ET-1 induces mitogenesis in ovine airway smooth muscle cells via ET(A) and ET(B) receptors

The proliferation of airway smooth muscle cells is a characteristic feature of asthma. Endothelin (ET)-1, a member of a family of three isopeptides (ET-1, ET-2, and ET-3), functions as a spasmogen and mitogen for airway smooth muscle cells. Two types of ET receptors have been identified in mammalian species (ET(A) and ET(B)). Because the respective roles of ET(A) and ET(B) receptors in ET-1-induced mitogenesis are not known, we determined the effect of two selective ET(A) and ET(B) 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 mitogenesis in a concentration- dependent manner, with BQ-788 exhibiting more 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 ET(A)-ET(B) antagonist, bosentan, also inhibited ET-1-induced mitogenesis (IC₅₀ = 20 nM, slope of 0.60). The effects of BQ-788 and bosentan appear to be mediated via the same receptor (ET(B)), as their slopes are comparable. These observations suggest that both receptor subtypes are utilized in ET-1- induced proliferation of ovine airway smooth muscle. ET receptor expression may be important in the increase in airway smooth muscle mass seen in the airways of patients with bronchial asthma.