Effects of indomethacin on the duodenal mucosa of rats: comparative study with cysteamine

Effects of indomethacin and cysteamine on the duodenal mucosa of rats were studied microscopically (using scanning electron microscopy) and also functionally. Indomethacin (5 mg/kg, s.c.) induced no microscopic damage to the duodenal epithelium for up to 6 hr after administration. Indomethacin had no effects on gastric H+ output and the amount of H+ in the duodenum, but did reduce the duodenal HCO3- secretion (both basal and 10 mM-HCl stimulated). PGE2 contents in the duodenal mucosa were markedly reduced by indomethacin for 6 hr. These results suggest that reductions of duodenal HCO3- secretion and endogenous prostaglandins per se do not impair the H+ disposal system of the duodenum and so do not damage the epithelial cells. In contrast, cysteamine (100 mg/kg, s.c.) produced microscopic damage to the duodenal epithelium as early as 2 hr later. Cysteamine significantly increased gastric H+ output and reduced duodenal HCO3- secretion, resulting in an increased amount of H+ in the duodenum 3 hr later. Cysteamine had no effect on PGE2 contents in the duodenum. The time lag between damage formation and functional changes suggests that the earliest damage caused by cysteamine occurs by mechanisms other than erosive action of H+ emptied by the stomach. The increased amount of H+ may contribute to an enhancement of the initial damage.     

The effect of prostaglandins on gastric parietal and non-parietal secretion in the anaesthetized rat

The effects of prostaglandin E2 (PGE2), 16,16-dimethyl prostaglandin E2 (dmPGE2) and prostaglandin F2 alpha (PGF2 alpha) on gastric secretion have been examined in the anaesthetized rat. The prostaglandins stimulated the secretion of a non-parietal juice which was rich in Na+ and Cl- with smaller amounts of K+ and HCO3-. Doses of the prostaglandins that stimulated gastric non-parietal secretion also inhibited histamine stimulated gastric acid secretion, and thus the same rank order of potency was obtained for the prostaglandins on the two secretory mechanisms, viz. dmPGE2 greater than PGE2 greater than PGF2 alpha. During the secretion of endogenous gastric acid the secretagogue effect of the prostaglandins on non-parietal secretion was diminished, and this effect appeared to be due to the presence of intraluminal acid since it was mimicked by application of exogenous HCl to the gastric mucosal surface. Thus, the present results show that prostaglandins affect both the parietal and non-parietal secretions in the rat stomach and that these mechanisms show some interdependence.     

Effect of H2-receptor blockade by ranitidine on ulcer healing and gastric acid secretion in patients with gastric and duodenal ulcers

The effect of treatment for 4 weeks with the H2-receptor antagonist ranitidine 200 mg daily on ulcer healing, clinical symptoms and antacid consumption, and on gastric acid secretion, was studied in a double blind trial in 48 patients with a total of 50 endoscopically confirmed duodenal, prepyloric or corporeal gastric ulcer. Patients whose ulcers did not show complete healing within 28 days were continued openly on ranitidine for up to a further 4 weeks. Endoscopy, basal gastric acid secretion (BAO) and pentagastrin-stimulated maximal secretion (PAO) studies were performed at 2-week intervals. After four weeks, 73% of the gastro-duodenal ulcers in the ranitidine group showed complete healing versus 42% in the placebo group (p less than 0.05). Gastric acid secretion was considerably inhibited both under basal (89%; p less than 0.001) and maximal challenge (71%; p less than 0.001) conditions. The inhibitory effect was still pronounced 13-15 h after administration of ranitidine 100 mg. Symptoms and the need for antacids were significantly reduced. Ranitidine appears to be an efficacious, safe and well tolerated medicine principle for the treatment of gastro-duodenal ulcer disease.     

