Effects of Sulfhydryl-Related Compounds on Indomethacin-Induced Gastric Lesions in Rats: Role of Endogenous Sulfhydryls in the Pathogenesis.

Abstract

ABSTRACT-The role of mucosal sulfhydryl (SH) in the pathogenesis of indomethacin induced gastric lesions was investigated in rats. Indomethacin (25 mg/kg, s.c.) caused high-amplitude gastric contractions, resulting in linear hemorrhagic lesions in the cor pus mucosa within 4 hr, but did not induce any changes in the mucosal SH levels. These lesions were prevented significantly by prior s.c. administration of cysteamine, glutathione (GSH) or diethylmaleate (DEM), irrespective of whether the mucosal SH was increased by the former two agents or reduced by the latter. N-Ethylmaleimide (NEM) tended to worsen such lesions without any effect on the mucosal SH contents. Gastric hypermotility caused by indomethacin was inhibited significantly by DEM, cysteamine and GSH, while acid secretion was reduced by DEM and NEM. Both cysteamine and GSH prevented the indomethacin-induced linear lesions even in the stomach perfused with 150 mM HC1, whereas in the animals treated with DEM, non linear damage was induced exclusively in the antrum by indomethacin in the presence of acid. We conclude that the mucosal SH has no relation to the ulcerogenicity of in domethacin in the gastric corpus mucosa.The mechanisms of gastric protection are considered to involve at least two endogenous mediators such as prostaglandins (PGs) and sulfhydryl (SH) substances in the mucosa (1). Participation of PGs has been demonstrated in various experimental ulcer models (2-4), while the role of SH has been exclusively studied in relation to gastric cytoprotection against necrotizing agents (5-7). Since en dogenous SH substances, mainly present as in tracellular glutathione (GSH), have a variety of actions in the body (8), they might have roles in the development of other lesion mod els which have different pathogenetic mecha nisms. In fact, Konturek et al. (9) recently re ported the involvement of mucosal SH in the pathogenesis of stress ulcers. Yet, it remains undetermined whether the mucosal SH has some relation to indomethacin-induced gastric lesions.In the present study, we thus examined the effect of an ulcerogenic dose of indomethacin on the mucosal SH levels in the rat stomach, and investigated the relationship of endo genous SH to the ulcerogenicity of this agent by modulating the mucosal SH levels using SH-related compounds (cysteamine and GSH), an SH alkylator (N-ethylmaleimide) or an SH depletor (diethylmaleate).

Amifostine (Wr-2721) Prevents Indomethacin-Induced Gastric Damage in Rats: Role of Non-Protein Sulfhydryl Groups and Leukocyte Adherence

“…Amifostine alone, s.c. or i.p., increased the NP-SH concentration in gastric tissue and also reversed the decrease in NP-SH concentration in the gastric tissue induced by indomethacin ( Table 2). Our data are in accordance with the literature; Ueshima et al [21] demonstrated that exogenous glutathione (GSH), a sulfhydryl compound, inhibits indomethacin-induced gastric damage. Szabo et al [22] showed that substances containing sulfhydryl radicals, such as dimercaprol, cysteamine, and dimercaptosuccinic acid, work in the protection of the gastric mucosa in a manner similar to that of prostaglandins, and that sulfhydryl group blockers, such as diethylmaleate and iodoacetamide, reverse the gastric protective effect of PGF 2α .…”

Role of neutrophils in indomethacin-induced gastric mucosal lesions in rats

“…This suggests that lipid peroxidation might not be an important process in the development of mucosal lesions in this model. Two additional studies have also shown that lipid peroxidation is not involved in the pathogenesis of acute gastric mucosal injury caused by indomethacin [20] and that mucosal sulfhydryl levels have no relation to the ulcerogenicity of indomethacin [21] and these results agree with our data.…”

Lipopolysaccharide from Escherichia coli prevents indomethacin-induced gastric damage in rats: role of non-protein sulfhydryl groups and leukocyte adherence

“…In accordance to literature, this present study also showed that oral administration of indomethacin (20 mg/kg) results in gastric hemorrhagic erosions, increase in neutrophil infiltration [2,18] and decrease in NP-SH concentration in the gastric tissue [19,20]. Recently, we demonstrated that LPS, at a dose 300 lg/kg, completely eliminated indomethacin-induced gastric damage and neutrophil infiltration.…”

“…Our group demonstrated that a SH compound (amifostine) protects indomethacininduced gastric damage by an increase in the NP-SH group in the gastric mucosa [20]. Ueshima [19] demonstrated that exogenous glutathione (GSH) inhibits indomethacininduced gastric damage and that substances containing sulfhydryl radicals, such as dimercaprol, cysteamine and dimercaptosuccinic acid, work in the protection of the gastric mucosa in the same way prostaglandins do, and that sulfhydryl group blockers, such as diethylmaleate and iodoacetamide, reverse the gastric protective effect of PGF 2a [17]. Then, we suggested that LPS gastroprotective effect against indomethacin-induced gastric damage could be secondary to an increase in gastric GSH concentration.…”