Gastric cytoprotection by acetazolamide: role of endogenous prostaglandins

This study was designed to determine the influence of acetazolamide, a potent inhibitor of carbonic anhydrase, on the formation of gastric mucosal lesions induced by acidified aspirin (ASA) or absolute ethanol and on gastric cytoprotection induced by prostaglandin E2 (PGE2). Acetazolamide prevented dose-dependently ethanol-induced gastric lesions and this effect was accompanied by an increased biosynthesis of mucosal PGs, indicating that endogenous PGs may be involved in cytoprotection by acetazolamide. This is supported by the finding that acetazolamide failed to affect gastric ulcerations produced by acidified ASA when mucosal PG biosynthesis was almost completely suppressed. Pretreatment with acetazolamide did not influence the protective action of PGE2 on ethanol-induced mucosal lesions and only slightly inhibited the protective effect of PGE2 on ASA-induced gastric ulcerations. This study indicates that: (1) acetazolamide prevents ethanol- but not ASA-induced gastric mucosal lesions probably via stimulation of PG biosynthesis and (2) gastric alkaline secretion, mediated by carbonic anhydrase, is probably not an essential mechanism responsible for this cytoprotection induced by PGE2.     

Gastric mucosal protection by agents altering gastric mucosal sulfhydryls. Role of endogenous prostaglandins

Intragastric administration of sulfhydryl-containing cysteamine or sulfhydryl-oxidizing diethylmaleate caused a dose-dependent reduction in the mean area of gastric lesions induced by absolute ethanol. The protective effects of these agents are abolished by the sulfhydryl blocker N-ethylmaleimide, while indomethacin, a potent inhibitor of cyclooxygenase, caused only about 50% reduction in this protection. This study indicates that mucosal generation of prostaglandins contributes to the gastric cytoprotection by these agents administered intragastrically, but endogenous sulfhydryls are also involved in the gastric mucosal protection by sulfhydryl-containing or sulfhydryl-oxidizing compounds.     

Gastric cytoprotection by antacids and papaverine in rats

Prostaglandin E2 (PGE2) prevented hemorrhagic ulceration of rat stomach mucosa induced by various procedures when given orally at a non-antisecretory dose. This effect of PGE2 is called gastric cytoprotection. We used absolute ethanol, 0.6 N hydrochloric acid and 0.2 N sodium hydroxide as damaging agents. Ranitidine at an antisecretory dose did not exhibit any cytoprotective effect. However, the poorly absorbable antacids, magnesium hydroxide plus aluminium hydroxide and aluminium phosphate inhibited the development of hemorrhagic lesions significantly. A similar protective effect was seen after intragastric administration of papaverine, which is known to stimulate endogenous prostaglandin synthesis. However, the question as to whether or not stimulation of endogenous prostaglandin synthesis is the mode of action of the cytoprotective effect of papaverine and poorly absorbable antacids, cannot yet be answered.     

Gastric protection by sucralfate. Role of mucus and prostaglandins

Sucralfate promotes the healing of peptic ulcers and, in large doses, increases gastric mucosal prostaglandins. The present study was designed to further elucidate the protective effect of sucralfate and to evaluate the role of prostaglandins in this action. Eight chair-adapted rhesus monkeys received a subcutaneous injection of either 150 mg/kg of aspirin or vehicle in combination with either a therapeutic oral dose of sucralfate (50 mg/kg X day) or water. Gastric soluble mucus concentration was determined in samples of gastric juice by Alcian blue dye binding of acidic glycoproteins, and mucus output was determined using a technetium 99m-diethylenetriaminepentaacetic acid dilution technique. Monkeys underwent endoscopy to assess gastric mucosal damage, which was ranked blindly on a scale of 0-5, and to obtain biopsy specimens for determination of mucosal prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha. Aspirin did not alter soluble mucus but did significantly increase gastric mucosal damage and suppress tissue levels of all prostaglandins. Sucralfate significantly increased the output of soluble mucus, even after aspirin treatment, and protected against aspirin-induced damage, although it did not modify aspirin-induced suppression of prostaglandins. These results suggest that the gastric protection afforded by sucralfate is related to a prostaglandin-independent increase in mucus production.     

Role of mucosal prostaglandins in vagally-mediated adaptive cytoprotection in the rat.

