Evidence that adaptive cytoprotection in rats is not mediated by prostaglandins

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...

Section: Studies Of the Gastroprotective Mechanisms Of Frg-8813mentioning

confidence: 97%

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

Onodera

Shibata

Tanaka

et al. 1995

“…Hawkey et al (4) have shown that 20% ethanol never stimulated ex vivo release of PGE2, whereas Robert et al (2) reported that NaOH given at concentrations up to 0.1 M significantly increased both the PGE2 and PGF2a contents of the gastric mucosa. We therefore investigated whether 0.35 N HCl stimulated PG generation, and found that it increased the PGE2 content of the gastric mucosa by 25.4%, the concentration of 6-keto PGFIa in the plasma by 21.7% and the concen tration of PGE2 in the plasma by 128.5%, although none of these effects were significant (unpublished data, Y. Hatakeyama et al), indicating that it is difficult to dem onstrate the increment in PG in response to mild irritants by measuring a specific type of PG in a specific part of the stomach.…”

Section: Discussionmentioning

confidence: 99%

“…Hawkey et al (4) have shown that indomethacin failed to reverse adaptive cyto protection, even though it markedly inhibited PGE2 re lease by more than 80% and that 20% ethanol did not stimulate the ex vivo release of PGE2. These results are similar to the findings of Wallace (5), who noted that indo methacin never blocked the adaptive cytoprotection afforded by 1 M NaC1 against 70% ethanol-induced damage using an ex vivo gastric chamber preparation, although the dose of indomethacin applied was sufficient to cause a profound depression of 6-keto PGFIa synthe sis.…”

Section: Discussionmentioning

confidence: 99%

“…Since 1988, however, several reports have questioned the involvement of PG in this phenom enon. It has been shown that adaptive cytoprotection occurs even when PG generation is almost completely inhibited (4,5). Furthermore, Balaa (6) has suggested the existence of endogenous protective products which are different from PG, and that they are responsible for the mediation of adaptive cytoprotection.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multiple Mediators and Mechanisms Are Involved in the Adaptive Cytoprotection Provided by Certain Mild Irritants

Hatakeyama

Matsuo

Tomoi

et al. 1993

ABSTRACT-We investigated the participation of prostaglandins (PG) and nitric oxide (NO) in adaptive cytoprotection using 0.6 N HCl-induced gastric lesions in the rat stomach. Indomethacin reversed the pro tective effect of 0.2 N HCl more strongly than that of 0.35 N HCI, both of which markedly inhibited HCI ulcer. lV°-Nitro-L-arginine (L-NNA) did not affect the protective effect afforded by either 0.2 N HCl or 0.35 N HCI. Combined pretreatment with indomethacin and L-NNA did not diminish the protective action induced by 0.35 N HCI, but almost completely abolished the indomethacin-resistant protection afforded by 0.1 N NaOH. Acid mild irritant increased the gastric fluid volume concentration-dependently, whereas alkaline mild irritant had little or no effect on the volume. These results suggest that: 1) The mediators involved in adaptive cytoprotection afforded by 0.1 N NaOH may be fully ascribed to PG and NO; 2) PG is a major mediator in the protection induced by 0.2 N HCI; 3) In the case of 0.35 N HCI, the mediators remain to be determined since increased gastric fluid volume could contribute to the protection through dilution. These findings thus may indicate that multiple mediators and mechanisms are implicated in adaptive cyto protection.

“…In addition, Hawkey et al (33) recently ob served that adaptive cytoprotection by 20% ethanol still occurred after pretreatment with indomethacin. As they suggested, the mucus, fibrin and cellular debris released after super ficial damage (33) in response to stress may provide a microenvironment responsible for the resistance to ethanol injury.…”

Section: Discussionmentioning

confidence: 99%

Gastric Mucosal Protection Induced by Restraint and Water-Immersion Stress in Rats

Uramoto

Ohno

Ishihara

1990

Abstract-Wefound that the gastric mucosal lesion induced by 60% ethanol containing 150 mM HCI was reduced by pre-loading the rat with restraint and water-immersion stress (22'C). The resistance to ethanol injury was maximal in 1-hr stress loaded rats and gradually decreased with increasing time of stress (2-6 hr). The protective effect of stress was markedly decreased by subdiaphrag matic truncal vagotomy, and electrical stimulation of vagal nerves afforded similar protection as observed after stress.In contrast, pretreatment with atropine markedly reduced ethanol injury in both the control and 1 hr stress-loaded rats. One-hour stress produced surface epithelial cell damage in sham vagotomized rats, but the surface cells were almost intact in vagotomized rats. Pretreatment with indo methacin significantly mitigated the protective effect of stress against ethanol injury. However, the level of mucosal prostaglandin E2 was not changed 1 hr after stress, and it tended to decrease 6 hr after stress.Pretreatments with 1-hr stress and vagal stimulation weakly reduced localized staining of gastric mucosa with gentian violet. We conclude that adaptive protection can be achieved by restraint and water-immersion stress.