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

Background & Aims: Endothelins are expressed in many enteric neurons of the gut. Because activation of endothelin ETA and ETB receptors is known to al ter intestinal muscle activity, the effect of ETA and ETB receptor agonists and antagonists on propulsive peristalsis was examined, Methods: Repetitiv e peristalsis in fluid-perfused segments of the guinea pig isolated small i ntestine was elicited by a rise of the intraluminal pressure and recorded v ia the pressure changes generated by the peristaltic waves. Results: Endoth elin 1 (0.3-10 nmol/L added to the organ bath) stimulated peristalsis as sh own by a decrease in the pressure threshold at which peristaltic waves were triggered, whereas the endothelin analog sarafotoxin 6c (0.3-10 nmol/L) in hibited peristalsis as reflected by an increase in the pressure threshold. The ETA receptor antagonist BQ-123 (3 mu mol/L) converted the properistalti c action of endothelin 1 to an antiperistaltic action, whereas the ETB rece ptor antagonist BQ-788 (3 mu 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 endoth elin 1 is mediated by enteric neurons, whereas the peristaltic motor effect s of sarafotoxin 6c and BQ-788 are caused by a direct action on the muscle. Conclusions: ETA receptor activation stimulates, whereas ETB, receptor act ivation inhibits, intestinal peristalsis. The ability of BQ-788 to facilita te peristalsis per se points to a physiologic role of ETB receptors in peri staltic motor regulation.