Pharmacologic modulation of endothelin-induced contraction in isolated rat tracheal segments

Porcine endothelin was found to be the most potent of the tested bronchoconstrictor agents on isolated rat tracheal segments. The calculated EC50S were as follows: endothelin = 106 nM, 5-HT = 1.45 microM, acetylcholine = 6 microM, KCl = 26.3 mM, and CaCl2 = 0.4 mM. Rat trachea is insensitive to histamine, neurokinin-A, and LTC4/LTD4. PAF (5.1 +/- 2.2 microM) produced strong contractile responses (1076 + 91 mg). Verapamil (1 microM, 60 min) antagonized CaCl2 but did not influence endothelin-induced contractile responses. In Ca2(+)-free Krebs solution, endothelin-induced responses were inhibited significantly. Relatively high concentrations of nifedipine and cadmium chloride (10 microM) attenuated endothelin-induced contractile responses. Indomethacin (5 microM, 60 min) slightly enhanced the endothelin-induced concentration-effect curve. These data show that endothelin induces slowly developing and sustained stimulus-contraction coupling in rat tracheal smooth muscle cells mainly by utilizing receptor-operated Ca2+ channels which are resistant to verapamil.