ET-1 INDUCES MITOGENESIS IN-OVINE AIRWAY SMOOTH-MUSCLE CELLS VIA ETA AND ETB RECEPTORS

The proliferation of airway smooth muscle cells is a characteristic fe ature of asthma. Endothelin (ET)-1, a member of a family of three isop eptides (ET-1, ET-2, and ET-3), functions as a spasmogen and mitogen f or airway smooth muscle cells. Two types of ET receptors have been ide ntified in mammalian species (ETA and ETB). Because the respective rol es of ETA and ETB receptors in ET-1-induced mitogenesis are not known, we determined the effect of two selective ETA and ETB antagonists (BQ -610 and BQ-788) on ET-1-induced mitogenesis of cultured ovine airway smooth muscle cells. Both BQ-610 and BQ-788 inhibited ET-1-induced mit ogenesis in a concentration-dependent manner, with BQ-788 exhibiting m ore potent antagonism [half-maximal inhibitory concentration (IC50)=3. 5 nM, slope of 0.49] compared with BQ-610 (IC50=20 nM, slope of 0.27). The combined ETA-ETB antagonist, bosentan, also inhibited ET-1-induce d mitogenesis (IC50=20 nM, slope of 0.60). The effects of BQ-788 and b osentan appear to be mediated via the same receptor (ETB), as their sl opes are comparable. These observations suggest that both receptor sub types are utilized in ET-1-induced proliferation of ovine airway smoot h muscle. ET receptor expression may be important in the increase in a irway smooth muscle mass seen in the airways of patients with bronchia l asthma.