The effects of 11-methyl 16,16 dimethyl prostaglandin E2 on canine gastric acid secretion

11-Methyl 16,16 Dimethyl Prostaglandin E₂ (TM-PGE₂) at peak effectiveness inhibited acid output stimulated submaximally by histamine in the dog by 95 and 84% when administered by the intravenous and oral routes, respectively. Inhibition of secretion was maintained for hours following intravenous administration while with the oral route, secretory inhibition was still present at the end of two hours after administration of the drug. The degree of inhibition of acid secretion caused by TM-PGE₂, its duration of action and the lack of side effects observed following administration of this drug makes it a suitable compound for evaluation as an anti-secretory agent in man.     

Effects of the synthetic PGE1 derivative misoprostol on basal, stimulated and nocturnal acid secretion in duodenal ulcer cases. Mechanism of action

We studied the antisecretory effect of the synthetic PGE1 derivative misoprostol. Basal, histamine-stimulated and nocturnal acid secretion were determined on separate days in 3 groups of endoscopically confirmed duodenal ulcer patients. Misoprostol or placebo were given in random order in doses of 200, 400 and 800 mcg. H+ concentration, acid output and pH of gastric content were determined. Additionally, the effect of misoprostol on purified and gastric mucosa carbonic anhydrase was determined according to Maren's micromethod. Misoprostol reduced dose-dependently basal acid secretion (by 54% after 200 mcg, by 82% after 400 mcg and, respectively, by 94% after 800 mcg) as well as stimulated secretion which was reduced after the same doses by 22% (p less than 0.05), 48% and 64% (p less than 0.001), respectively. Nocturnal secretion was significantly reduced for a period of 4 h, with a consecutive rise of gastric pH. In vitro, misoprostol inhibited dose-dependently purified and gastric mucosa carbonic anhydrase basal activity. In conclusion, misoprostol inhibits basal, nocturnal and histamine-stimulated secretion in duodenal ulcer patients, an effect which could be mediated by inhibition of carbonic anhydrase.     

A new prostaglandin E1 analogue (CL-115,574) II. Effects on gastric acid secretion in the dog

The efficacy of CL-115,574, a prostaglandin E₁ analogue, as an acid antisecretory agent was evaluated in dogs. CL-115,574 inhibited acid secretion maximally at an oral dose of 20 μg/kg causing 100% inhibition of acid secretion up to one hour after administration, with significant inhibition of secretion (30%) still present nearly four hours after drug administration. The wide disparity between the maximally effective antisecretory dose 20 μg/kg and the dose at which reproducible side effects occurred (1 mg/kg) suggests that this compound may be developed as an antisecretory compound for use in man.     

Partial purification of a novel stimulant of gastric acid secretion from canine non-antral mucosa

A novel stimulant of gastric acid secretion was extracted and purified from the non-antral gastric mucosa of the canine stomach and some of its biological properties were examined. Tissue was boiled in water and extracted in 2% trifluoroacetic acid. The stimulatory activity was purified by a combination of reverse-phase high pressure liquid chromatography (HPLC) and gel filtration. Fractions were assayed for a stimulation of basal, pentagastrin- and histamine-stimulated gastric acid secretion in the anaesthetized rat. Stimulatory activity was eluted from reverse-phase HPLC columns with acetonitrile and its elution from Sephadex G-10 and G-50 columns suggested a molecular weight of 1,000 to 3,000. The highly purified extracts enhanced basal, pentagastrin- and histamine-stimulated acid secretion in the rat. A stimulatory fraction was purified which was devoid of immunoreactive gastrin and gastrin-releasing peptide and contained only small amounts of histamine. Its chromatographic properties differed from those of histamine and acetylcholine. On two occasions the stimulant was purified to homogeneity and found to contain amino acids. Insufficient pure material was obtained for full characterization. The stimulant has been tentatively called oxyntin.     

