Endothelins‐induce cyclicAMP formation in the guinea‐pig trachea through an ETA receptor‐ and cyclooxygenase‐dependent mechanism

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Abstract
1 The non-selective endothelin agonist, endothelin-1 (ET-1), and the selective ETB receptor agonist, sarafotoxin-S6c (SRTX-c), contracted guinea-pig isolated trachea in a concentration-dependent manner. The EC50 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 ETA 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 t1/2 value of 4.3 min, an EC50 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 μm) 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 μm. 4 Pre-incubation of the trachea with BQ-610 (1 μm) or indomethacin (1 μm) 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 ETB-triggered mechanical response. This effect is likely to be mediated by activation of adenylate cyclase through a cyclo-oxygenase-dependent mechanism.