THE IMPORTANCE OF TACHYPHYLAXIS AND RELEASE OF CYCLOOXYGENASE PRODUCTS IN THE MODULATION OF ENDOTHELIN-1 INDUCED RESPONSES IN RAT AND GUINEA-PIG TRACHEAL CHAINS

Responses to endothelin-1 (ET-1) were studied in both rat and guinea pig tracheal chains in vitro. Indomethacin potentiated contractile responses to ET-1 in the guinea pig but had no effect in the rat. Furthermore, relaxation responses to ET-1 observed in some guinea pig preparations only were abolished by indomethacin. Studies using repeated full cumulative dose-response curves and repeated single-dosing techniques demonstrated tachyphylaxis to ET-1 in both rat and guinea pig. However, the degree of tachyphylaxis in the guinea pig was dependent on the initial response to the peptide, and in single-dose studies in this species, tachyphylaxis to ET-1 was more prominent in the presence of indomethacin. It is suggested that both tachyphylaxis and inconsistent release of cyclooxygenase products may be responsible for the wide differences in potency estimates for ET-1 that have been observed in airways smooth muscle.