Prostacyclin analogues inhibit canine parietal cell activity and cyclic AMP formation

To assess further the mechanism by which prostacyclin inhibits acid secretion, the actions of two stable prostacyclin analogues on parietal cell function and cyclic AMP formation were tested using enzymatically dispersed cells from canine fundic mucosa. Accumulation of ¹⁴C-aminopyrine (AP) was used as an index of parietal cell response to stimulation. The 16-phenoxy derivative of PGI₂ inhibited accumulation of AP stimulated by histamine (10 μM), with 50% inhibition (ID₅₀) at 10 nM. 6_β-PGI₁ also inhibited the action of histamine (ID₅₀ 0.5μM) but failed to block stimulation by carbachol or the dibutyryl derivative of cyclic AMP (dbcAMP). In similiar concentrations to those producing inhibition of histamine-stimulated AP accumulation, the 16-phenoxy analogue and 6_β-PGI₁ inhibited histamine-stimulated cyclic AMP generation by parietal cells. At 100 fold higher concentrations, 6_β-PGI₁ stimulated cyclic AMP formation, presumably in non-parietal cells. Even in high concentrations the 16-phenoxy analogue failed to increase cyclic AMP formation by mucosal cells. These data indicate that the stable prostacyclin analogues are potent, direct inhibitors of histamine-stimulated parietal cell function and that it is the inhibition, rather than the stimulation, of cyclic AMP formation that is linked to the antisecretory actions of these prostanoid compounds.     

Calcium modulates the generation of inositol 1,3,4-trisphosphate in human platelets by the activation of inositol 1,4,5-trisphosphate 3-kinase.

Histamine (0.5 mM) stimulated the cyclic AMP content of cell suspensions containing greater than 80% parietal cells. Epidermal growth factor (EGF) inhibited this stimulatory effect of histamine, but had no effect on basal cyclic AMP content. The half-maximally effective concentration of EGF for inhibition of histamine-stimulated cyclic AMP was 3.9 nM. The equivalent measurement for the inhibition of histamine-stimulated aminopyrine accumulation was 3.0 nM. Aminopyrine accumulation was measured because it provides an index of the secretory activity of the cell. The cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) prevented the inhibitory effect of EGF on cyclic AMP content. This effect of IBMX was not caused by its ability to raise cellular cyclic AMP content in the presence of histamine. Prevention by IBMX of the inhibitory action of EGF on histamine-stimulated aminopyrine accumulation had been shown previously [Shaw, Hatt, Anderson & Hanson (1987) Biochem. J. 244, 699-704]. EGF stimulated prostaglandin E2 (PGE2) production in the cell fraction containing greater than 80% parietal cells, with the half-maximally effective concentration being 7.5 nM. EGF was ineffective in stimulating PGE2 production if the cell fraction was depleted of parietal cells (12%), or if 0.5 mM-histamine was added to the enriched parietal-cell fraction. In conclusion, EGF may inhibit histamine-stimulated acid secretion by decreasing the cyclic AMP content of parietal cells. This effect could be mediated by an increase in cyclic AMP phosphodiesterase activity, but it is unlikely to involve an effect of EGF on parietal-cell prostaglandin production.     

Peptide histidine valine-42 stimulates gastric acid secretion in man

The effect of peptide histidine valine-42 (PHV-42) on gastric acid secretion was studied in man. PHV-42 was infused into 5 healthy volunteers at a dose of 10 pmol/kg/min. This dose caused a significant stimulation of basal gastric acid and potassium output. there were no significant changes in circulating gastrin throughout the infusion. In 2 subjects with a background of submaximal pentagastrin stimulation, PHV-42 infusion at the same dose did not alter acid secretion in either subject. The previous observation that PHV-42 is found particularly in the stomach and the new finding that it stimulates basal gastric secretion suggest the possibility that PHV-42 could have a role in local control of acid secretion.     