Effects of cytochalasin E on H+ and volume secretion in gastric fistula rats

Effects of cytochalasin E on the secretion of H+ and volume of gastric juice were investigated in gastric fistula rats. Direct exposure of the gastric mucosa to cytochalasin E (5-20 micrograms/ml) inhibited H+ secretory rate in all of the pentagastrin-, histamine- as well as non-stimulated rats but it did not affect the secretory volume of gastric juice. The inhibitory action of cytochalasin E on H+ secretion had a rapid onset and showed a dose-dependent pattern. The mechanism of inhibitory action was not related to its interaction with plasma membrane receptors or membrane enzyme, K+-stimulated ATPase. Interference with cellular energy production as well as alteration of microfilament function, which are essential for H+ production and secretion respectively, are likely to be the bases of the cytochalasin inhibition.     

Effects of a new histamine H2-receptor antagonist, Z-300, on gastric secretion and gastro-duodenal lesions in rats: comparison with roxatidine.

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.     

Cellular mechanisms and inhibitors of gastric acid secretion

Hydrochloric acid (HCl) secretion into the gastric lumen is a specialized process driven primarily by H(+)/K(+)-ATPase or proton pump, a unique enzyme expressed in high quantities by the parietal cells. Physiological regulation of this secretion involves central signals conveyed by the vagus nerve and local mechanisms mediated by cholinergic and peptidergic fibers of the gastric wall, as well as amine or peptide secreting cells located in the fundic and antral epithelia. Among these cells, the enterochromaffin-like (ECL) cell plays a major role: it responds to gastrinic, cholinergic and adrenergic stimulations to secrete histamine, which in turn activates an H(2) receptor on the parietal cell. The H(2) receptor is responsible for intracellular production of cAMP, a second messenger critical for the secretory machinery to be triggered. The blockade of this receptor by specific antagonists results in a dramatic albeit surmountable inhibition of HCl output. The blockade of the proton pump is an alternative means of inhibition. This can be achieved by a series of benzimidazole derivatives which specifically accumulate in the parietal cell secretory canaliculus and covalently bind to ATPase extracellular sites. The resulting inhibition is stronger and lasts longer than with the H(2) antagonists. Furthermore, it is effective regardless of the stimulatory status. Therefore, proton pump inhibitors (PPIs) are of special interest in the treatment of acid-related diseases such as gastric and duodenal ulcer, as well as reflux esophagitis.     

Absence of tachyphylaxis in gastric acid secretion during pentagastrin infusion

Tachyphylaxis to stimulation of gastric juice secretion during intravenous pentagastrin (PG) infusion has been reported in animal studies. We assessed the course of gastric response to PG 2 micrograms/kg/hr over eight hours in eight healthy subjects. Peak H+, pepsin, and volume secretions occurred during the second half hour of stimulation. Peak H+ output was 11.6 +/- 1.3 mmol/0.5 hr or 7.6 +/- 0.8% of the total eight-hour secretion. During subsequent half-hour collection intervals, there was no significant decline in response, and the average output was 10.3 +/- 0.4 mmol/0.5 hr (6.5 +/- 0.1%). Peak pepsin and volume secretions were respectively 10.0 +/- 1.4% (74.8 +/- 11.6 mg/0.5 hr) and 8.8 +/- 1.1% (146.3 +/- 17.4 mL/0.5 hr) of the total eight-hour secretion. Although there was a significant decline in pepsin and volume response subsequent to the peak output, the decline was not continuous, and pepsin and volume secretions were maintained, respectively, at 6.0 +/- 0.2% (46.1 +/- 2.5 mg/0.5 hr) and 6.2 +/- 0.1% (107.5 +/- 3.0 mL/0.5 hr) of the total eight-hour secretion. Our study did not demonstrate any tachyphylaxis in H+ response to continuous PG stimulation. This model appears to be a valid tool for the assessment of histamine-H2 antagonist effects on stimulated gastric juice secretion over 8 hours in humans.     

Effects of H2-receptor antagonists and anticholinoceptor drugs on gastric and salivary secretion induced by bethanechol in the anaesthetized dog

1 The H2-receptor antagonists, ranitidine and cimetidine, have been compared with atropine and pirenzepine for their effects on gastric acid output, and on salivary secretion from the left parotid gland in the anaesthetized dog. Gastric and salivary secretions were elicited by intravenous infusion of bethanechol. 2 Atropine (0.3-1 microgram/kg) or pirenzepine (3-10 micrograms/kg) reduced both gastric and salivary secretions, pirenzepine showing little evidence of any selectivity for gastric secretion. 3 The H2-receptor antagonists, ranitidine (30-1000 micrograms/kg) and cimetidine (100-3000 micrograms/kg), selectively inhibited gastric secretion and even at relatively high dose levels did not alter salivary volume.     

