Role of ATP-sensitive potassium channels in prostaglandin-mediated gastroprotection in the rat.
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.
Peskar
Brigitta M
BM
Department of Experimental Clinical Medicine, Ruhr University of Bochum, D-44780 Bochum, Germany. dorothea.seier@ruhr-uni-bochum.de
Ehrlich
Karlheinz
K
Peskar
Bernhard A
BA
D015064:16,16-Dimethylprostaglandin E2 / Q000008:administration & dosage; D018528:ATP-Binding Cassette Transporters; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D004112:Dimercaprol / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005905:Glyburide / Q000008:administration & dosage; D054086:KATP Channels; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D008298:Maleates / Q000627:therapeutic use; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000627:therapeutic use; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*
D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D008298:Maleates; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011453:Prostaglandins; C092520:uK-ATP-1 potassium channel; D004112:Dimercaprol; D000431:Ethanol; D000255:Adenosine Triphosphate; D018021:Lithium Chloride; C014476:diethyl maleate; D015064:16,16-Dimethylprostaglandin E2; D005905:Glyburide; D012980:Sodium Salicylate