The effect of atropine, propantheline and poldine on the vagally stimulated gastric motility and the histamine-stimulated acid gastric secretion in the rat

Histamine-induced acid gastric secretion in the anaesthetized rat was not diminished by poldine in a dose which reduced vagally stimulated gastric contractions by approximately 75%. A dose of atropine, twice as large as the dose which reduced gastric contractions by 75%, had no apparent effect on the histamine-stimulated acid gastric secretion up to 2 hr after the injection. Only when more than 40 times as much atropine was injected did a slight inhibition of the acid secretion occur in 80 to 120 min. Propantheline, in a dose which inhibited gastric contractions by approximately 75%, slightly diminished acid secretion in 40 to 80 min. This effect was not increased by a further dose of propantheline. It was concluded that, in so far as any inhibition of acid gastric secretion had occurred, this could not be interpreted as an anti-muscarine or a direct toxic effect, but rather as an indirect effect possibly due to interference with the blood flow through the stomach wall.     

Inhibition of gastrin- and histamine-stimulated gastric acid secretion by gastrin and cholecystokinin antagonists in the rat

The gastric acid inhibitory activities of a peptide-like gastrin receptor antagonist, Boc-beta Ala-Trp-Leu-Asp-O(CH2)2-Ph-4-F (CH-486), a nonpeptide gastrin/CCK-B antagonist (L-365,260), and a CCK-A antagonist (L-364,718), were investigated in the gastric lumen-perfused anaesthetized rat. A single i.v. injection of CH-486, 100 mumol/kg, reduced acid secretion stimulated by pentagastrin, 15 micrograms kg/h, to unstimulated levels, with no recovery within 50 min. Histamine-, 0.1 mumol kg/min, and carbamylcholine-, 0.1 mg kg/h, stimulated acid secretion were also reduced to unstimulated levels by CH-486, 100 mumol/kg, although with these latter two stimulants the inhibition was transient. L-365,260 and L-364,718, 10 mumol/kg, significantly inhibited both pentagastrin- and histamine-stimulated acid secretion, the latter again transiently. We conclude that the non-selective nature of the gastric acid inhibitory activity of gastrin antagonists might allow novel approaches to control gastric acid secretion in peptic ulcer disease.     

The stimulatory effect of forskolin on gastric acid secretion in rats

Adenylate cyclase is involved in the histamine pathway of the parietal cell. We therefore studied the effect of forskolin, a direct activator of the membrane-bound adenylate cyclase, on gastric acid secretion in anaesthetized rats. Forskolin in the range of 0.1-1 mg/kg i.v. caused a dose-dependent stimulation of acid secretion. Higher doses were not tolerated. The duration of action of the forskolin-induced acid secretion was also dose-related. The combined infusion of forskolin (0.3 mg/kg per h i.v.) and histamine at a low rate (0.5 mg/kg per h i.v.) produced a maximal stimulation of acid secretion which was comparable to that with a histamine infusion of 10 mg/kg per h i.v. without forskolin. Administration of desglugastrin at a low rate (10 micrograms/kg per h i.v.) plus forskolin by i.v. infusion produced similar results. In contrast, infusion of carbachol (3 micrograms/kg per h i.v.) together with forskolin caused only an additive effect on acid secretion. Including an isobutyl-methyl-xanthine (IBMX) i.v. injection of 3 mg/kg at the beginning of the forskolin infusion (0.3 mg/kg per h i.v.) produced an acid output after 60 min which was approximately 50% of the maximal stimulation during a histamine (10 mg/kg per h i.v.) infusion. The IBMX/forskolin-induced stimulation was completely inhibited by 0.5 mg/kg omeprazole i.v. while the equipotent antisecretory dose (during histamine stimulation) of cimetidine caused only a weak decrease in acid output.     

The effect of clonidine on gastric acid secretion in rats and dogs

Summary The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED₅₀ 12 g/kg p.o.). In addition, gastric secretion stimulated by insulin hypoglycaemia was inhibited by clonidine in anaesthetized stomach lumen perfused rats and in conscious dogs with gastric fistula. In the rat gastric secretion stimulated by electrical vagus stimulation was inhibited as well. However, clonidine had no effect on the gastric acid secretion stimulated by carbachol in stomach lumen perfused rats and in dogs with denervated fundic pouch.These results suggest that the inhibition of gastric acid secretion by clonidine probably is due to an inhibition of acetylcholine release at the vagus nerve endings. Additional central gastric antisecretory effects can, however, not be excluded by this study.     