Histamine receptors in the CNS as targets for therapeutic intervention

Histamine has long been known to trigger allergic reactions and gastric acid secretion. However, it was later discovered that, in the brain, histamine regulates basic homeostatic and higher functions, including cognition, arousal, circadian and feeding rhythms. The sole source of brain histamine is neurons localized in the hypothalamic tuberomammillary nuclei. These neurons project axons to the whole brain, are organized into functionally distinct circuits influencing different brain regions and display selective control mechanisms. Although all histamine receptors (H1R, H2R, H3R and H4R) are expressed in the brain, only the H3R has become a drug target for the treatment of neurologic and psychiatric disorders, such as sleep disturbances and cognitive deficits. In this review, we discuss recent developments in the pharmacological manipulation of H3Rs and the implications for H3R-related therapies for neurological and psychiatric disorders. The legacy of Sir James Black.     

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H2-receptor antagonists (fagamet [cimetidine] , Zantac [ranitidine], Pepcid [famotidine] , Axid [nizatidine]) decrease the volume and concentration of gastric acid secretion by competitively inhibiting histamine-2 receptor function. They suppress basal, nocturnal, and histamine-stimulated gastric acid secretion. H2-blockers do not affect antigeninduced histamine release (at HI receptors) or humoral and cell-mediated immune responses. H2 -antagonists are used to treat duodenal and gastric ulcers, gastroesophageal reflux disease (GERD), and pathological hypersecretory disorders.     

Gas mediators involved in modulating duodenal HCO3(-) secretion

The secretion of HCO3(-) in the duodenum is increased by mucosal acidification, and this process is modulated by gas mediators such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), in addition to prostaglandins (PGs). The secretion is increased by NOR3 (NO donor), NaHS (H2S donor), and CORM-2 (CO donor). The HCO3(-) responses to NOR3 and CORM-2 are attenuated by indomethacin, while that to NaHS is mitigated by indomethacin and L-NAME as well as sensory deafferentation. NOR3 and CORM-2 increase mucosal PGE2 production, while H2S increases mucosal PGE2 content and luminal NO release. The HCO3(-) response to mucosal acidification is attenuated by indomethacin, propargylglycine, and SnPP, each inhibiting PG, H2S and CO production, respectively. The acid-induced duodenal damage is worsened when either PG, H2S or CO is lacking. These findings suggest that 1) NO, H2S, and CO, generated endogenously or exogenously, stimulate HCO3(-) secretion in the duodenum; 2) the stimulatory action of NO and CO is mediated, at least partly, by endogenous PGs, while that of H2S is mediated by PGs and NO as well as sensory neurons; 3) these gas mediators are involved in the local regulation of acid-induced HCO3(-) secretion, in addition to endogenous PGs; 4) the acid-induced duodenal damage is worsened by agents inhibiting the endogenous production of NO, H2S or CO. It is assumed that these gas mediators play a role in maintaining the integrity of the duodenal mucosa by modulating the secretion of HCO3(-).     

Effects of elcatonin, a synthetic analogue of eel calcitonin, on acute gastric and duodenal lesions and gastroduodenal function in rats