This study was designed to investigate whether vagal innervation and mucosal prostaglandins (PGs) participate in gastric adaptive cytoprotection. Rats were divided into three groups; sham operation (control), truncal vagotomy or splanchnicotomy. In the first experiment, 100% ethanol (EtOH) was orally administered 15 min after pretreatment with 20% EtOH to all 3 groups. One hour later, the gastric mucosa was examined macroscopically. In a second experiment, the mucosal PG contents 15 min after administration of either 20% EtOH or saline were measured by high performance liquid chromatography. In truncal vagotomized rats, the adaptive cytoprotection caused by exposure to 20% EtOH in control and splanchnicotomized rats was not observed and an increase in hemorrhagic lesion severity was seen. In the control and splanchnicotomized rats, PGE2 contents were elevated following 20% EtHO treatment, as compared to those in the saline-treated rats. However, PGE2 contents in vagotomized rats were not altered by EtOH exposure, and were significantly lower than in the control and splanchnicotomized groups, whereas PGF2 alpha and PGD2 contents were significantly higher after EtOH administration as compared to those in saline-treated rats. These results suggest that vagal innervation is essential for adaptive cytoprotection and that the vagotomy-induced decrease in PGE2 and increases in PGF2 alpha and PGD2 following 20% EtOH administration, may be caused by a disturbance in adaptive cytoprotection.     

Role of locally generated prostaglandins in adaptive gastric cytoprotection

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE₂ and PGI₂-like substances. Exogenous PGE₂ and PGI₂ applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.     

Role of mucosal prostaglandins and DNA synthesis in gastric cytoprotection by luminal epidermal growth factor.

This study compares the effect of epidermal growth factor and prostaglandins (PGE2 or PGI2), applied topically to gastric mucosa, on gastric secretion and formation of ASA-induced gastric ulcerations in rats. Epidermal growth factor given topically in non-antisecretory doses prevented dose-dependently the formation of ASA-induced ulcers without affecting prostaglandin generation but with a significant rise in DNA synthesis in the oxyntic mucosa. The anti-ulcer effect of topical prostaglandins was also accompanied by an increase in DNA synthesis. This study indicates that topical epidermal growth factor, like PGE2 or PGI2, is cytoprotective and that this cytoprotection is not mediated by the inhibition of gastric secretion or prostaglandin formation but related to the increase in DNA synthesis in oxyntic mucosa.     

Gastrocytoprotection by colloidal bismuth subcitrate (De-Nol) and sucralfate. Role of endogenous prostaglandins.

This study compares the gastroprotective effects of colloidal bismuth subcitrate (De-Nol) with those of sucralfate and a methylated analogue of prostaglandin E2 (PGE2) against acute gastric lesions induced by acidified aspirin and absolute ethanol in rats. Both De-Nol and sucralfate given orally prevented dose dependently the formation of gastric lesions by these ulcerogens, De-Nol being, respectively, twice and seven times more potent, on a weight basis, than sucralfate. As the gastroprotective activities of both De-Nol and sucralfate on ethanol lesions can be reversed by pretreatment with indomethacin and as De-Nol and sucralfate increase the mucosal generation and luminal release of PGE2, we postulate that mucosal prostaglandins may be involved in the mechanism of action of these drugs on the gastric mucosa.     

Gastric cytoprotection by amoxycillin in the rat

Abstract Amoxycillin in combination with anti-ulcer agents has been shown to prolong duodenal ulcer remission. While this effect can be related to the eradication of Helicobacter pylori , it is not known if amoxycillin might possess cytoprotective properties. Protection against ethanol-induced gastric mucosal damage by intragastric instillation of amoxycillin suspension (prepared from capsule form) and solution (from injection form, 100% pure amoxycillin), and by intraperitoneal injection of amoxycillin solution was studied using an ex vivo gastric chamber in the rat. Intragastric and intraperitoneal administration of amoxycillin dose-dependently protected the rat gastric mucosa from damage by absolute ethanol. This protection was lost when the rats were pretreated with indomethacin. Gastric mucosal blood flow as measured by laser Doppler flowmetry and gastric acid output were unaffected by amoxycillin. Amoxycillin imparts gastric cytoprotection, and one possible mechanism is by the release of prostaglandins.     

Gastric cytoprotection by tetraprenylacetone in human subjects

We assessed the inhibition by tetraprenylacetone (TPA) of gastric mucosal damage caused by ethanol in human subjects. Seventeen healthy volunteers were given either TPA (a 50-mg capsule) or a placebo 3 times daily for 5 days. Then, 20 ml of 70% ethanol were sprayed onto the gastric antrum and 15 min later, visible mucosal lesions were evaluated with an endoscope, and biopsy specimens were taken from mucosa that looked normal but had been sprayed with ethanol. The specimens were observed by light microscopy and scanning electron microscopy. The gross mucosal damage was significantly less (p less than 0.05) in the subjects given TPA than in those given the placebo. Hyperemia and hemorrhage in the mucosa and surface epithelial damage were also significantly less (p less than 0.05) in the subjects given TPA. The results suggested that TPA protects the gastric mucosa from damage by ethanol as judged not only by the gross appearance of the mucosa but also by microscopic observation.     

Gastric mucosal cytoprotection in the rat by scavenging oxygen-derived free radicals.

