Physiological significance of ECL-cell histamine.

In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin injection or pylorus ligation) was unaffected by alpha-FMH treatment but inhibited by an H2 antagonist. These results suggest that gastrin stimulates acid secretion via release of ECL-cell histamine, whereas vagally-induced acid secretion--although histamine-dependent--does not rely on ECL-cell histamine. Gastrin is known to have a trophic effect on the oxyntic mucosa. By combining long-term hypergastrinemia with continuous infusion of alpha-FMH, we were able to show that gastrin-evoked trophic effects in the stomach do not depend on ECL-cell histamine.     

Regulation of histamine release from oxyntic mucosa.

The regulation of histamine release from oxyntic mucosa is complex because of two potential sources of histamine: mast cells and enterochromaffin-like (ECL) cells. A gastrin-responsive histamine pool was identified in the rat oxyntic mucosa two decades ago, but these ECL cells from the rat have not yet been isolated or characterized in vitro. In vivo studies in canine and human mucosa have been more difficult because of the high content of histamine in mast cells. Using enzyme-dispersed canine oxyntic mucosal cells, we have studied regulation of histamine release from a mast cell-depleted fraction prepared by sequential elutriation and density gradient. Histamine-like immunoreactivity was demonstrated, using peroxidase-anti-peroxidase immunohistochemistry. After short-term culture, histamine was released in response to gastrin, cholecystokinin, carbachol, and forskolin. Somatostatin potently and effectively inhibited the response to gastrin. The cultures used for these studies also contained somatostatin cells, and, furthermore, the response to gastrin was enhanced by incubation with monoclonal antibodies to somatostatin. The latter findings suggested that somatostatin was acting in these cultures by a paracrine route. This pattern contrasts with that obtained in previous studies of canine oxyntic mucosal mast cells.     

CCK2 receptor antagonists: pharmacological tools to study the gastrin-ECL cell-parietal cell axis

Gastrin-recognizing CCK2 receptors are expressed in parietal cells and in so-called ECL cells in the acid-producing part of the stomach. ECL cells are endocrine/paracrine cells that produce and store histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. The ECL cells are the principal cellular transducer of the gastrin-acid signal. Activation of the CCK2 receptor results in mobilization of histamine (and pancreastatin) from the ECL cells with consequent activation of the parietal cell histamine H2 receptor. Thus, release of ECL-cell histamine is a key event in the process of gastrin-stimulated acid secretion. The oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration are useful markers for the activity of the gastrin-ECL cell axis. Powerful and selective CCK2 receptor antagonits have been developed from a series of benzodiazepine compounds. These agents are useful tools to study how gastrin controls the ECL cells. Conversely, the close control of ECL cells by gastrin makes the gastrin-ECL cell axis well suited for evaluating the antagonistic potential of CCK2 receptor antagonists with the ECL-cell HDC activity as a notably sensitive and reliable parameter. The CCK2 receptor antagonists YF476, YM022, RP73870, JB93182 and AG041R were found to cause prompt inhibition of ECL-cell histamine and pancreastatin secretion and synthesis. The circulating pancreastatin concentration is raised, was lowered when the action of gastrin on the ECL cells was blocked by the CCK2 receptor antagonists. These effects were associated with inhibition of gastrin-stimulated acid secretion. In addition, sustained receptor blockade was manifested in permanently decreased oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and CGA mRNA concentrations. CCK2 receptor blockade also induced hypergastrinemia, which probably reflects the impaired gastric acid secretion (no acid feedback inhibition of gastrin release). Upon withdrawal of the CCK2 receptor antagonists, their effects on the ECL cells were readily reversible. In conclusion, gastrin mobilizes histamine from the ECL cells, thereby provoking the parietal cells to secrete acid. While CCK2 receptor blockade prevents gastrin from evoking acid secretion, it is without effect on basal and vagally stimulated acid secretion. We conclude that specific and potent CCK2 receptor antagonists represent powerful tools to explore the functional significance of the ECL cells.     