We studied the effects of elcatonin (eel calcitonin), on various gastric and duodenal lesions, gastric acid and duodenal alkaline secretion, and gastric motility in rats. Elcatonin at 1-30 unit/kg, given subcutaneously, dose-dependently inhibited the development of HCl-aspirin-, HCl-ethanol-, water-immersion stress- and indomethacin-induced gastric lesions. This agent also significantly prevented the formation of duodenal lesions induced by indomethacin plus histamine at 30 unit/kg, although it showed only a tendency of inhibition against mepirizole-induced duodenal lesions. 16, 16-Dimethyl prostaglandin E2 (3-30 micrograms/kg), given orally as a reference drug, showed a potent inhibition against all types of lesions tested herein at the dose of 3 micrograms/kg or greater. Elcatonin dose-dependently inhibited gastric secretion (volume, acid and pepsin output) in pylorus-ligated rats and gastric motility in conscious rats, but had no effect on duodenal alkaline secretion in anesthetized rats. On the other hand, 16, 16-dimethyl prostaglandin E2 at 10 micrograms/kg, given intraduodenally, significantly inhibited gastric secretion and motility, but stimulated duodenal alkaline secretion. We conclude that elcatonin markedly protects the gastrointestinal mucosa from injury induced by stress or various irritants. These effects might be in part accounted for by the antisecretory and antimotility activities of this peptide, although some other unknown mechanisms may be involved in the mucosal protection afforded by elcatonin.     

Effects of prostaglandin biosynthesis inhibitors and ouabain on duodenal mucosa and HCO3- secretion in rats

A single injection (s.c.) of prostaglandin biosynthesis inhibitors such as indomethacin (5 mg/kg), aspirin (200 mg/kg) and quinacrine (100 mg/kg) or a Na+.K+ ATPase inhibitor such as ouabain (10 mg/kg) significantly reduced the adaptive increase of HCO3- output caused by acid in the duodenum of anesthetized rats. These agents had no effect on basal duodenal HCO3- secretion and histamine-stimulated gastric acid secretion. Either of these agents, when given alone, had no effect on the duodenal mucosa of conscious rats, but produced damage in the proximal duodenum within 8 hr when given together with histamine (40 mg/kg X 3, s.c., every 2.5 hr). A significant relationship was found between the degrees of inhibition of acid-induced HCO3- output and the severity of duodenal lesions induced by these drugs (r = 0.8620, P less than 0.01). These results suggest that an impairment of the mechanisms related to acid-induced HCO3- secretion may be particularly relevant to the pathogenesis of duodenal lesions.     

5-HT and the brain–gut axis: opportunities for pharmacologic intervention

Interactions between the enteric nervous system of the gut and the brain occur bidirectionally over sympathetic and parasympathetic pathways. Coordinated actions of the central, autonomic and enteric nervous systems modulate intestinal motor, sensory and secretory activities by neuromodulators, including 5-HT, noradrenaline and dopamine. 5-HT is an important signaling molecule in the brain–gut axis and the 5-HT released from enterochromaffin cells modulates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. Irritable bowel syndrome is associated with altered motility, secretion and sensation; enteric 5-HT signaling may be defective in this disorder. In this editorial, recent data are reviewed and the potential for the development of pharmacologic intervention is assessed.     

The effect of secretagogue selection on potency determinations for gastric acid antisecretory agents

The most common treatment for gastric and duodenal ulcers is by suppressing the secretion of gastric acid by the parietal cells of the stomach. Two major categories of drugs can accomplish this specifically: histamine H2-receptor antagonist and (H+ + K+)ATPase inhibitors. Using a canine model of gastric acid secretion and either histamine or food as secretagogues, the effects of two drugs from each of these classes were investigated. The two H2-antagonists (ranitidine, Wy-45,727) demonstrated a significantly greater antisecretory potency when acid secretion was stimulated by histamine as compared to a food stimulus. Conversely, the (H+ + K+)ATPase inhibitors (omeprazole, timoprazole) were equipotent regardless of stimulus.     

Histamine H3 receptors are not involved in the regulation of rat gastric secretion.

The effects of histamine H3 receptor activation [(R)alpha-methylhistamine] and blockade (thioperamide) on rat gastric secretion were determined in vivo and in vitro. (R)alpha-Methylhistamine (0.1-5 mumol/kg i.p.) did not modify secretory volume and acidity in pylorus-ligated rats; it did not affect basal acid secretion and the secretion stimulated by histamine, pentagastrin and 2-deoxy-D-glucose in the lumen-perfused stomach of anaesthetized rats, when administered by continuous infusion (0.01-1 mumol/kg/h) or bolus injection (0.05-25 mumol/kg). In this preparation, the H3 agonist increased acid secretion at doses of 3-25 mumol/kg i.v., the effect being antagonized by famotidine. In the isolated gastric fundus from immature rats both (R)alpha-methylhistamine (0.01-10 mumol/l) and thioperamide (0.01-1 mumol/l) were totally ineffective against both spontaneous and stimulated gastric secretion. These results suggest that histamine H3 receptors are unlikely to have a role in regulating gastric acid secretion in the rat.     

