Endothelin receptor blockers protect against ischemia/reperfusion impairment of gastrointestinal motility in rats

Abstract

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 (1 h superior mesenteric artery clamping followed by 2–24 h 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 2–24 h 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 2 h but not 24 h of reperfusion compared to SO animals and ET(1–21) was higher in tezosentan pretreated rats.