Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of KATP channel

To determine whether iptakalim inhibited endothelin-1 (ET-1)-induced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) through the activation of ATP-sensitive potassium (K-ATP) channel, the effect of iptakalim on the ET-1-induced proliferation of human PASMCs was examined by [H-3]thymidine incorporation, staining with propidium iodide and flow cytometry analyses, measurement of cytosolic free Ca2+ concentration ([Ca2+](cyt)) and Western blot for the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in vitro. The results showed that iptakalim inhibited the ET-1-induced proliferation of human PASMCs, including [H-3]thymidine incorporation and the transition of cell cycle phase, and blocked the ET-1-induced transient raise of [Ca2+](cyt), and the ET-1-induced phosphorylation of ERK1/2 in the human PASMCs. Iptakalim exerted a similar role as pinacidil did in human PASMCs and both inhibited the [H-3] thymidine incorporation and the transition of cell cycle phase induced by ET-1 in the human PASMCs. Furthermore, we found that the inhibition of iptakalim and pinacidil on the ET-1 -induced proliferation of human PASMCs was blocked by glyburide, a selective K-ATP channel antagonist. These findings provide a strong evidence to support that iptakalim acts as a specific K-ATP channel opener to antagonize the proliferating effect of ET-1 in the human PASMCs. This study provides further evidence that iptakalim may serve as another candidate drug to treat pulmonary hypertension. (C) 2008 Elsevier Inc. All rights reserved.