Regulation of guinea-pig intestinal peristalsis by endogenous endothelin acting at ETB receptors

Abstract

Background & Aims:Endothelins are expressed in many enteric neurons of the gut. Because activation of endothelin ET A and ET B receptors is known to alter intestinal muscle activity, the effect of ET A and ET B receptor agonists and antagonists on propulsive peristalsis was examined. Methods: Repetitive peristalsis in fluid-perfused segments of the guinea pig isolated small intestine was elicited by a rise of the intraluminal pressure and recorded via the pressure changes generated by the peristaltic waves. Results: Endothelin 1 (0.3-10 nmol/L added to the organ bath) stimulated peristalsis as shown by a decrease in the pressure threshold at which peristaltic waves were triggered, whereas the endothelin analog sarafotoxin 6c (0.3-10 nmol/L) inhibited peristalsis as reflected by an increase in the pressure threshold. The ET A receptor antagonist BQ-123 (3 mol/L) converted the properistaltic action of endothelin 1 to an antiperistaltic action, whereas the ET B receptor antagonist BQ-788 (3 mol/L) prevented the antiperistaltic action of sarafotoxin 6c. BQ-788, but not BQ-123, facilitated peristalsis on its own. Additional experiments indicated that the properistaltic action of endothelin 1 is mediated by enteric neurons, whereas the peristaltic motor effects of sarafotoxin 6c and BQ-788 are caused by a direct action on the muscle. Conclusions: ET A receptor activation stimulates, whereas ET B receptor activation inhibits, intestinal peristalsis. The ability of BQ-788 to facilitate peristalsis per se points to a physiologic role of ET B receptors in peristaltic motor regulation.