Endothelins-induce cyclicAMP formation in the guinea-pig trachea through an ET(A) receptor- and cyclooxygenase-dependent mechanism

1 The non-selective endothelin agonist, endothelin-1 (ET-1), and the selective ET(B) receptor agonist, sarafotoxin-S6c (SRTX-c), contracted guinea-pig isolated trachea in a concentration-dependent manner. The EC(50) value for ET-1 (11+/-2.1 nM) was significantly higher than that of SRTX-c (3.2+/-0.21 nM) and the maximal developed tension due to SRTX-c was 42.8+/-2.3% higher than that produced by ET-I (P<0.05). 2 Pretreatment with the ET(A) antagonist, BQ-610, appreciably enhanced the developed tension due to ET-1 but not SRTX-c. Likewise, the cyclo-oxygenase inhibitor, indomethacin, markedly potentiated the contractile responses to ET-1, but not to SRTX-c. Combining BQ-610 with indomethacin was not more effective than either of them in augmenting ET-1-evoked tension. 3 ET-I significantly increased cyclic AMP formation in the trachea in concentration- and time-dependent manners. A t(1/2) value of 4.3 min, an EC(50) value of 20+/-3 nM and a maximal cyclic AMP increment of 124% above the basal level, were obtained for ET-1. Similarly but less effectively, ET-3 (0.1 mu M) increased cyclic AMP level (35+/-3.7% compared to 94+/-7.8% for the same concentration of ET-1). By contrast, SRTX-c did not alter the cyclicAMP level when applied in concentrations up to 1 mu M. 4 Pre-incubation of the trachea with BQ-610 (1 mu M) or indomethacin (1 mu M) prevented cyclicAMP formation by either ET-1 or ET-3. 5 The results of the present study indicate a negative regulatory role mediated by the ETA receptor on the ET(B)-triggered mechanical response. This effect is likely to be mediated by activation of adenylate cyclase through a cyclo-oxygenase-dependent mechanism.