酸化胃窦对组织胺性胃酸分泌的抑制作用

用具有胃窦小胃、胃体小胃和胃肠吻合制备的狗做慢性实验,观察酸化胃窦粘膜对胃体小胃组织胺性胃酸分泌的抑制作用。一次皮下注射磷酸组织胺0.04mg/kg 体重,可使胃体小胃的胃酸分泌达到最大分泌量;在3—4h 内,每隔15分钟皮下注射磷酸组织胺0.01mg/kg体重,从第四次注射以后,即可使胃体小胃的酸分泌持续稳定在高水平。用0.1mol/L 盐酸灌注胃窦小胃,上述两种组织胺性胃酸分泌均受到抑制,而用生理盐水灌注则无影响。由此得出结论:酸化幽门部粘膜能抑制组织胺性胃酸分泌。由于这种抑制现象出现的潜伏期较长(15min 以上),作用持续时间较久(超过2h),提示酸化幽门部粘膜对组织胺性胃酸分泌的抑制作用,可能是通过某种抑制性体液因素实现的。     

Effects of various physiologic adenine derivatives on the secretion of acid in isolated gastric glands in rabbits

The physiological adenine derivatives, adenosine (ADO), adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP) at concentrations ranging from 10 microM to 1 mM caused concentration-related modifications on gastric H+ secretion, as measured by the aminopyrine accumulation method, in resting and histamine-stimulated rabbit gastric glands. In resting glands, ADO caused significant concentration-related increases of the basal H+ secretion, whereas no changes were obtained in response to the other purines tested. In histamine-stimulated glands, ADO and AMP caused concentration-related potentiation of the histamine-raised H+ secretory rate, while ATP and ADP induced graded inhibition. The results suggest the involvement of purinergic mechanisms in the physiological regulation of the gastric acid secretory process.     

Gastric acid inhibitory profile of ebrotidine, a novel H2-receptor antagonist in humans.

This study was designed to assess the gastric secretory effects of ebrotidine, a novel H2 receptor antagonist, in humans. Three groups (A, B and C) of male subjects with normal gastric mucosa were used. Group A (6 subjects) was used to determine the dose-dependency of gastric inhibitory effect of ebrotidine on basal and pentagastrin-induced maximal acid output. Group B (8 subjects) was employed to examine the duration of the inhibitory effect of ebrotidine on basal and pentagastrin-induced acid secretion. In group C (6 subjects), the 24h pH-metry was assessed using intraluminal pH-electrode placed in the gastric corpus and connected to a portable recording unit. Single oral dose of ebrotidine (200, 400 or 800 mg) caused a dose-dependent reduction in basal and pentagastrin-induced acid secretion that at a dose of 800 mg amounted to about 89% and 93%, respectively. This inhibition was still observed after 6h and averaged 72% and 50%, respectively. After 12 and 24h upon the drug intake, both basal and pentagastrin-induced acid secretion returned to the control values. Single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant reduction of intragastric acidity for about 6h upon the administration. This inhibition was accompanied by a transient increase in basal and postprandial gastrin levels. We conclude that ebrotidine is highly effective inhibitor of basal, pentagastrin-induced and circadian gastric acid secretion in humans.     

Inhibition of acid secretion by the nonsteroidal anti-inflammatory drugs diclofenac and piroxicam in isolated gastric glands: analysis of a multifocal mechanism

