EFFECTS OF ET ANTAGONISTS (PD143296 AND PD145065) ON CONTRACTIONS IN GUINEA-PIG HILAR BRONCHUS INDUCED BY ENDOTHELIN-1 AND ITS RELATED PEPTIDE

ETs-induced contractions were resistant to ET(A)-selective antagonists and believed to be mediated by activation of ET, receptors in guinea pig bronchus. In the present study, the effects of the ET antagonists, PD143296 (Ac-D-Phe-L-Leu-L-Phe-L-Ile-L-Ile-L-Trp . 2Na) and PD145065 (Ac-[{R}-2-10, 11-dihydro-5H-dibenzo{a, yclohepten-5-yl]Gly)-L-Leu-L-A sp-L-Ile-L-Ile-L-Trp . 2Na), on contractions induced by ET-1, ET-3, sa rafotoxin S6c (STXc), and IRL1620 in the isolated hilar bronchus of th e guinea pig were investigated. An ET(A/B) nonselective antagonist, PD 145065 antagonized contractions induced by ET-1, ET-3, STXc, and IRL16 20. Its antagonistic activity against ET-1, with pK(B) of 5.77 +/- 0.0 2 (n = 16, 3-10 mu M), was significantly lower than that against ET-3, with pK(B) of 6.18 +/- 0.02 (n = 12, 3-10 mu M), STXc, with pK, of 5. 97 +/- 0.01 (n = 14, 3-10 mu M), and IRL1620, with pK, of 6.80 +/- 0.0 4 (n = 14, 0.3-1 mu-M) Conversely, although a putative ET(B)-selective antagonist, PD143296 (10 mu M) slightly but significantly antagonized the concentration-response curve of IRL1620 (pK(B) 5.28 +/- 0.14, n = 6), it had no effect on ET-1-, ET-3-, or STXc-induced contractions. T hese results suggest that ETs possibly activate ET(B2) or an atypical ET(B) receptor subtype in guinea pig hilar bronchus.