A new PGE1 analogue (CL115,574) III. Effects on gastric acid and mucus secretion in man

CL115,574, an analogue of PGE₁, is a potent inhibitor of gastric acid secretion in animals. The effects of this compound on gastric acid and mucus secretion were studied in 8 male volunteers. The compound was well tolerated, and its maximally effective antisecretory dose (750 μg) inhibited pentagastrin stimulated acid secretion by approximately 40% over a 2-hour period, with stimulation beginning one hour after the drug was orally administered. CL115,574 proved to have a significant and sustained effect upon the stimulation of mucus secretion into gastric juice. Considering the possible role that mucuse may play in mucosal cytoprotection, CL115,574 because of its antisecretory and mucogenic actions may prove to be an important clinical anti-ulcer compound.     

A new prostaglandin E1 analogue (CL115, 574): I. Antisecretory and cytoprotectige effects in the rat

The effect of a new analogue of PGE₁ (CL115, 574) on gastric acid secretion, mucus secretion and protection against stress and indomethacin- induced ulcers were studied in the rat. CL115, 574 was more potent than PGE₁ and cimetidine in inhibiting acid secretion. CL115, 574 protected against the development of stress and indomethacin-induced ulcers prevented the indomethacin-induced decrease in hematocrit at an ED₅₀ (3 μg/kg) far below the antisecretory ED₅₀ (1 mg/kg). While the inhibiting acid secretion, CL115, 574 increased the volume of gastric secretion indicating a stimulation of nonparallel cell secretion by the rat stomach. In addition the compound stimulated the secretion of mucus into the gastric juice. On the basis of its potency as an inhibitor of acid secretion and these additional effects which are indicative of cytoprotective activity, CL115, 574 should be further studied as a possible anti-ulcer agent in man.     

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.     

Effects of prostaglandin E2, 16,16-dimethyl prostaglandin E2 and a prostaglandin endoperoxide analogue (U-46619) on gastric secretory volume, [H+] and mucus synthesis and secretion in the rat

The effects of orally administered prostaglandin E2, 16,16-dimethyl prostaglandin E2 and U-46619, an analogue of the prostaglandin endoperoxide PGH2, on gastric secretory volume, acid and mucus were studied in the rat. All of the compounds significantly increased the volume of gastric secretion, mucus secretion, measured as N-acetylneuraminic acid and mucus synthesis measured as the incorporation of [3H]-glucosamine into mucosal glycoprotein; however, only PGE2 and 16,16-dimethyl PGE2 inhibited acid secretion. U-46619, 1.5 mg/kg provided significant protection against ethanol-induced gastric ulcers, an effect that has been previously shown for the other two compounds. These studies provide additional evidence that prostaglandin induced mucosal protection may be related to an effect on mucus and on stimulation of nonparietal cell gastric secretion. Further study of these parameters may be important in the development of antiulcer drugs for long term clinical use.     

Potentiation of the gastro-protective effect of sulglicotide in the presence of cimetidine in the rat

The effects of sulglicotide, alone or combined with cimetidine, have been investigated on mucosal lesions induced in rats by pylorus ligation. In the same animals, the measurement of acid and pepsin output and of soluble and barrier mucus has been performed. Dose-dependent sulglicotide prevented the development of mucosal lesions and its protective effect was achieved without significant modifications in gastric acid secretion. The secretion of pepsin and of mucus was markedly inhibited at every dosage of the compound. Neither the damage to gastric mucosa nor the secretion of acid, pepsin and mucus were affected by cimetidine. The combination of the highest doses of both compounds resulted in a synergistic gastro-protective effect, not dependent on a synergistic effect on the reduction in acid secretion.     