In nonstimulated rabbit gastric glands, acetylsalicylic acid (10-500 microM) and indomethacin (3-300 microM) did not significantly modify the basal rate of acid secretion, whereas diclofenac and piroxicam (10-1,000 microM each) caused a marked and dose-dependent inhibitory effect (EC(50) = 138 and 280 microM, respectively). In gastric glands stimulated by histamine (100 microM), diclofenac also reduced the rate of acid formation in a dose-dependent manner. In contrast, acetylsalicylic acid, indomethacin, and piroxicam exerted a biphasic effect; thus low concentrations (3-100 microM) of these three agents significantly increased the rate of histamine-stimulated acid secretion (10-20% over the corresponding control value) by a cAMP-independent mechanism, whereas higher concentrations reduced the rate of acid formation. With respect to underlying biochemical mechanisms that could mediate inhibitory effects of NSAIDs on gastric acid formation, it was observed that both diclofenac and piroxicam, but not acetylsalicylic acid or indomethacin, decreased the glandular content of ATP, inhibited hydrolytic activity of gastric gland microsomal H(+)-K(+)-ATPase, and reduced the rate of H(+)-K(+)-ATPase-dependent proton transport across microsomal membranes in a dose-dependent manner. Furthermore, diclofenac and piroxicam also significantly increased passive permeability of microsomal membranes to protons. In conclusion, our work shows that diclofenac and piroxicam cause a significant reduction in the rate of basal and histamine-stimulated acid formation in isolated rabbit gastric glands at concentrations that can be attained in the gastric lumen of patients treated with these drugs. Mechanisms involved in these inhibitory effects appear to be multifocal and include different steps of stimulus-secretion coupling.     

Gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys

The gastric antisecretory actions of (15S)-15-methyl prostaglandin E₂ methyl ester (Me-PGE₂) and Prostaglandin E₂ (PGE₂) were evaluated in the unanesthetized gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and i.g. antisecretory doses of Me-PGE₂ ranged from 3 to 10 μg/kg, while PGE₂ showed significant antisecretory activity at i.v. bolus doses of 30–100 μg/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE₂ is estimated to be at least 10 and 300 times more potent than PGE₂ by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.     

Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones

Calcitonin gene-related peptide (CGRP) is a recently discovered widespread regulatory peptide which is encoded in the same gene as calcitonin. We assessed the effect of systemic infusion of synthetic rat CGRP at low dose (range 0.32-2.56 pmol/kg per min) on submaximal pentagastrin-stimulated gastric secretion and on gastrointestinal hormones. To assess its pharmacokinetic parameters in man the MCR and plasma half-life were estimated by the continuous infusion method. Gastric acid output and pepsin secretion were significantly reduced by CGRP (-29% of basal, P less than 0.01 and -40% of basal, P less than 0.005, respectively). There was a significant fall in basal levels of gastrin (-39%, P less than 0.001); gastric inhibitory peptide (-44.7%, P less than 0.001); enteroglucagon (-25%, P less than 0.001) and neurotensin (-33%, P less than 0.05). There was no significant change in plasma levels of insulin, motilin, pancreatic polypeptide or glucose. Suppression of gastric secretion and the fall in gastrointestinal hormones was prolonged and basal levels were not re-established after stopping the CGRP infusion. The disappearance curve of immunoreactive CGRP from the plasma was bi-exponential. The plasma half-life of immunoreactive CGRP was calculated as 6.9 +/- 0.9 min for the fast decay and 26.4 +/- 4.7 min for the slow decay. The calculated MCR was 11.3 +/- 1.2 ml/kg per min. Except for flushing of the face no untoward effects were observed. The results of this study suggest the possibility that CGRP could play a role in the regulation of gastric secretion and gastrointestinal hormone release.     

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.     

Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion

The effect of orally administered prostaglandin E₂ and its synthetic 15-methyl analogues on gastric secretion in man was studied. The parent E₂ compound did not inhibit basal secretion, whereas both the 15 (S) 15-methyl-E₂ methyl ester and its isomer, 15 (R) 15-methyl-E₂ methyl ester inhibited basal acid secretion. This action is likely to be a direct one on the parietal cell, and it could prove of value in the treatment of peptic ulcer.     

