Endothelin ETA and ETB receptors facilitating parasympathetic neurotransmission in the rabbit trachea

In the isolated rabbit trachea, electrical field stimulation (EFS) induced contraction that was inhibited by atropine or tetrodotoxin. Nonselective endothelin (ETA/ETB) receptor agonist, ET-1, relatively selective ETB receptor agonist, ET-3, and selective ETB receptor agonists, IRL 1620 and sarafotoxin S6c (STXc), augmented the EFS-induced contraction by 2- to 3-fold with similar EC50 (0.4-1 nM). These agonists also showed direct contractile effect in the trachea. However, the threshold concentration of ET-1 (3 fM) to augment the electrical field stimulation-induced contraction was 100,000 times lower than that needed to directly stimulate smooth muscle. In contrast, these agonists did not augment the contraction induced by stimulation of muscarinic receptor by carbachol. An ETA receptor antagonist, BQ-123, was almost ineffective in antagonizing the effects of ET-1, ET-3 and STXc although if weakly antagonized the effects of IRL 1620. An ETB receptor antagonist, RES-701-1, antagonized the effects of ET-3 and IRL 1620 without changing the effect of STXc and antagonized the effects of only lower concentrations of ET-1. In the trachea in which the ETB receptor was desensitized by strong activation, IRL 1620 and STXc were ineffective and ET-3 showed only small effect at higher concentrations. In contrast, the ETB desensitization inhibited the effects of only lower concentrations of ET-1. The effect of ET-1 in the ETB-desensitized trachea was partially, but not fully, antagonized by BQ-123. A potent ETB antagonist, BQ-788, showed similar effects to the ETB desensitization. These results suggest that ET-1 enhances nervous acetylcholine release by simultaneously activating the ET-1-selective ETA receptor and the isopeptide-nonselective ETB receptor (ETB1 subtype that is sensitive to both RES-701-1 and BQ-788 and the ETB2 subtype that is sensitive only to BQ-788).