油酸对消炎痛引起的胃粘膜损伤大鼠胃粘液分泌的影响

本工作研究油酸对消炎痛引起胃粘膜损伤大鼠胃粘液分泌的影响。胃粘液测定采用阿尔新蓝(Alcian blue)与胃液中糖蛋白结合的方法。将1.0ml 油酸注入到结扎幽门的大鼠空肠内,就可引起胃壁粘液及游离粘液分泌量的明显增加。以0.25、0.5和1.0ml 油酸注入到不结扎幽门的大鼠空肠内,也能显著增加胃壁粘液分泌,保护胃粘膜。这两种作用表现着剂量依赖关系。不论以油酸灌胃或注入空肠、回肠,都能明显增加胃壁粘液量,而灌胃的作用比注入肠内更明显。以1.0ml 30%甘油、0.1%乙酸及1/15N HCl 分别注入空肠,都不能刺激胃壁粘液的分泌。上述结果表明,油酸具有刺激胃粘液分泌的作用。因此,加强胃粘液分泌可能对粘膜起到屏障作用,这是油酸保护胃粘膜损伤的机制之一。     

Effects of prostaglandin E2, 16,16-dimethyl prostaglandin E2 and a prostaglandin endoperoxide analogue (U-46619) on gastric secretory volume, [H] and mucus synthesis and secretion in the rat

The effects of orally administered prostaglandin E₂, 16,16-dimethyl prostaglandin E₂ and U-46619, an analogue of the prostaglandin endoperoxide PGH₂, on gastric secretory volume, acid and mucus were studied in the rat. All of the compounds significantly increased the volume of gastric secretion, mucus secretion, measured as N-acetylneuraminic acid and mucus synthesis measured as the incorporation of [³H]-glucosamine into mucosal glycoprotein; however, only PGE₂ and 16,16-dimethyl PGE₂ inhibited acid secretion. U-46619, 1.5 mg/kg provided significant protection against ethanol-induced gastric ulcers, an effect that has been previously shown for the other two compounds. These studies provide additional evidence that prostaglandin induced mucosal protection may by related to an effect on mucus and on stimulation of nonparietal cell gastric secretion. Further study of these parameters may be important in the development of antiulcer drugs for long term clinical use.     

Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers

To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H(+),K(+)-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H(+),K(+)-ATPase inhibitory activity through reversible and K(+)-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.     

Effect of somatostatin on the secretin-induced gastric secretions of pepsin and mucus in cats

The effect of somatostatin 14 on gastric stimulation produced by secretin was determined in 6 conscious cats equipped with a gastric fistula and a denervated fundic pouch. Somatostatin strongly inhibited the basal and secretin-induced pepsin secretion. It did not, however, inhibit the secretin-induced mucus secretion, even though it decreased the basal mucus secretion. During somatostatin administration, the secretagogue effect of secretin on mucus secretion might be dissociated from its stimulatory action on pepsin secretion.     

Antigastrolesive, gastric antisecretory, diarrheagenic and mucus-stimulating effects in rats following topically applied rioprostil, a synthetic prostaglandin E1 analog

Prostaglandins may have many biological actions including hypotensive and antipeptic ulcer activity. The purpose of this investigation was to determine if the primary alcohol prostaglandin E1 analog rioprostil1 prevents ethanol-induced gastric lesions (antigastrolesive activity), inhibits gastric acid secretion (antisecretory activity), or causes diarrhea in rats when administered topically, and to compare these responses to the effect of rioprostil following enteral (oral or intraduodenal) administration. Rioprostil exhibited antigastrolesive activity in rats when administered either orally or when applied topically. The topical antigastrolesive potency of rioprostil against ethanol-induced lesions [ED50 = 3.7 (0.5-12) micrograms/kg] was similar to its oral potency [ED50 = 1.9 (1.7-2.2) micrograms/kg]. In 4 hr pylorus-ligated rats, topically administered rioprostil inhibited total gastric acid output with a potency [ED50 = 5.1 (2.6-24) mg/kg] similar to intraduodenal administration [ED50 = 3.7 (2.8-5.3) mg/kg]. In addition, in these rats rioprostil increased mucin levels and did not cause dermal irritation. Finally, the incidence of diarrhea was lower when rioprostil was applied topically than when given orally with a 16-fold difference in potency between these two routes of administration. These data show that when rioprostil is applied via the skin it has antigastrolesive, gastric antisecretory and mucus stimulatory effects in rats equal to enteral administration, and a diarrheagenic potency lower than following oral administration. This profile suggests that topical administration of rioprostil may be a useful means of delivery for clinical treatment of peptic ulcer disease.     

