phe, earlier shown to inhibit mammalian histidine decarboxylase, was analysed concerning its effect in vivo on pentagastrin-induced gastric acid secretion. Chronic gastric fistula rats were used and the effectors in saline were given as continuous i.v. infusions while acid was collected from the fistula. Addition of pentagastrin to the infusion solution resulted in an immediate increase in the acid output of the control runs. In the His-Phe experiments the dipeptide was introduced one hour before pentagastrin. A significant decrease in the acid output was obtained. This effect was optimal at a dose of about 6 mg/h and during the first few hours of the experiments. In spite of the continuous His-Phe infusion the acid secretion increased with time to the control values. These results are discussed in relation to preliminary observations on effects of alpha-fluoromethyl histidine on gastric acid secretion and the effect of this and His-Phe on gastric histamine content and histidine decarboxylase activity.

Gastric acid response to pylorus ligation in rats: is gastrin or histamine involved?

1. Pylorus ligation stimulated the acid output in vagally intact rats. The serum gastrin concentration and the gastric mucosal histamine content were not affected. The gastric histidine decarboxylase activity was initially slightly elevated and then greatly reduced (12-20 hr after ligation).2. Pylorus ligation stimulated the acid output in chronically, but not in acutely, vagotomized rats. Chronic vagotomy raises the serum gastrin concentration, the gastric histamine content and histidine decarboxylase activity. The serum gastrin concentration was further raised by pylorus ligation. The histamine content was initially lowered but returned to preligation values after 20 hr. The histidine decarboxylase activity first decreased, but increased to very high levels 5-6 hr after ligation. Twelve hours after ligation it was lower than before ligation.3. Following pylorus ligation pentagastrin and histamine stimulated the acid output in vagally intact and in acutely vagotomized but not in chronically vagotomized rats. By contrast, pentagastrin raised the histidine decarboxylase activity in vagally intact and in chronically vagotomized, but not in acutely vagotomized rats.4. The two major populations of endocrine cells of the oxyntic gland area (ECL cells and A-like cells) are argyrophil, store histamine and are capable of taking up exogenous DOPA and of decarboxylating it to dopamine which is retained in the cytoplasm for several hours. As evidenced by light and fluorescence microscopy pylorus ligation did not affect their argyrophilia or their ability to produce and store dopamine.5. Pylorus ligation caused ultrastructural changes in the gastrin cells of the pyloric gland area and in the histamine-storing ECL and A-like cells of the oxyntic gland area. The two endocrine cell types in the oxyntic gland area were enlarged by pylorus ligation, more so after 16 hr than after 4 hr. The size of the gastrin cells seemed unaffected. In all three cell types pylorus ligation reduced the number of cytoplasmic granules. There was no increase in the Golgi area or in the endoplasmic reticulum in any of the endocrine cell types of the oxyntic gland area. It appears unlikely that the ultrastructural changes of the ECL and A-like cells reflect an increased rate of histamine mobilization.6. The acid response to pylorus ligation probably reflects neuronal reflex mechanisms exclusively. There is no evidence that gastrin or histamine released from gastric endocrine cells mediate the response.

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.

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

In the nephrectomized rat gastrin (and pentagastrin) does not evoke acid secretion but retains its ability to activate gastric hirtidine 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.

Reserpine-induced mobilization of histamine and vitamin B 12-binding proteins from a special type of endocrine cells in rat stomach

Reserpine was found to mobilize histamine from a large number of the enterochromaffin-like cells in the oxyntic gland area of the rat stomach, as revealed by fluorescence histochemistry. Chemical estimations demonstrated a 50 per cent reduction in the gastric histamine content upon reserpinization. Histamine persisted in gastric mast cells and in a population of reserpine-resistant enterochromaffin-like cells. The results indicate the existence of three separate pools of gastric histamine. Vitamin B 12-binding proteins (including the intrinsic factor) have been suggested to occur in the histamine-containing enterochromaffin-like cells of the rat stomach. Reserpine treatment caused an almost total depletion of gastric vitamin B 12-binding proteins, whereas the intrinsic factor activity (i.e. the ability to absorb ingested [ 58Co] labelled cyanocobalamin) was only moderately impaired. It is suggested that the vitamin B 12-binders reside in the reserpine-sensitive population of enterochromaffin-like cells, and that also under conditions of impaired storage, the formation and continuous release of intrinsic factor is sufficient to satisfy the normal demands of vitamin B 12 absorption.

Cellular stores of histamine and monoamines in the dog stomach

The gastric mucosa of the dog is rich in histamine. Fluorescence microscopic analysis showed that in this species gastric histamine is stored in mast cells, which differ from mast cells at other sites in that they are resistant to the histamine-releasing action of Compound 48/80. Previously, it has been established that in the rat the major portion of gastric histamine is stored in a specific, enterochromaffin-like epithelial cell system in the oxyntic gland area; in contrast to the enterochromaffin cells of the pyloric region they contain no 5-hydroxytryptamine. A morphologically similar cell system could be demonstrated in the antral region of the dog stomach. In this species, however, these enterochromaffin-like cells are devoid of histamine, as well as of histochemically detectable monoamines. Nevertheless, they were found capable of producing and storing monoamines from exogenous precursor amino acids. In the rat, gastric histamine is probably produced locally since the enterochromaffin-like cells are rich in histidine decarboxylase. Histidine decarboxylase activity in the dog stomach was found to be low, which contrasts with the high gastric histamine content. The origin of gastric histamine in this species is still unknown. It is possible that most of it results from an active uptake of preformed, circulating histamine rather than from local biosynthesis.

The effect of cortisone on gastric histamine content and gastric secretion in pylorus ligated guinea-pigs.

The effect of cortisone on gastric histamine content and gastric secretion in pylorus ligated guinea-pigs.