Antiulcerogenic effect of a pyrido-benzodiazepine derivative (L-S 519) on experimental ulcers

Effects of a tricyclic, pyrido-benzodiazepnie derivative, 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-6][1,4]-benzodiazepin-6-one-dihydrochloride (L-S 519) on experimental ulcers produced by pylorus ligation, cold restraint-stress, and reserpine, and on gastric secretions stimulated by histamine, tetragastrin and carbachol in rats were studied. L-S 519 was half as potent as atropine in preventing these experimental acute ulcers and in decreasing the spontaneous gastric secretion. This compound inhibited to various degrees the gastric secretion stimulated by histamine, tetragastrin and carbachol in acute fistula rats. On the other hand, the antimuscarinic effects of L-S 519 were much weaker than those of atropine in both in vivo and in vitro experiments. Furthermore, the antigastric secretory effect of L-S 519 was observed even in pylorus-ligated, vagotomized rats. By contrast, the effect of L-S 519 was reduced by pretreatment with 6-hydroxydopamine. These results suggest that the adrenergic mechanisms, in addition to a weak antimuscarinic property, are involved in antisecretory and antiulcerogenic effects of L-S 519.     

Effects of IGN-2098, a new histamine H2-receptor antagonist, on gastric secretion and gastric and duodenal lesions induced in rats. Comparison with roxatidine]

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.     

Effects of S-0509, a novel CCKB/gastrin receptor antagonist, on acid secretion and experimental duodenal ulcers in rats

Background:

S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ureidomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and selective CCK_B/gastrin receptor antagonist that does not affect the central nervous system.

Methods:

We evaluated the effects of S-0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L-365,260, another CCK_B/gastrin receptor antagonist.

Results:

S-0509 (0.1~10 mg/kg, i.d.) was able to dose-dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 μg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 μg/kg/h, i.v.). L-365,260 (10 and 30 mg/kg, i.d.) caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including peptone treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/kg, s.c.) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 weeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole when it was given as a pre-treatment. It also promoted significantly the healing of these ulcers (> 3 × 2 mg/kg, p.o.) when it was given twice daily for 14 days. In contrast, L-365,260 (30 mg/kg) tended to reduce the severity of mepirizole-induced duodenal ulcers, with a slight inhibition of acid secretion, but it caused no influence on the healing response of these ulcers.

Conclusion:

These results confirmed that S-0509 is a selective CCK_B/gastrin receptor antagonist with potent antisecretory action in vivo conditions, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCK_B/gastrin receptors.

     

In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults

We evaluated the environment in TIM-1 luminal compartments using paracetamol and danazol solutions and suspensions and the fed state configuration. Data were compared with recently published data in healthy adults. TIM-1 experiments were performed with a 3-fold downscale. Volumes of secretions in gastric and duodenal compartments adequately reflected the luminal data in adults up to 3 h post drug dosing. pH values in duodenal and jejunal compartments adequately reflected average pH values in adults. In gastric compartment pH values where initially higher than average values in adults and reached baseline levels earlier than in adults. The environment in the TIM-1 gastric compartment and jejunal compartment adequately reflected the average total paracetamol and danazol amounts per volume of contents in the adult stomach and upper small intestine, respectively. Total bile acids concentrations in the micellar phase of contents in duodenal and jejunal compartments overestimated micellar concentrations in the upper small intestine of adults. Adjustments in gastric emptying/acid secretion rates and bile acids identities in the duodenal and jejunal compartments, and application of dynamic bile acids secretion rates are expected to further improve the relevance of luminal conditions in TIM-1 compartments with those in adults.