Cytoprotection by Prostaglandin Occurs in Spite of Penetration of Absolute Ethanol Into the Gastric Mucosa

Robert, André; Lancaster, C. Roy D.; Davis, John P.; Field, SL; Sinha, A. J. Wickrema; Thornburgh, Bruce A.

doi:10.1016/s0016-5085(85)80187-6

Cited by 78 publications

(20 citation statements)

References 25 publications

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“…In the study by Lamont et al (27), N-ethylmaleimide, a known inhibitor of cytoprotection by cystamine, had no effect on mucin secretion, whereas indomethacin inhibited mucin secretion by cystamine but did not influence cytoprotection. dPGE2 protected gastric mucosa from 100% ethanol without preventing entry of the ethanol into the gastric mucosa (28). The present study showed that the baseline thickness of mucus is decreased in newborn rats, who are more susceptible to ethanol-induced injury (5).…”

Section: Discussionmentioning

confidence: 66%

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Developmental Changes in Gastric Mucus Gel Thickness: Responsiveness to 16,16-Dimethyl Prostaglandin E2 and Mucosal Protection in the Rat

et al. 1992

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ABSTRACT. The gastric mucosa of newborn rats is sen-there may be some deficiency in defensive factors that predispose sitive to the damaging effects of acid and ethanol. We neonates to mucosal injury. measured gastric mucus gel thickness in newborn, suckling,In this study, we investigated age-related changes in mucus and weaned rats by inversion microscopic observation. The layer thickness and its responsiveness to PG in developing rats. thickness in newborn rats was 52.2 2 6.7 pm and increased We also studied the effect of PG on ethanol-induced gastric with age, reaching 96.8 f 5.6 pm in 8-wk-old rats (p < mucosal damage, using PG doses identical to those used to test 0.001). Oral administration of 16,16-dimethyl prostaglan-mucus thickness. din Ez at concentrations of 10 and 100 pg/kg body weight increased mucus thickness in 8-wk-old rats but had no effect in 1-wk-old rats. We also assessed the effect of MATERIALS AND METHODS 16,16-dimethyl prostaglandin E2 on the prevention of gastric mucosal damage induced by ethanol. Oral 16,16-diMeasurement of mucus gel layer thickness. Newborn (3 d), methyl prostaglandin E2 reduced damage in &wk-old rats, suckling (1 and 2 wk), and weaned (4 and 8 wk) Wistar rats were but there was no effect in 1-wk-old rats. These data suggest used. They were fasted 30-36 h (3-d-and I-and Zwk-old rats) that the susceptibility of newborn rats to gastric mucosal or 40-48 h (4-and 8-wk-old rats). Water was allowed ad libitum injury may be related to the relative thinness of the gastric until 30-36 h before the rats were killed. Preliminary studies mucus gel layer and the failure of prostaglandins to in-showed that those time intervals are the shortest times that insure crease the mucus gel layer thickness. (Pediatr Res 31: stomachs empty of food. Preliminary studies also showed that 193-195,1992) the mucus gel thickness in newborn rats given water containing 0.3% NaCl and 5% glucose every 12 h before death was not Abbreviations significantly different from the thickness in the newborn rats that were not given the solution. Newborn and suckling rats were put PG, prostaglandin in a box. Half of the bottom of the box was warmed to 37-4O0C, dPGE2, 16,16-dimethyl prostaglandin Ez and half was at room temperature (25°C). Rats were free to choose a position in the box. Twenty-four h before study, weanling rats were placed in cylindrical wire mesh cages to prevent coprophagy. Rats were killed by intrathecal or intraperitoneal injection of pentobarbital after a light ether anesthesia. Gastroduodenal mucosal lesions are relatively frequent inThe method reported by Kerss et al.( 1 9) was used with slight neonates (1-3) and may cause serious bleeding. The gastric modifications to measure surface mucus thickness. The stomach mucosa of newborn rats is more susceptible to injury after was removed and opened along the lesser curvature. The tissue, intragastric ingestion of HCl(4) and ethanol (5) than the mucosa luminal surface up, was mounted on a filter paper (Whatman of adult rats. Gastric mucosal lesions...

