Effects of several endothelin receptor antagonists on gastrointestinal transit of guinea pigs.

This study was undertaken to investigate the effects of endothelin(A) receptor antagonist (ET(A)-RA) BQ485; ET(B)-RA BQ788, and nonselective ET(A/B)-RA Bosentan on the gastrointestinal transit of guinea pigs. We further analyzed the distribution of ET-R subtypes on smooth muscle cells (SMC) of the gastrointestinal tract to investigate their direct involvement on SMC in gastrointestinal tract transit. A guinea pig model was used to measure intestinal transit. The effects of Bosentan (100 mg/kg, per os), BQ485 (1 mg/kg, intraperitoneally) and BQ788 (1 mg/kg, intraperitoneally) on transit in stomach, small intestine, and colon were evaluated. We separated SMC from stomach, small intestine, cecum, and colon by collagenase and analyzed the distribution of ET-R subtypes in each part by binding assay. Gastric transit and colon transit were significantly inhibited by BQ485, BQ788, and Bosentan. Small intestinal transit was not affected by any of these agents. ET(A)-R and ET(B)-R were widely distributed on SMC of stomach, small intestine, cecum, and colon. The ratio of ET(A)-R to ET(B)-R was 1:3 in stomach, small intestine, and cecum, but was 1:10 in colon. The ratio of the total number of ET-R on SMC of stomach, small intestine, cecum, and colon was 1:3:9:1. These results indicate that both ET(A)-R and ET(B)-R are strongly involved in the transit in the stomach and colon. However, the discrepancy between the effects of the various ET-R antagonists on gastrointestinal transit and the distribution of ET-R on SMC of the gastrointestinal tract suggests that ET-R on SMC of the gastrointestinal tract is not directly involved in gastrointestinal transit.