ENDOTHELIN-1 DEPRESSES TRACHEAL MUCUS VELOCITY IN OVINE AIRWAYS VIA ET-A RECEPTORS

Endothelin-1 (ET-1) is a potent constrictor of bronchial smooth muscle , but there is limited information on its actions on the airway mucoci liary clearance in vivo. The purpose of this study was to determine (1 ) the effect of aerosolized ET-1 on tracheal mucus velocity (TMV), a m arker of mucociliary clearance, in sheep and (2) if the ET-1-induced e ffects were mediated by ET-A or ET-B receptors. To measure TMV, radiop aque teflon particles were insufflated into six intubated, spontaneous ly breathing, adult sheep, and the velocity at which these particles t raveled up the trachea was measured using a previously reported roentg enographic technique. After baseline TMV measurements, 50 breaths of e ither ET-1 (10(-7) M) or vehicle (phosphate-buffered saline) were aero solized into the airways. TMV measurements were then obtained over a 2 -h period. After exposure to ET-1, mean TMV decreased significantly as compared with vehicle, the effects being most marked within 30 min af ter administration (54%, p < 0.05). On subsequent days, animals were p retreated with an aerosolized ET-A receptor antagonist (BQ-123) or an ET-B receptor antagonist (BQ-788) before exposure to ET-1. When ET-1 w as given after BQ-123, no significant drop in TMV was noted. in contra st, pretreatment with BQ-788 exhibited no protective effect on the dec rease in TMV. The ET-1 effects were not influenced by pretreatment wit h either the cyclo-oxygenase inhibitor indomethacin or the leukotriene receptor antagonist MK-571, indicating that ET-1-induced depression i n TMV does not involve the activation of prostanoids or peptide leukot rienes. Thus, exogenous ET-1 reduces TMV, an in vivo effect that is me diated through stimulation of ET-A receptors.