Modification by histamine H2-receptor blockade of acid secretion stimulated by histamine, pentagastrin and methacholine in the isolated whole mouse stomach.

The direct influences of the blockade of the gastric histamine H2-receptors on the secretory actions induced by histamine, pentagastrin and methacholine, have been studied on the isolated perfused whole mouse stomach. According to the results cimetidine did not modify the spontaneous basal acid secretion. The interactions of cimetidine with the secretagogues were of a competitive nature with histamine and non-competitive with pentagastrin, while no modification of methacholine stimulated acid secretion.     

The effect of pentagastrin and substance P on the gastric parietal glandulocytes]

Investigations on dogs show that substance P suppresses pentagastrin gastric acid secretion. This effect is abolished by acetylcholinesterase block by calimin. The results indicate that pentagastrin and substance P participate in cholinergic regulation of gastric acid secretion.     

Studies on adenyl cyclase in Necturus gastric mucosa

Adenyl cyclase activity of Necturus gastric mucosa was determined by measuring the amount of radioactive adenosine 3′,5′-cyclic monophosphate formed from ³H-labeled adenosine triphosphate. Histamine, pentagastrin, and fluoride added in vitro significantly increased fundic adenyl cyclase activity. The dose response curves show that the affinity of pentagastrin for adenyl cyclase is greater than that of histamine, whereas the peak response to pentagastrin is less than that to histamine. Additive stimulation was not obtained when maximal doses of pentagastrin and histamine were combined. These findings suggest that gastric mucosa contains a single adenyl cyclase unit which is coupled to distinctive selectivity sites for gastrin and histamine. N-Benzyl-3-pyrrolidyl acetate methobromide (AHR-602), the muscarinic compound, caused a significant reduction in adenyl cyclase activity, indicating a different mechanism of stimulation of gastric acid secretion for cholinergic muscarinic compounds.     

Inhibitory role on gastric secretion of a central NK-3 tachykinin receptor agonist, senktide

When administered intracerebroventricularly, the highly selective NK-3 tachykinin receptor agonist senktide possesses a potent and dose-related inhibitory effect on gastric acid secretion. The central mechanism governing the antisecretory effect of senktide was examined in perfused-stomach rats by studying its influence on gastric acid secretion elicited by the secretagogues histamine, pentagastrin and bethanechol. Given intracerebroventricularly, senktide reduced the acid response to histamine, but not that to pentagastrin or bethanechol. Stimulation of NK-3 receptors in rat brain thus appears to inhibit gastric acid secretion through histaminergic pathways.     

Gastric secretion in dogs following three day fasting and resumed feeding

The investigation into the influence of a three-day starvation on the gastric secretion in dogs with Pavlov pouches stimulated by meat, histamine and pentagastrin, was carried out. A 72-hour starvation did not change the summary volume of the gastric juice, debit of the gastric acid, and quantity of pepsin. At the same time the starvation decreased the average rate of gastric juice secretion, gastric acid and pepsin secretion in response to histamine and decreased the pepsin secretion in response to pentagastrin. In this way re-feeding enhanced the average rate of gastric juice secretion and gastric acid secretion on 3-day and pepsin on 5-day in response to meat. The average rate of gastric juice secretion increased on the 5-day after refeeding in response to histamine and the average rate of gastric juice, gastric acid and pepsin secretion in response to pentagastrin.     

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.     

Inhibition of gastric acid secretion in dogs by neurotensin

Neurotensin is a tridacapeptide which has been isolated from bovine hypothalamus. The action of synthetic neurotensin was studied on gastric acid secretion in dogs provided with gastric pouches. Intravenously infused neurotensin, 50 ng × kg^?1 × min^?1, was found to produce a considerable inhibition of pentagastrin stimulated gastric acid secretion. On the other hand, there was no sign of inhibition of histamine induced gastric acid secretion. The experiments show that neurotensin, isolated from the central nervous system is a potent gastric secretory inhibitor and that it has a selective action in inhibiting gastric acid responses to pentagastrin but not to histamine.     