PACAP stimulates gastric acid secretion in the rat by inducing histamine release

Previous studies have shown that pituitary adenylate cyclase-activating peptide (PACAP) stimulates enterochromaffin-like (ECL) cell histamine release, but its role in the regulation of gastric acid secretion is disputed. This work examines the effect of PACAP-38 on aminopyrine uptake in enriched rat parietal cells and on histamine release and acid secretion in the isolated vascularly perfused rat stomach and the role of PACAP in vagally (2-deoxyglucose) stimulated acid secretion in the awake rat. PACAP has no direct effect on the isolated parietal cell as assessed by aminopyrine uptake. PACAP induces a concentration-dependent histamine release and acid secretion in the isolated stomach, and its effect on histamine release is additive to gastrin. The histamine H2 antagonist ranitidine potently inhibits PACAP-stimulated acid secretion without affecting histamine release. Vagally stimulated acid secretion is partially inhibited by a PACAP antagonist. The results from the present study strongly suggest that PACAP plays an important role in the neurohumoral regulation of gastric acid secretion. Its effect seems to be mediated by the release of ECL cell histamine.     

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

Summary Treatment 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.     

Role of gastrin in the development of gastric mucosa,ECL cells and A-like cells in newborn and young rats

Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK(2)) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 15-22 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but not before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point.We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK(2) receptor blockade is associated with a somewhat impaired development of the oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages.     

Histamine dependence of pentagastrin-stimulated gastric acid secretion in rats.

Does gastrin stimulate gastric acid secretion by direct action on oxyntic cells, by releasing histamine, or by being potentiated by histamine? Previous studies in the mouse pointed to gastrin-regulated histamine release. Guinea pig and rat are well known to vary in their sensitivity to histamine. Therefore, the effects of histamine and pentagastrin were compared quantitatively on isolated, lumen-perfused, stomach preparations from these species in the absence and presence of histamine H2-receptor blockade. The loss of potency of histamine in the rat was mirrored by a loss of potency of pentagastrin consistent with the idea that pentagastrin acts by releasing histamine. In the rat, a well-defined pentagastrin curve was obtained in the presence of histamine H2-receptor block as though pentagastrin acts both directly on the oxyntic cell and indirectly by releasing histamine. It was not necessary to invoke a potentiating interaction between histamine and pentagastrin at the oxyntic cell; the two effects appeared simply to add. Potentiation was observed, however, between other combinations of stimuli, for example, between vagal nerve and pentagastrin stimulation. The physiological consequences of these results are discussed.     

Relationship of ECL cells and gastric neoplasia.

The enterochromaffin-like (ECL) cell in the oxyntic mucosa has a key role in the regulation of gastric secretion since it synthesizes and releases the histamine regulating the acid secretion from the parietal cell. Gastrin is the main regulator of the ECL cell function and growth. Long-term hypergastrinemia induces ECL cell hyperplasia, and if continued, neoplasia. ECL cell carcinoids occur in man after long-term hypergastrinemia in conditions like pernicious anemia and gastrinoma. There is also accumulating evidence that a proportion of gastric carcinomas of the diffuse type is derived from the ECL cell. Furthermore, the ECL cell may, by producing substances with angiogenic effects (histamine and basic fibroblast growth factor), be particularly prone to develop malignant tumors. Although the general opinion is that gastrin itself has a direct effect on the oxyntic mucosal stem cell, it cannot be excluded that the general trophic effect of gastrin on the oxyntic mucosa is mediated by histamine or other substances from the ECL cell, and that the ECL cell, therefore, could play a role also in the tumorigenesis/carcinogenesis of gastric carcinomas of intestinal type.     

Neural, hormonal, and paracrine regulation of gastrin and acid secretion.

Physiological stimuli from inside and outside the stomach coverage on gastric effector neurons that are the primary regulators of acid secretion. The effector neurons comprise cholinergic neurons and two types of non-cholinergic neurons: bombesin/GRP and VIP neurons. The neurons act directly on target cells or indirectly by regulating release of the hormone, gastrin, the stimulatory paracrine amine, histamine, and the inhibitory paracrine peptide, somatostatin. In the antrum, cholinergic and bombesin/GRP neurons activated by intraluminal proteins stimulate gastrin secretion directly and, in the case of cholinergic neurons, indirectly by eliminating the inhibitory influence of somatostatin (disinhibition). In turn, gastrin acts on adjacent somatostatin cells to restore the secretion of somatostatin. The dual paracrine circuit activated by antral neurons determines the magnitude of gastrin secretion. Low-level distention of the antrum activates, preferentially, VIP neurons that stimulate somatostatin secretion and thus inhibit gastrin secretion. Higher levels of distention activate predominantly cholinergic neurons that suppress antral somatostatin secretion and thus stimulate gastrin secretion. In the fundus, cholinergic neurons activated by distention or proteins stimulate acid secretion directly and indirectly by eliminating the inhibitory influence of somatostatin. The same stimuli activate bombesin/GRP and VIP neurons that stimulate somatostatin secretion and thus attenuate acid secretion. In addition, gastrin and fundic somatostatin influence acid secretion directly and indirectly by regulating histamine release. Acid in the lumen stimulates somatostatin secretion, which attenuates acid secretion in the fundus and gastrin secretion in the antrum.     

Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice

Histamine plays an important role in the regulation of gastric acid secretion; however, its role in maintenance of gastric morphology remains unclear. To clarify the necessity of histamine for gastric mucosal development and maintenance, we evaluated two different kinds of mice that lacked either mast cells (one of the gastric histamine-producing cell types) or histidine decarboxylase (HDC; a histamine-synthesizing enzyme). Measurements of stomach weight, intragastric pH, mucosal histamine levels, as well as serum gastrin and albumin levels were performed in mice. Gastric mucosal appearance was examined by immunohistochemical techniques. Although gastric mucosal histamine levels in mast cell-deficient mice were half of those observed in the wild-type mice, intragastric pH, serum gastrin levels, and gastric morphology at 12 mo were unchanged compared with the wild-type mice. In contrast, HDC-deficient mice possessed no detectable gastric histamine, but did exhibit hypergastrinemia, as well as marked increases in intragastric pH and stomach weight compared with the wild-type mice. Histological analysis revealed that 9-mo-old HDC-deficient mice demonstrated hyperplasia in the oxyntic glandular base region, as well as increased numbers of parietal and enterochromaffin-like cells. These results indicate that enterochromaffin-like cell-derived histamine is potentially involved in gastric mucosal morphology regulation.     

Physiology of the ECL cells.

The enterochromaffin-like (ECL) cells of the oxyntic mucosa (fundus) of the stomach produce, store and secrete histamine, chromogranin A-derived peptides such as pancreastatin, and an unanticipated but as yet unidentified peptide hormone. The cells are stimulated by gastrin and pituitary adenylate cyclase activating peptide and suppressed by somatostatin and galanin. Choline esters and histamine seem to be without effect on ECL cell secretion. The existence of a gastrin-ECL cell axis not only explains how gastrin stimulates acid secretion but also may help to explore the functional significance of the ECL cells with respect to the nature and bioactivity of its peptide hormone. From the results of studies of gastrectomized/fundectomized and gastrin-treated rats, it has been speculated that the anticipated ECL-cell peptide hormone acts on bone metabolism.     

The biology and pathobiology of the ECL cells.

The enterochromaffin-like (ECL) cells represent the predominant endocrine cell population in the acid-producing part of the stomach of both experimental animals and man. These cells actively produce and store histamine in addition to an anticipated but as yet unidentified peptide hormone and are under the control of gastrin. An acute gastrin stimulus causes exocytosis of the cytoplasmic granules/vesicles (and release of histamine and activation of the histamine-forming enzyme, histidine decarboxylase), while a more sustained gastrin stimulus causes first hypertrophy and then hyperplasia of the ECL cells in the rat (at most, a fivefold increase in the cell number). These effects can be demonstrated following infusion of gastrin or following an increase in the concentration of circulating gastrin of endogenous origin. The growth of the ECL cells reflects an accelerated self-replication rate. As studied in the rat, the self-replication rate is accelerated quite soon after induction of hypergastrinemia (blockade of acid secretion), the rate is maximally elevated within two weeks and then declines to control values at ten and 20 weeks despite the sustained hypergastrinemia. Lifelong hypergastrinemia in rats is associated not only with ECL-cell hyperplasia but also with an increased incidence of ECL-cell carcinoids. Recently, we could show that alpha-fluoromethylhistidine, which is a suicide inhibitor of histidine decarboxylase, effectively depletes the ECL cells of histamine and that the histamine-depleted ECL cells respond to gastrin with hyperplasia in a manner identical to normal ECL cells. Other factors beside gastrin seem to participate in the control of ECL-cell function and proliferation. Although exogenous somatostatin is known to suppress the activity of the ECL cells, we have failed to obtain evidence that the somatostatin cells in the oxyntic mucosa play a role in the physiological control of the ECL cells. The vagus, however, is important for the ability of the ECL cells to respond to gastrin. This conclusion is based on the observation that vagal denervation suppresses the hyperplastic response of the ECL cells to gastrin. Porta-cava shunting, on the other hand, greatly enhances the responsiveness of the ECL cells to gastrin. The mechanism behind this effect is unknown.     

