Effects of endothelin-1 and nitric oxide on proliferation of cultured guinea pig bronchial smooth muscle cells

Abstract

The proliferative effects of endothelin-1 (ET-1), both alone and in combination with epidermal growth factor (EGF), and the effect of nitric oxide (NO) on the cell proliferation were investigated in cultured guinea pig bronchial smooth muscle cells. ET-1 (10–100 nM) alone augmented cell proliferation, and was additive to the effect of EGF (0.48 nM) in a concentration-dependent manner. An ET A antagonist, BQ-123 (10 μM), reduced the cell-proliferative effect of ET-1, whereas an ET B antagonist, BQ-788 (10 μM), did not influence the effect. A NO donor, SIN-1 (10 nM–1 μM), reduced the cell-proliferative effect of ET-1 in a concentration-dependent manner. The effect of SIN-1 (1 μM) was partly, but significantly, reversed by a soluble guanylyl cyclase inhibitor, ODQ (1 μM). These results suggest that ET-1 acts not only as a co-mitogen with EGF but also as a mitogen alone, and that its action is mediated through activation of ET A receptors. Therefore, ET-1 may contribute to airway remodeling, a pathophysiological hallmark of asthma. In addition, NO, which is produced mainly in the airway epithelium and is partly mediated through cGMP-dependent pathway, may reduce the phenomenon.