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Section: Discussionmentioning

confidence: 66%

“…The relative importance of the mucus gel in gastric mucosal protection has been a subject of debate (6,11,12,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). The mucus gel generates an unstirred layer that prevents lumenal hydrogen ions from reaching the epithelial surface.…”

Section: Discussionmentioning

confidence: 99%

Developmental Changes in Gastric Mucus Gel Thickness: Responsiveness to 16,16-Dimethyl Prostaglandin E2 and Mucosal Protection in the Rat

et al. 1992

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“…Subsequent observations demonstrated that although the gastric cells localized deep in the mucosa were protected, cytoprotective agents did not prevent disruption of the surface epithelium by necrotizing agents (7,8). Therefore, this beneficial effect of prostaglandins and other compounds was appropriately referred to as gastroprotection or mucoprotection.…”

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confidence: 99%

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Onodera

Shibata

Tanaka

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-FRG-8813 ((±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions against 1076 NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl-and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11.1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection.Furthermore, prior administration of tetrodotoxin, the calcitonin generelated peptide (CGRP) antagonist hCGRP8_37 or N~-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813. Keywords:FRG-8813, Gastroprotection, Histamine H2-receptor antagonist, Capsaicin-sensitive nerve, Antiulcer drug Successful peptic ulcer therapy depends on the restoration of the compromised integrity of the gastroduodenal mucosa by either reducing the aggressive factors or enhancing the defensive process in the mucosa. This has been mainly accomplished by reducing intraluminal acid with an histamine H2-receptor antagonist for more than 10 years. The histamine H2-receptor antagonists are among the most frequently employed drugs worldwide, and their leading position can be explained by their proven high antisecretory potency (1, 2). However, numerous reports showed that the incidence of ulcer relapse after discontinuation of the histamine H2-receptor antagonist reaches the same level as that in patients receiving a placebo (3 -5). From these viewpoints, further improvement in ulcer therapy, with regard to quality of ulcer healing and/or ulcer relapse, might be achieved if the agent could enhance the mucosal defensive capacity in addition to decreasing gastric acid secretion.The property of agents that protect the gastric mucosa against necrotizing agents such as ethanol was defined as so-called "cytoprotection"by Robert et al. (6). Subsequent observations demonstrated that although the gastric cells localized deep in the mu...

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“…For gastric mucosal integrity, PGs play an important role (1 -3, 15), and the administration of PGs inhibits lesion formation induced by necrotic agents such as ethanol, HCl, NaOH, hypertonic NaCl or boiling water (4,5). We also reported the inhibitory effect by PGE 2 on ethanol-or HClinduced gastric lesions in rats (16).…”

Section: Discussionmentioning

confidence: 99%

“…Prostaglandins (PG)s, in particular, play an important role in the defensive mechanism (1 -3). Robert et al reported that the administration of PG inhibited the lesion formation induced by necrotic agents such as HCl, NaOH or boiling water (4,5). On the other hand, nitric oxide (NO) also plays many important roles in the stomach (6 -8).…”

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confidence: 99%

Nitric Oxide Donating Compounds Inhibit HCl-Induced Gastric Mucosal Lesions Mainly via Prostaglandin

Uchida

Matsueda

Shoda

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Prostaglandin (PG) and nitric oxide (NO) have been known to inhibit the lesion formation induced by necrotic agents. However, no clear correlation between PG and NO has been shown in the gastroprotective action against necrotic agent-induced gastric mucosal lesions in rats. Thus, the present study was performed to clarify this correlation. Gastric mucosal lesions were induced by the oral administration of 0.6 M HCl in rats. 16,16-Dimethyl PGE2 (0.3 -3 mg/ kg, p.o.; dim-PGE2), sodium nitrite (0.3 and 1 mg /kg, s.c.) and sodium nitroprusside (30 and 100 m g/kg, i.v.; SNP) dose-dependently inhibited the lesion formation. Orally administered sodium nitrite or SNP (3 mg/kg) also significantly inhibited the lesion formation. The gastroprotective action by dim-PGE 2 was not affected by the pre-treatment with N G -nitro-Larginine methylester (10 mg /kg, i.v.). The gastroprotective effect by sodium nitrite or SNP was markedly attenuated by the pre-treatment with indomethacin (10 mg/ kg, s.c.). These findings suggest that NO donating compounds inhibit the HCl-induced mucosal lesions mainly through prostaglandin, but dim-PGE2 directly inhibits the lesions without involvement of NO in rats.

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Cytoprotection by Prostaglandin Occurs in Spite of Penetration of Absolute Ethanol Into the Gastric Mucosa

Cited by 78 publications

References 25 publications

Developmental Changes in Gastric Mucus Gel Thickness: Responsiveness to 16,16-Dimethyl Prostaglandin E2 and Mucosal Protection in the Rat

Developmental Changes in Gastric Mucus Gel Thickness: Responsiveness to 16,16-Dimethyl Prostaglandin E2 and Mucosal Protection in the Rat

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Nitric Oxide Donating Compounds Inhibit HCl-Induced Gastric Mucosal Lesions Mainly via Prostaglandin

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