Gastroprotective effects of ‘Amla’ Emblica officinalis on in vivo test models in rats

An ethanol extract of 'Amla' Emblica officinalis Gaertn. was examined for its antisecretory and antiulcer activities employing different experimental models in rats, including pylorus ligation Shay rats, indomethacin, hypothermic restraint stress-induced gastric ulcer and necrotizing agents (80% ethanol, 0.2 M NaOH and 25% NaCl). Oral administration of Amla extract at doses 250 mg/kg and 500 mg/kg significantly inhibited the development of gastric lesions in all test models used. It also caused significant decrease of the pyloric-ligation induced basal gastric secretion, titratable acidity and gastric mucosal injury. Besides, Amla extract offered protection against ethanol-induced depletion of stomach wall mucus and reduction in nonprotein sulfhydryl concentration. Histopathological analyses are in good agreement with pharmacological and biochemical findings. The results indicate that Amla extract possesses antisecretory, antiulcer, and cytoprotective properties.     

Specific inhibition by ATP of histamine-stimulated acid secretion in the gastric glands of the rabbit]

The influence of adenosine 5'-triphosphate on gastric acid secretion stimulated by histamine, carbachol, dibutyryl-cAMP and the phosphodiesterase inhibitors 8-phenyl-theophylline and rolipram in isolated rabbit gastric glands was studied. Changes oi gastric acid secretion were measured by the aminopyrine accumulation method. Histamine-stimulated acid secretion was significantly inhibited by ATP 1 mM, whereas the secretory responses elicited by carbachol, dibutyryl-cAMP, 8-phenyl-theophylline or rolipram were not. Assays with indomethacin, a well known prostaglandin synthesis inhibitor, showed that this agent significantly reduced the inhibitory effect of ATP on histamine responses. The results indicate that the antisecretory effect of ATP was specific for histamine and that it was mediated, at least in part, via stimulation of endogenous prostaglandin production.     

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.     

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.     

Bombesin and the brain-gut axis

Bombesin is the first peptide shown to act in the brain to influence gastric function and the most potent peptide to inhibit acid secretion when injected into the cerebrospinal fluid (CSF) in rats and dogs. Bombesin responsive sites include specific hypothalamic nuclei (paraventricular nucleus, preoptic area and anterior hypothalamus), the dorsal vagal complex as well as spinal sites at T9-T10. The antisecretory effect of central bombesin encompasses a variety of endocrine/paracrine (gastrin, histamine) or neuronal stimulants. Bombesin into the CSF induces an integrated gastric response (increase in bicarbonate, and mucus, inhibition of acid, pepsin, vagally mediated contractions) enhancing the resistance of the mucosa to injury through autonomic pathways. The physiological significance of central action of bombesin on gastric function is still to be unraveled.     

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.     

Gastric antisecretory and antiulcer activity of oxytocin in rats and guinea pigs.

The effect of oxytocin (1 mg/kg s.c) on gastric acid secretion and on different experimentally induced gastric and duodenal ulcers was studied. The acute gastric ulcer models used were pylorus ligation, indomethacin, ethanol and histamine induced acute gastric ulcers. Chronic gastric ulcers were induced using acetic acid and duodenal ulcers by cysteamine hydrochloride. Oxytocin showed significant antisecretory and antiulcer activity in pylorus ligated rats. Similarly oxytocin reduced the ulcer index in histamine induced gastric ulcers in guinea pigs and cysteamine induced duodenal ulcers in rats. The antiulcer and antisecretory effect was comparable to that of ranitidine (50mg/kg, i.p) though less in intensity. However, it did not show any gastric cytoprotective effect in ethanol and indomethacin induced ulcer models but ranitidine showed protection (p<0.05) in later model. Oxytocin enhanced gastric ulcer healing in acetic acid induced chronic gastric ulcer model. The reversal of oxytocin effect by atosiban, an oxytocin receptor antagonist indicates a role for oxytocin receptors. The antiulcer activity of oxytocin can be attributed to its antisecretory effect.     