Oxygen-derived free radicals are cytotoxic and promote tissue damage. Dimethyl sulfoxide (DMSO) and allopurinol scavenge hydroxyl radicals, and the latter agent also inhibits the enzyme xanthine oxidase, which is responsible for the formation of superoxide anions. These agents were given daily by gavage (1 ml/d). After 2 days of administration as 1, 2, or 5% solutions, the H+ output of the rat with or without pyloric ligation was not significantly affected. After six hours reserpine (5 mg/kg i.p.) or serotonin (50 mg/kg i.p.) produced ischemic mucosal injury in all stomachs (39 +/- 5.2 mm2 and 25.9 +/- 2.8 mm2, mean +/- standard error of the mean [SEM], n = 10). Pretreatment for 2 days with 1 ml/d of 1% allopurinol or DMSO significantly (p less than 0.001) protected the rat against the reserpine (23 +/- 2.1 mm2 and 24 +/- 1.9 mm2, respectively, vs 39 +/- 5.2 mm2, n = 10) and serotonin injury (10 +/- 1.5 mm2 and 11 +/- 1.8 mm2, respectively, vs 25.9 +/- 2.8 mm2, n = 10). However, 2 days pretreatment with 1 ml/d of 2% allopurinol or DMSO was more effective (p less than 0.001) in this respect, and injury only developed in 40% of the rats given reserpine (8 +/- 1.2 mm2 and 9 +/- 1.6 mm2) and in 20% of those given serotonin (2.4 +/- 0.4 mm2 and 1.9 +/- 0.5 mm2). Similar pretreatment with 5% solutions completely protected the rat stomach against the reserpine and serotonin injuries without significantly influencing the H+ output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of endogenous prostaglandins in protection of rat gastric mucosa by tripotassium dicitrate bismuthate

Gross and microscopic examination of rat gastric mucosa demonstrated that intragastric administration to rats of tripotassium dicitrate bismuthate (TDB), a colloidal bismuth compound, protects against gastric lesions induced by 85% ethanol. Indomethacin, a prostaglandin synthetase inhibitor, significantly blocked the gastric mucosal protective effect of TDB. The release of gastric mucosal prostaglandins was greater in animals treated with TDB than in control animals, both time- and dose-dependently. These results seem to indicate involvement of prostaglandins in the action of TDB.     

Role of endogenous prostaglandins in somatostatin-induced inhibition of gastrointestinal hormone secretion

Endogenous prostaglandins have been reported to be essential for the inhibitory effect of somatostatin on acid secretion. From these results it could be suggested that the effect of somatostatin on the secretion of gastroentero-pancreatic hormones may also be medulated by prostaglandins. This hypothesis was investigated in man and in the rat. Somatostatin-induced inhibition of postprandial gastrin, cholecystokinin, pancreatic polypeptide, and insulin release was not influenced by indomethacin pretreatment in healthy subjects. Using the isolated perfused rat stomach preparation, inhibition of acetylcholine-stimulated gastrin secretion by somatostatin was found to be unchanged by indomethacin treatment. It is concluded that endogenous prostaglandins are unlikely to be indispensable for the inhibitory effect of somatostatin on gastroentero-pancreatic endocrine cells.     

Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins.

Paracetamol or sodium salicylate given intragastrically 30 minutes before the administration of absolute ethanol or acidified aspirin dose-dependently reduced the formation of mucosal lesions. The generation of gastric mucosal prostaglandin-like activity increased with ethanol and was completely suppressed by acidified aspirin. Paracetamol or sodium salicylate given alone increased the generation of mucosal prostaglandin-like material. Indomethacin, the prostaglandin synthesis inhibitor, suppressed this effect and inhibited the protective influence of paracetamol or sodium salicylate on the production of gastric lesions.     

Gastroprotection by an aluminium- and magnesium hydroxide-containing antacid in rats. Role of endogenous prostanoids

This study was designed to determine the gastroprotective actions of an antacid (Maalox 70) and its components, Al(OH)3 and Mg(OH)2, against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. Given orally, the antacid prevented dose-dependently the formation of gastric lesions by all three ulcerogens, and these effects were similar to those obtained with a methylated prostaglandin E2 (PGE2) analog. Active Al(OH)3 gel was equipotent with Maalox, whereas Mg(OH)2 was significantly less effective in gastroprotection than Maalox 70. Chemically inactive Al(OH)3 wet gel showed only small and insignificant protective properties. Since the gastroprotective activities of Maalox 70 against ethanol lesions cannot be reversed by pretreatment with indomethacin, and since neither Maalox 70 nor its active components affected the mucosal generation of PGE2 and leukotriene C4, we postulate that mucosal prostanoids are not the primary mediators in the mechanism of their protective action on the gastric mucosa.