Inhibitory effect of somatostatin on gastric acid secretion in rats

Effects of somatostatin on parasympathetically induced increases in gastric acid secretion and mucosal blood flow (MBF) were studied in anesthetized rats with a gastric fistula. Intravenous infusion of small doses of somatostatin (0.1-0.5 microgram/kg/min) dose-dependently inhibited the increases in the vagally stimulated gastric acid secretion. Larger doses of somatostatin (0.5-2.5 micrograms/kg/min) also dose-dependently inhibited the bethanechol-induced gastric acid secretion. The dose of somatostatin required to inhibit the gastric acid secretion by about 50% of the preinfused control values was 0.25 microgram/kg/min for vagally stimulated acid secretion and 2.5 micrograms/kg/min for bethanechol-induced acid secretion. Thus, the inhibitory potency of somatostatin on the vagally stimulated gastric acid secretion was about 10-fold higher than that on bethanechol-induced acid secretion. Somatostatin had no effect on the increase in gastric MBF during vagus nerve stimulation or bethanechol infusion. Pretreatment with indomethacin or phentolamine had no effect on the inhibitory effect of somatostatin on the increase in gastric acid secretion during vagus nerve stimulation or bethanechol infusion. These results suggest that somatostatin exerts an inhibitory effect on gastric acid secretion by acting on the parasympathetic neurons in the gastric wall more than on the structures peripheral to the parasympathetic nerve terminals, and it reduces parasympathetically stimulated gastric acid secretion in rats. This inhibitory effect of somatostatin on the gastric acid secretion is independent of the changes in the gastric MBF and probably not related to prostaglandin-involved or alpha adrenoceptor-mediated mechanisms.     

The effect of phloxin on bethanechol and histamine stimulated gastric acid secretion in rats

Summary The effect of phloxin (Na salt of tetrabromo-tetrachlorofluorescein) on histamine- and bethanechol-stimulated gastric acid secretion was studied in anaesthetized rats. Concentrations of phloxin, equimolar with those of the stimulants, depressed the secretory response to histamine and had no influence on the bethanechol effect. The results suggest that histamine is not involved in the events triggered by bethanechol which stimulate gastric acid secretion in rats.Supported by the Deutsche Forschungsgemeinschaft and the Gesellschaft der Freunde der Universität Tübingen.     

Effect of amodiaquine on gastric histamine methyltransferase and on histamine-stimulated gastric secretion.

1 Amodiaquine was found to be a potent inhibitor in vitro of gastric histamine methyltransferase from human and canine corpus and from pig antrum. The ID50 for the enzyme, purified from pig antrum mucosa by ultracentrifugation and chromatography on DEAE-cellulose, was 2.5 muM. 2 In six dogs with Heidenhanin pouches the maximum secretory response to histamine (40 mug/kg i.m.) was augmented by i.m. injection of amodiaquine. The augmentation depended on the dose of amodiaquine, the optimum effect (40% increase in volume of gastric juice, 80% in acid output) being achieved with 2 mg/kg. The maximum secretory response to betazole was also enhanced by amodiaquine. 3 It was suggested that amodiaquine may enhance the histamine and betazole stimulated gastric secretion by an inhibition of gastric histamine methyltransferase in vivo.     

The effect of submaximal doses of pentagastrin on gastric acid secretion, histamine and histidine decarboxylase in rats

In Lai-rats gastric mucosal histamine and histidine decarboxylase were estimated after stimulation of gastric acid secretion by intravenous infusions of submaximal doses of pentagastrin for 1 or 2 h. Pentagastrin produced a dose-dependent acid response with a maximum of 26 μ equiv H⁺ per 10 min at a dose of 2.56 μg kg^?1 min^?1. There was a linear relation between the log dose of pentagastrin and the activation of gastric histidine decarboxylase. The highest dose of pentagastrin yielded a histidine decarboxylase activity of 200% of the unstimulated level when infused for 1 h and of 290% when infused for 2 h. No reduction of gastric mucosal histamine could be detected whatever the dose of pentagastrin or the duration of infusion. It was concluded (1) that stimulation of gastric histidine decarboxylase is a physiological function of gastrin-like peptides, (2) that a reduction of gastric mucosal histamine by gastrin or pentagastrin is a pharmacological rather than a physiological effect, and (3) that no negative feedback relation exists beween gastric mucosal histamine and the activation of histidine decarboxylase.     