Rat gastric histamine release: a sensitive gastrin bioassay.

Acid secretion and histamine release from the totally isolated vascularly perfused rat stomach are sensitive parameters for the biological effects of gastrin. By optimalizing the Ca2+ concentration of the vascular perfusate the sensitivity for stimulation of acid secretion was improved from 65 to 16 pmol/l gastrin 1-17 (G-17). Measurement of venous histamine before and after gastrin in each stomach preparation excluded inter-stomach variability and improved the sensitivity to 2 pmol/l G-17. This is the most sensitive gastrin bioassay reported, with a detection limit comparable to that of radioimmunoassay.     

Absence of a relationship between immunoreactive-gastrin and somatostatin-like immunoreactivity secretion in the perfused rat stomach

The possible interaction between somatostatin-like immunoreactivity (SLI) and immunoreactive-gastrin release was studied in an isolated perfused rat stomach preparation. Gastrin release was abolished by antrectomy but basal and gastric inhibitory polypeptide-stimulated SLI levels were unchanged from control experiments, implicating the corpus as the major source of SLI released into the vasculature. Perfused stomachs of vagotomized rats exhibited basal hypergastrinaemia with no alteration in basal or stimulated SLI release, suggesting an uncoupling of SLI and gastrin release. This study indicated that SLI released into the vasculature originated in the acid secretory region of the stomach and therefore may be involved in the regulation of acid secretion at the level of the parietal cell mass.     

Effect of histamine and cimetidine on amino acid meal-stimulated gastrin release at a controlled intragastric pH in healthy human beings

Results of several experiments have suggested that histamine-2 receptors play an inhibitory role in regulating gastrin release. We evaluated this prospectively in healthy human beings by infusing intravenously either histamine (0.33 μg/kg/min) or cimetidine (3.33 mg/min) during a continuous 3-h intragastric infusion of a 3% mixed amino acid meal, a potent stimulus of gastrin release. In order to be certain that effects of histamine or cimetidine on gastrin release were independent of their known effects on gastric acid secretion, intragastric pH was maintained at 5.0 by in vivo intragastric titration with sodium bicarbonate or hydrochloric acid. Although histamine and cimetidine had significant effects on gastric acid secretion, neither significantly affected the rises in serum gastrin concentrations during intragastric amino acid infusion. For example, mean gastrin rises above basal concentrations were 39 ± 9 pg/ml on the control day, 39 ± 9 pg/ml on the histamine day and 44 ± 11 pg/ml on the cimetidine day (P > 0.05). Thus, blockade or stimulation of H₂-receptors at the doses tested had no effect on gastrin release in response to an amino acid meal in humans when intragastric pH was maintained at 5.0.     

The effects of substance P, histamine and histamine antagonists on somatostatin and gastrin release from the isolated perfused rat stomach

Secretion of somatostatin-like immunoreactivity (SLI) from the isolated perfused rat stomach has been shown to be inhibited by substance P. The present study was initiated to examine the possibility that this action of substance P was mediated via release of histamine. Substance P (1 microM) reduced basal secretion of SLI in agreement with earlier studies. Neither pyrilamine nor cimetidine influenced this action. Basal immunoreactive gastrin (IRG) secretion was unaffected by substance P. Addition of pyrilamine during substance P perfusion increased IRG secretion whereas addition of cimetidine resulted in a delayed decrease on removal of both compounds. Histamine (1 and 10 microM) increased SLI secretion and reduced IRG secretion. Pyrilamine increased and cimetidine decreased IRG secretion but neither drug influenced SLI secretion. Pyrilamine had no effect on histamine-stimulated SLI secretion but inhibition of IRG secretion by histamine was converted to stimulation. Cimetidine potentiated histamine stimulation of SLI secretion and inhibition of IRG secretion. In conclusion: (1) substance P inhibition of SLI secretion is unlikely to be mediated via release of histamine. (2) The gastrin cell appears to have both H1- and H2-receptors which mediate opposite actions but H1-receptor-mediated inhibition is predominant. (3) Histamine weakly stimulates SLI secretion but there may be both inhibitory and stimulatory pathways acting via H2- and H1-receptors, respectively.     