大鼠浸水应激性胃粘膜损伤机制的研究

本工作观察了室温下单纯束缚加生理盐水,浸水应激加生理盐水,浸水应激加阿托品(0.5mg/kg),浸水应激加酚苄明(10mg/kg),浸水应激加戊巴比妥钠(30mg/kg)5组大鼠的胃粘膜损伤程度,胃酸分泌,胃壁结合粘液分泌和胃运动的变化。结果表明:大鼠浸水应激后胃粘膜损伤严重,胃酸分泌增加,胃壁结合粘液分泌减少,胃运动亢进;预先应用阿托品再浸水应激可显著减轻胃粘膜损伤程度,抑制胃酸分泌和胃运动,但增加胃壁结合粘液的分泌;预先应用应巴比妥钠亦显著减轻胃粘膜损伤程度,抑制胃运动和增加胃壁结合粘液的分泌,但对胃酸分泌无影响;预先应用酚苄明对胃粘膜损伤程度、胃酸分泌、胃壁结合粘液分泌和胃运动均无明显影响。上述结果提示,胃运动亢进、胃壁结合粘液分泌减少及胃酸分泌增加均不同程度地参与了浸水应激性胃粘膜损伤的形成,但在胃运动受到抑制及胃壁结合粘液分泌增加的情况下,仅胃酸的存在不致引起胃粘膜严重损伤。     

Interactions between sialoadenectomy and capsaicin-sensitive afferent fibers on gastric acid secretion in rats

In this study we have investigated the relative influence of capsaicin-sensitive afferents and sialoadenectomy on gastric acid secretion. Sialoadenectomized (SALX) rats showed a decrease in gastric acid secretion and an increase in gastric calcitonin gene-related peptide-like immunoreactivity (CGRP-li) as compared to sham-operated animals. Capsaicin pretreatment (50 + 100 mg kg-1 in two days) markedly decreased gastric CGRP-li in both sham and SALX-operated rats and increased acid concentration and output only in SALX animals. In this latter case the concomitant absence of two potent endogenous antisecretory agents (CGRP and epidermal growth factor; EGF) may contribute to the observed hypersecretion. Gastric content of vasoactive intestinal polypeptide (VIP)-li was unaffected in SALX and capsaicin-treated rats. Capsaicin-sensitive afferents and EGF contained in the salivary glands may interact in the regulation of the gastric acid secretion.     

Gastroprotective Mechanisms of the Monoterpene 1,8-Cineole (Eucalyptol)

Recently, our research group identified and reported 1,8-cineole (CIN), a monoterpene that naturally occur in many aromatic plants, as one of the major constituent of the essential oil from leaves of Hyptis martiusii (EOHM), as well as characterized the gastroprotective action of this oil. The aim of this study was to investigate the mechanisms of action involved in the antiulcer and healing activity of CIN, in order to confirm its correlation with the gastroprotective effect of EOHM. Wistar rats were exposed to different protocols (acute ulceration, gastrointestinal motility and antisecretory activity). In addition, were determinated the involvement of nitric oxide and sulphydryl groups; the levels of gastric mucus, lipid peroxidation, sulphydryl groups and myeloperoxidase activity. The healing ability was evaluated by acetic acid-induced chronic ulcer and histological and immunohistochemical analysis (PCNA, Ki-67 and BrdU). The treatment with CIN inhibited ethanol-, ethanol/HCl- and indomethacin-induced gastric lesions. The highest doses of CIN inhibited gastric emptying, but did not affect intestinal transit. CIN (100 mg/kg) reduced the volume of basal but not stimulated acid secretion. CIN increased levels of mucus (89.3%), prevented depletion of –SH groups (62.6%) and reduced the level of lipid peroxidation (55.3%) and myeloperoxidase activity (59.4%) in the gastric mucosa. In chronic ulcer model, CIN reduced in 43.1% the gastric area lesion, promoted significant regeneration and restoration of the levels of mucus in glandular cells as confirmed by histological analysis; and promoted increase in cell proliferation as evidenced by reactivity for PCNA, Ki-67 and BrdU. This findings demonstrate the role of 1,8-cineole as an important ulcer healing agent and indicate the involvement of antioxidant and cytoprotective mechanisms in the gastroprotective effect of compound. This study also provides evidence that 1,8-cineole is related to the gastroprotective effect of the essential oil of Hyptis martiusii.