Inhibition of pentagastrin-stimulated gastric acid secretion by intraileal administration of bile and elevation of plasma concentrations of gut glucagon-like immunoreactivity in anesthetized dogs

The effects of intraileal administration of bile on gastric acid secretion stimulated by a submaximal dose of intravenous pentagastrin infusion and on plasma concentrations of gut glucagon-like immunoreactivity (gut GLI) were studied in anesthetized dogs. Gastric acid secretion was measured for a 2-h period at 15-min intervals before and after intraluminal instillation of test solutions. 100 ml of canine bladder bile diluted to 10% in saline evoked a significant inhibition (20%) of gastric acid secretion. The inhibition of gastric acid secretion was accompanied by an elevation of plasma concentration of gut GLI, whereas saline instillation (in controls) caused no responses. Although the inhibition of gastric acid secretion and the elevation of plasma gut GLI are parallel phenomena, gut GLI can be reasonably postulated as one of the candidate mediators of bile-induced inhibition of gastric acid secretion, since its structurally related peptides, pancreatic glucagon, glicentin and oxyntomodulin have been reported as inhibitors of gastric acid secretion.     

Neurotensin inhibition of gastric exocrine secretions in the cat

The gastric exocrine inhibitory activities of neurotensin were characterized in conscious cats prepared with gastric fistulae. Neurotensin was a potent inhibitor of pentagastrin-stimulated pepsin secretion (ID50, approx. 0.3 mumol . kg-1 . h-1) but was approximately 60 times less potent against acid secretion. Neurotensin did not significantly reduce submaximal histamine-stimulated acid or pepsin secretions. the total 2 h acid and pepsin outputs in response to insulin-hypoglycaemia were not reduced by neurotensin, although the peak 15-min outputs were reduced. The reduction in peak secretion was possibly related to neurotensin antagonism of the ability of insulin to lower blood glucose concentrations. Neurotensin alone was not hyperglycaemic when given as an intravenous infusion. Two C-terminal fragments of neurotensin, the dodecapeptide and nonapeptide, inhibited pentagastrin-stimulated pepsin secretion, but were less potent than neurotensin. The observations with the C-terminal fragments indicate that the major determinants of gastric exocrine inhibitory activity of neurotensin reside in its C-terminal; this agrees with observations on other biological activities of neurotensin. The reduced potency of the dodecapeptide indicates the importance of the N-terminal pyroglutamyl residue for full gastric exocrine inhibitory activity.     

Effect of Basal Gastric Acid Secretion on the Pharmacodynamics of Ranitidine

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured ± every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 ± 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 ±1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. ± 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion–as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC₅₀) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC₅₀ and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.     

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.     

Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole

A hydrophobic amine, SCH 28080, 2-methyl-8-(phenylmethoxy)imidazo(1,2a)pyridine-3-acetonitrile, previously shown to inhibit gastric acid secretion in vivo and in vitro, was also shown to inhibit basal and stimulated aminopyrine accumulation in isolated gastric glands when histamine, high K+ concentrations, or dibutyryl cAMP were used as secretagogues. Stimulated, but not basal, oxygen consumption was also inhibited. Neutralization of the acid space of the parietal cell by high concentrations of the weak base, imidazole, reduced the potency of the drug, suggesting that SCH 28080 was active when protonated. Studies on the isolated H+,K+-ATPase showed that the compound inhibited the enzyme competitively with K+, whether ATP or p-nitrophenyl phosphate were used as substrates. In contrast, the inhibition was mixed with respect to p-nitrophenyl phosphate and uncompetitive with respect to ATP. The drug reduced the steady state level of the phosphoenzyme but not the observed rate constant for phosphoenzyme formation in the absence of K+ nor the quantity of phosphoenzyme reacting with K+. The drug quenched the fluorescence of fluorescein isothiocyanate-modified enzyme and also inhibited the ATP-independent K+ exchange reaction of the H+,K+-ATPase. Its action on gastric acid secretion can be explained by inhibition of the H+,K+-ATPase by reversible complexation of the enzyme. This class of compound, therefore, acts as a reversible inhibitor of gastric acid secretion.