Pharmacodynamic modeling of pantoprazole's irreversible effect on gastric acid secretion in humans and rats

The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, i.v.) and 22 healthy volunteers (10 to 80 mg, i.v. and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after i.v. administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half-lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h-1 and 0.031 h-1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of i.v. and oral pantoprazole on gastric secretion and may be used to predict effects under other dosage regimens.     

Stimulatory effect of prostaglandin F2 alpha on gastric acid secretion in rats

The effect of intravenously administered prostaglandin F2 alpha on gastric acid secretion was investigated in anaesthetized rats. Doses of 0.03-0.3 mg/kg PGF2 alpha stimulated gastric acid output in rats with intact vagi, whereas an inhibitory effect was observed in vagotomized animals. Treatment with 5 mg/kg of Na-meclofenamate intravenously attenuated the secretory response to PGF2 alpha, while 10 mg/kg of indomethacin intravenously and 3 mg/kg of 8-phenyltheophylline intraperitoneally were without any effect. The results indicate that intravenously administered PGF2 alpha stimulates gastric acid secretion in anaesthetized rats via activation of the vagus nerve. The effects of Na-meclofenamate and indomethacin suggest that PGF2 alpha may exert its secretagogue action via specific receptors. The lack of the effect of 8-phenyltheophylline indicates that adenosine which reportedly had a similar effect on gastric secretion after intravenous injection seems not to be involved here.     

Effect of a prostaglandin analogue,SC-30249, on canine gastric secretion

We previously reported the prostagladin analogue SC-29333 [(±)(16RS)-15-deoxy-16 hydroxy,-16-methyl prostaglandin E₁ methyl ester] to be a potent inhibitor of gastric secretion in animals. SC-29333 is comprised of four stereoisomers in approximately equal proportions. It is believed the major antisecretory activity of SC-29333 results from one isomer, SC-30249 (16S-16-hydroxy-16-methyl, 15-deoxy-PGE₁ methyl ester). Our purpose was to investigate the canine gastric antisecretory action of SC-30249 relative to SC-29333. The studies were carried out in maximally stimulated (histamine) Heidenhain pouch (HP) and gastric fistula (GF) dogs. Administered intravenously (i.v.) to HP dogs at the steady-state plateau of gastric secretion, SC-30249 was found to be approximately three times more potent than SC-29333. Administered intragastrically to GF dogs, SC-30249 is approximately ten times more potent as an inhibitor of gastric secretion than SC-29333. SC-30249 (1.0 μg/kg, i.v.) completely inhibited meal-stimulated gastric secretion but had no significant effect on postprandial serum gastrin concentration. SC-30249 shared with SC-29333 the capability of totally antagonizing the histamine-stimulated gastric secretion in HP dogs without reducing gastric mucosal blood flow. These studies indicate that SC-30249 is a potent gastric antisecretory agent that merits clinical evaluation.     

Effect of 3-isobutyl-1-methylxanthine on histamine-stimulated gastric secretion in dogs

The effect of IMX on histamine-stimulated gastric secretion has been studied in dogs equipped with gastric cannulas. After determining the histamine dose response, IMX, histamine, and IMX plus histamine were given by a constant intravenous infusion for 3 h, and acid was collected at 15-min intervals. In a separate series of experiments a single dose of 100 mg of db-cAMP was given 1 h after initiation of infusion of IMX, histamine, and histamine plus IMX. Results show that IMX, a potent inhibitor of phosphodiesterase, is a weak stimulant of acid secretion, and augments histamine-stimulated secretion. However, during stimulated acid secretion, there were no significant changes in tissue cAMP levels, Administration of exogenous dib-cAMP did not produce any significant changes in acid secretion in dogs, but did contribute to elevated cAMP levels.