ROLE OF ENDOTHELIN-1 IN REGULATING RABBIT AIRWAY CONTRACTILITY

Endothelin 1 (ET-1) is a potent vasoconstrictor peptide recently isolated from vascular endothelial cells. Because its role and mechanisms of action in regulating airway contractility remain to be identified, we examined the contractile effects of ET-1 in isolated rabbit tracheal smooth muscle (TSM) segments. In TSM under passive tension, ET-1 elicited dose-dependent contractions with a mean +/- SE -log 50% of maximal response value of 7.82 +/- 0.13 vs. a value of 5.61 +/- 0.07 -log M for acetylcholine (ACh). In TSM half-maximally contracted with ACh, however, ET-1 exerted dual and opposing contractile effects. Lower doses of ET-1 (less-than-or-equal-to 10(-9) M) produced a 74.2 +/- 16.6% decrease in active TSM tension. This relaxant response to ET-1 was associated with an accelerated accumulation of prostaglandin (PG) I2 and PGE2 and was attenuated by cyclooxygenase inhibition with indomethacin (10(-5) M). The combination of indomethacin and removal of the airway epithelium completely inhibited the TSM relaxant response to ET-1. In contrast, higher doses of ET-1 ( > 10(-9) M) induced airway contractions that were attenuated by the Ca2+ channel blockers nifedipine (10(-5) M) and diltiazem (10(-5) M) and ablated in Ca2+ -free buffer. Moreover, ET-1-induced TSM contractions were inhibited by the protein kinase C (PK-C) antagonists 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, and staurosporine. Collectively, these findings demonstrate that ET-1 exerts a duality of action on rabbit TSM, wherein 1) at lower doses ET-1 elicits relaxation that is due both in part to the release of bronchodilatory PGs and to the release of an airway epithelium-derived relaxing factor and 2) at higher doses ET-1 produces airway contraction that is dependent on the presence of extracellular Ca2+ and coupled to the activation of PK-C.