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.
Xie
Weiping
W
Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
Wang
Hong
H
Ding
Jianhua
J
Wang
Hai
H
Hu
Gang
G
D018528:ATP-Binding Cassette Transporters / Q000819:agonists*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D054086:KATP Channels; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists*; D011437:Propylamines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D013936:Thymidine / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D019332:Endothelin-1; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D024661:Potassium Channels, Inwardly Rectifying; D011437:Propylamines; C092520:uK-ATP-1 potassium channel; D002118:Calcium; D013936:Thymidine