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‐1 ( 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‐1 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 μ 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 μ m . 4 Pre‐incubation of the trachea with BQ‐610 (1 μ m ) or indomethacin (1 μ 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 ET A 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.