Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of K(ATP) channel.

Abstract

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 [3H]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 [3H]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 [3H] 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.

• Authors: Yuming Zhu, Shijiang Zhang, Weiping Xie, Qingling Li, Yanjuan Zhou, Hong Wang
• Journal: Vascular pharmacology (Vascul Pharmacol) 2008 Feb-Mar Vol. 48 Issue 2-3 Pg. 92-9 ISSN: 1537-1891 [Print] United States
• PMID: 18276195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Endothelin-1
• KATP Channels
• Membrane Transport Modulators
• N-(1-methylethyl)-1,1,2-trimethylpropylamine
• Potassium Channel Blockers
• Propylamines
• Pinacidil
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Glyburide
• Calcium

Topics

• Antihypertensive Agents (pharmacology)
• Blotting, Western
• Calcium (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• DNA Replication (drug effects)
• Dose-Response Relationship, Drug
• Endothelin-1 (metabolism)
• Flow Cytometry
• Glyburide (pharmacology)
• Humans
• KATP Channels (agonists, metabolism)
• Membrane Transport Modulators (pharmacology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Phosphorylation
• Pinacidil (pharmacology)
• Potassium Channel Blockers (pharmacology)
• Propylamines (pharmacology)
• Pulmonary Artery (drug effects, metabolism)