Endothelin receptor blockers protect against ischemia/reperfusion impairment of gastrointestinal motility in rats.
Intestinal ischemia/reperfusion (I/R) injury remains associated with high morbidity and mortality. The protective efficacy of the following endothelin (ET) receptor blockers: BQ-123 (ET(A) receptor), BQ-788 (ET(B)); tezosentan (dual ET blocker) was tested against the inhibition of gastrointestinal (GI) motility induced by intestinal I/R. Intestinal Evans blue transit was measured in untreated (UN) rats and animals subjected to skin incision (SI), I/R (1h superior mesenteric artery clamping followed by 2-24h reperfusion) or sham operation (SO). Surgical procedures were conducted under diethyl ether anesthesia. Anesthesia and SI did not affect the GI transit compared to UN rats. In contrast both SO and I/R significantly reduced GI motility, the latter evident at 2-24h of reperfusion. Tezosentan (1-10 mg/kg), BQ-123 and BQ-788 (0.1-1 mg/kg) protected against I/R-induced inhibition of intestinal motility in a time- and dose-dependent manner at the early and late stages of reperfusion. Furthermore tezosentan alleviated the I/R-induced decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro. The serum ET(1-21) level was increased at 2h but not 24h of reperfusion compared to SO animals and ET(1-21) was higher in tezosentan pretreated rats.
Ługowska-Umer
H
H
Department of Pharmacology, Medical University of Gdańsk, Debowa 23, 80-204 Gdańsk, Poland.
Umer
A
A
Sein-Anand
J
J
Sokołowska-Wojdyło
M
M
Włodarkiewicz
A
A
Korolkiewicz
R P
RP
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D004986:Ether; D005070:Evans Blue; D005769:Gastrointestinal Motility / Q000502:physiology*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009842:Oligopeptides / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013514:Surgical Procedures, Operative; D013777:Tetrazoles / Q000627:therapeutic use
D018685:Anesthetics, Inhalation; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D018721:Muscarinic Agonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011725:Pyridines; D013777:Tetrazoles; D004986:Ether; C086539:BQ 788; D005070:Evans Blue; C120582:tezosentan; D002217:Carbachol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)