Anti-proliferating effect of iptakalim, a novel KATP channel opener, in cultured rabbit pulmonary arterial smooth muscle cells

ATP-sensitive potassium (K(ATP)) channels of pulmonary arterial smooth muscle cells (SMCs) have been implicated in pulmonary hypertension. Iptakalim, designed and synthesized by ourselves, is a newly selective K(ATP) channel opener. Here, we explored the effects of iptakalim on the rise of cytoplasmic free CA(2+) concentration ([CA(2+)](cyt)) induced by endothelin-1 (ET-1) and on the proliferation of cultured rabbit pulmonary arterial SMCs. The results showed that iptakalim inhibited the [CA(2+)](cyt) increase. The enhanced [(3)H]thymidine incorporation was inhibited and the transition of cells from static phase (G(0)/G(1)) to DNA synthesis (S) and mitotic phase (G(2)/M) was held back by iptakalim in a concentration-dependent manner. Glyburide abolished the inhibitory effect of iptakalim. In conclusion, we have shown that iptakalim had an inhibitory effect on [CA(2+)](cyt) increase and the proliferation of pulmonary arterial SMCs induced by endothelin-1 through activation of K(ATP) channels. These findings suggest that iptakalim might be a promising candidate for the treatment of pulmonary arterial remodeling in pulmonary hypertension.