Prostaglandin synthesis inhibition reverses the gastric antisecretory activity of somatostatin in anaesthetized rats

The inhibitory action on somatostatin (ST) on the spontaneous and stimulated (pentagastrin 18 micrograms/kg/h i.v. and histamine 5 mg/kg/h i.v.) gastric acid secretion and its modification after pretreatment with an inhibitor of endogenous prostaglandins biosynthesis (indomethacin 5 mg/kg i.v.) has been studied in the anaesthetized rat. ST 30 micrograms/kg/h i.v. inhibits basal and stimulated gastric acid secretion. In the presence of indomethacin the inhibition elicited by ST on basal and pentagastrin induced gastric acid secretion was partially attenuated, whereas in the histamine group the inhibitory action was totally abolished. The antagonism elicited by indomethacin was not surmounted by increasing (X 3.3) the dose of ST. These findings suggest that endogenous prostaglandins may be involved in the mechanism by which ST exerts its antisecretory effect in this model.     

The effect of dibutyril cyclic guanosine monophosphate,a competitive antagonist to cholecystokinin-pancreozymin,on gastric acid secretion in the isolated mouse stomach

Dibutyryl cyclic guanosine monophosphate (dbcGMP), a specific competitive inhibitor of the gastrin, cholecystokinin-pancreozymin (CCK-PZ) family of peptides in pancreas, gallbladder and ileum, had no effect on basal acid secretion in the isolated mouse stomach nor on secretion stimulated by bethanechol or histamine. Secretion evoked by low doses of pentagastrin were likewise unaffected by dbcGMP but responses to high doses of pentagastrin were augmented. CCK-PZ and glucagon each inhibited acid secretion evoked by pentagastrin. DbcGMP blocked CCK-PZ-mediated inhibition but was without effect on inhibition by glucagon. These observations suggest that in the gastric glands there exist two receptors with different affinities for gastrin and CCK-PZ which mediate excitation and inhibition respectively.     

Ontogeny of gastric acidity in the ovine fetus

Hypoacidity and hypergastrinaemia have been reported in the newborn human. However, little is known about in utero gastric acid secretion, and the relationship to fetal plasma gastrin levels. The longitudinal pattern of development of basal and stimulated gastric acid secretion in the non-anaesthetized fetal sheep has been studied during the last 45 days of gestation. Fetuses had cannulae inserted into the jugular vein, carotid artery and stomach. Gastric juice and blood was sampled daily from 101 days gestation until birth (145 days). Intermittent basal acid secretion began between 120 and 133 days of gestation. These fluctuations in gastric juice pH continued until birth. Overall there was a decline in gastric pH from 7.5 +/- 0.2 (SEM), for fetuses 101-105 days to 4.3 +/- 0.5 by 131-135 days. Mean fetal plasma gastrin was higher than maternal levels after 111-115 days but no correlation between fetal plasma gastrin levels and gastric pH could be demonstrated. Pentagastrin and histamine infusion did not stimulate acid secretion in fetuses younger than 115 days. After this age the fetuses became responsive to both pentagastrin and histamine. In contrast, cholinergic stimulation, using bethanechol, did not stimulate acid production until 10 to 15 days later, suggesting a hierarchy in the development of the control of acid secretion in the fetus. The lack of response to endogenous gastrin and the hierarchy in the control of acid secretion suggest either a lack of receptors on the parietal cell or the presence of an inhibitor of acid secretion. These studies are relevant to human physiology since the present findings show that the sheep and human have a similar gastrin/acid profile at birth.     

Gastric acid secretion in streptozotocin-diabetic rats--different responses to various secretagogues.

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.     

The influence of a new prostaglandin E2 analogue (FCE 20700) on gastric acid and pepsin secretion in the dog.

The effects of FCE 20700, a new prostaglandin E₂ analogue, on gastric acid and pepsin secretion stimulated by different secretagogues were studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucose were simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF was not significantly affected. It is concluded that FCE 20700 possesses a weak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion.     

Effect of metiamide on acid secretion from isolated kitten fundic mucosa.

Isolated kitten fundic mucosa demonstrates low rates of spontaneous acid secretion in vitro when bathed in Krebs-Henseleit solution, and responds consistently to histamine, pentagastrin, and acetylcholine placed in the bath. High rates of spontaneous secretion or secretion in response to histamine and pentagastrin were significantly inhibited by addition of metiamide (5 X 10(-3) M); but mucosa stimulated by constant addition of acetylcholine chloride (10(-4) M) was not inhibited by metiamide at the same concentration.     

Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat

We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE(2) suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE(2) was mimicked by sulprostone (EP(1)/EP(3) agonist) but not butaprost (EP(2) agonist) or AE1-329 (EP(4) agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP(1) antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 mug/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 mug/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1-329 (EP(4) agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1-329 was totally abolished by cimetidine as well as AE3-208 (EP(4) antagonist). These results suggest that PGE(2) has a dual effect on acid secretion: inhibition mediated by EP(3) receptors and stimulation through EP(4) receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.     

Effect of resiniferatoxin on stimulated gastric acid secretory responses in the rat

The effect of the capsaicin analogue ‘resiniferatoxin’ (RTX) was studied on basal and stimulated gastric acid secretory responses following sc bethanechol (1.5 mg/kg), sc pentagastrin (50 μg/kg) and sc histamine (0.5 and 2.5 mg/kg) in the 1-h pylorusligated plus saline (2 ml ig)-treated rats. Resiniferatoxin applied intragastrically in doses of 0.6 and 1 μg/kg at time of pylorus-ligation and administration of the above secretagogues reduced acid secretory respones to bethanechol by 18.3 and 26.4%, to 0.5 mg/kg histamine by 39.9 and 44.6%, to 2.5 mg/kg histamine by 21.3 and 40.8% and to pentagastrin by 10.2 and 30.9% respectively. A single sc injection of 0.4 μg/kg of RTX abolished basal secretion in pylorus ligated rats (which did not receive ig saline). Our results indicate that locally applied RTX is capable of inhibiting basal secretory responses and modifying gastric acid responses stimulated with histamine, bethanechol or pentagastrin in the rat.     

Central nervous system inhibition of pentagastrin-stimulated acid secretion by insulin-like growth factor II

The ability of intracisternal insulin-like growth factor II (IGF II) to inhibit gastric acid secretion was studied in rats. Centrally-administered IGF II dose-dependently inhibited acid secretion stimulated by pentagastrin. The effect was abolished by vagotomy. IGF II did not inhibit acid secretion stimulated by histamine or PCP-GABA.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Pharmacological profile of a new peptidic gastrin antagonist

Boc-Trp-Met-Asp-NH2 was described as the smallest peptidic fragment which presented gastric antisecretory activity. Some pharmacological aspects of a peptide analogue, Boc-Trp-Leu-Asp-NH2 (Boc-WLD-NH2), were studied on the main biological functions of gastrin. This compound was found to inhibit the binding of gastrin to isolated gastric fundic mucosal cells (IC50 50 microM). On pentagastrin-induced gastric acid secretion in the rat, a dose-dependent inhibition was observed with an ID50 of 55 mumol/kg when pentagastrin (1 microgram/kg per h) was continuously infused and with an ID50 of 7.8 mumol/kg when pentagastrin (1 microgram/kg) was bolus i.v. injected. Similar inhibition was observed on acid secretion induced by pentagastrin in the isolated rat gastric mucosa (IC50 100 microM), whereas the tripeptide had no effect when acid output was triggered by histamine. A dose-dependent inhibition with the tripeptide was shown on pentagastrin induced guinea-pig ileum contractions (IC50 31 microM). The compound had no activity on histamine-stimulated guinea-pig atria (histamine H2-receptor). These results suggest some evidence for a selective antigastrin activity.     

Increased sensitivity to epinephrine stimulated lipolysis during starvation: tighter coupling of the adenylate cyclase complex

Histamine, bombesin, and pentagastrin produced different patterns of changes in short circuit current, electric conductance, potential difference, and acid secretion in isolated bullfrog gastric mucosa. Histamine produced a gradual increase in electric conductance, parallel to the increase in acid secretion, and a transient rise in short circuit current. Bombesin induced an abrupt increase in electric conductance and in short circuit current, which peaked after 8 minutes. Pentagastrin also produced an increase in short circuit current, which peaked after 8 minutes; electric conductance, however, rose more gradually. Bombesin produced only a short term increase in acid secretion. These experiments show that histamine, bombesin, and pentagastrin affect gastric mucosa by different mechanisms. Histamine may have a more pronounced effect on the fusion process and activation of the tubulovesicular system of the parietal cell; bombesin may act by transiently increasing the permeability of the basolateral membrane. Pentagastrin seems to have an effect on both the basolateral membrane and the tubulovesicular acid secretory apparatus. These observations are not consistent with the hypothesis that histamine is the final common mediator for the effects of other secretagogues.