16-16-dimethylprostaglandin-e2 and diethyl-maleate

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.

Topics: 16,16-Dimethylprostaglandin E2; Adaptation, Physiological; Adenosine Triphosphate; Administration, Oral; Animals; ATP-Binding Cassette Transporters; Dimercaprol; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Glyburide; KATP Channels; Lithium Chloride; Male; Maleates; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Prostaglandins; Rats; Rats, Wistar; Sodium Salicylate; Stomach Ulcer

The relationship between gastric mucosal glutathione (GSH) levels, vascular permeability, gastric motility and mucosal injury caused by ethanol was investigated in rats. Oral administration of 50% ethanol (1 ml) produced elongated reddish bands of lesions in the mucosa with a significant reduction of GSH levels and increase of microvascular permeability. These lesions were significantly inhibited by pretreatment with s.c. administered diethylmaleate (DEM: 1 ml/kg), cysteamine (100 mg/kg) and 16, 16-dimethyl prostaglandin E2 (dmPGE2, 10 micrograms/kg) but worsened markedly by N-ethylmaleimide (NEM: 10 mg/kg). Irrespective of whether the animals were treated with 50% ethanol or not, the mucosal GSH levels were significantly decreased or increased, respectively, by DEM or cysteamine, and were not affected by both NEM and dmPGE2. NEM significantly enhanced the vascular permeability in the absence or presence of ethanol (greater than 10%), whereas other agents significantly inhibited only the increased vascular permeability caused by ethanol. On the other hand, gastric motility was potently and persistently inhibited by either DEM, cysteamine or dmPGE2 at the doses which prevented ethanol-induced mucosal injury, whereas NEM had no effect on the motility. These results suggest that 1) the mucosal GSH levels do not relate directly to either development or prevention of ethanol-induced gastric injury, 2) potentiation by NEM of the mucosal injury may be accounted for by its enhancement of the vascular permeability and 3) inhibition of gastric motility may be associated with prevention of mucosal lesions.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Capillary Permeability; Cysteamine; Ethanol; Ethylmaleimide; Gastric Mucosa; Gastrointestinal Motility; Glutathione; Male; Maleates; Rats; Rats, Inbred Strains