Properties of isolated gastric enterochromaffin-like cells.

The gastric enterochromaffin-like cell (ECL) has been studied in gastric fundic glands by confocal microscopy and as a purified cell preparation by video imaging of calcium signaling and measurements of histamine release. Regulation of gastric acid secretion is largely due to alterations of histamine activation of the H2 receptor on the parietal cell and can be divided into central neural regulation, with direct actions of neuronally released mediators and into peripheral regulation by substances released from other endocrine cells. Gastric neuronal stimulation of acid secretion by alteration of ECL cell function is probably mediated by pituitary adenylate cyclase activating peptide (PACAP) receptors on the ECL cell, which activate calcium signaling and histamine release. Peripheral stimulation of acid secretion via the ECL cell is largely mediated by gastrin stimulation of calcium signaling and histamine release. Gastric neuronal inhibition of ECL cell function is probably mediated by galanin inhibition of calcium signaling, and histamine release and peripheral inhibition of ECL cell function is mainly due to somatostatin release from D cells.     

Differentiation of the gastric mucosa. I. Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes

Many physiological functions of the stomach depend on an intact mucosal integrity; function reflects structure and vice versa. Histamine in the stomach is synthesized by histidine decarboxylase (HDC), stored in enterochromaffin-like (ECL) cells, and released in response to gastrin, acting on CCK(2) receptors on the ECL cells. Mobilized ECL cell histamine stimulates histamine H(2) receptors on the parietal cells, resulting in acid secretion. The parietal cells express H(2), M(3), and CCK(2) receptors and somatostatin sst(2) receptors. This review discusses the consequences of disrupting genes that are important for ECL cell histamine release and synthesis (HDC, gastrin, and CCK(2) receptor genes) and genes that are important for "cross-talk" between H(2) receptors and other receptors on the parietal cell (CCK(2), M(3), and sst(2) receptors). Such analysis may provide insight into the functional significance of gastric histamine.     

Modulation of acetylcholine-induced secretion of gastric bombesin-like immunoreactivity by cholinergic and histamine H2-receptors, somatostatin and intragastric pH

Recently we have shown the release of bombesin-like immunoreactivity (BLI) from the isolated perfused rat stomach. In these experiments we have shown that BLI secretion is stimulated by acetylcholine. Gastric inhibitory peptide (GIP) exerts an inhibitory effect which is dependent on the intraluminal pH. The present study was designed to examine further the exact cholinergic mechanisms and to study the interaction between cholinergic and histaminergic mechanisms as well as the effect of the intraluminal pH. Acetylcholine elicited a dose-dependent increase in BLI and gastrin secretion (10(-6) M and 2 X 10(-6)M), whereas somatostatin release was suppressed at luminal pH 7. Blockade of muscarinic cholinergic receptors by atropine (10(-5)M) and nicotinic cholinergic receptors by hexamethonium (10(-5) M) abolished the effect of acetylcholine on all three peptides. Reduction of the intraluminal pH to 2 also abolished acetylcholine-induced stimulation of BLI and gastrin secretion and the inhibition of somatostatin secretion. Changes of intraluminal pH per se had no effect on the secretion of either peptide. Somatostatin (10(-7) M) reduced both BLI and gastrin secretion during stimulation with acetylcholine. The addition of the H2-receptor antagonist cimetidine (10(-5) M) abolished the effect of both doses of acetylcholine on BLI and somatostatin secretion and also the effect of the lower dose of acetylcholine (10(-6) M) on gastrin secretion during luminal pH 7. At luminal pH 2 cimetidine did not alter BLI and somatostatin secretion in response to acetylcholine, however, gastrin release was augmented in the presence of cimetidine. These data demonstrate that the effect of acetylcholine on BLI, gastrin, and somatostatin secretion is mediated by muscarinic and nicotinic cholinergic receptors and also by histamine H2-receptors. Somatostatin inhibits cholinergically induced BLI secretion. The cholinergic effects on BLI, somatostatin and gastrin secretion are abolished during an acidic intragastric pH. In this isolated perfused rat stomach model the inhibitory effect of intraluminal acid on gastrin secretion is, at least in part, mediated by H2-receptors. This suggests that the secretion of bombesin, a potential peptidergic neurotransmitter is modulated by neural, endocrine and local tissue factors and also by alterations of intragastric pH.