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Purpose: Voltage-dependent potassium (Kv) channels in pulmonary artery smooth muscle cells (PASMCs) are thought to play a crucial role in hypoxia-induced excessive proliferation of PASMCs.The hypoxiainduced downregulation of Kv channels expression decreases the number of functional Kv channels, which consequently depolarized resting membrane potential (Em) and decreased whole cell Kv current [I(Kv)], Hypoxiamediated decrease in I(Kv) not only stimulates PASMCs proliferation by depolarization-induced increase in intracellular concentrations of Ca2+ ([Ca2+]cyt) but also attenuates cell apoptosis by decelerating apoptotic cell decrease and by inhibiting cytoplasmic caspases and nucleases.Sildenafil, a type Ⅴ phosphodiesterase inhibitor that increases cellular cGMP, is recently identified as a promising agent for treatment of pulmonary hypertension.We previously demonstrated that sildenafil inhibits ET-1/hypoxia-induced PASMCs proliferation by attenuation of [Ca2+]cyt.This current study was designed to examine the mechanism of antiproliferative effect of sildenafil involvement of regulation of Kv channels to decrease [Ca2+]cyt in cultured human PASMCs under hypoxia.Materials and Methods: Human PASMCs were incubated with SMCM, SMBM (2% FBS), sildenafil (100nM) with or without KT-5823 (300 nM), sildenafil (100 nM) with or without Anti-Kv1.5 antibody (4 μg/mL)separately for 72 h under hypoxia (3% O2).Then anti-Kv1.5 antibody (1∶125) was administrated during whole cell configuration of patch clamp.The proliferation was detected by MTT and immunocytochemistry.The mRNA and protein expression of Kv1.5 channel were examined by real-time PCR and western blotting.I(Kv) and Em were recorded by patch clamp.Results: Hypoxia-induced downregulation of Kv1.5 channel enhanced proliferation of primary cultured human PASMCs, which was inhibited when treated with sildenafil.Sildenafil-increased mRNA and protein expression of Kv1.5 channel were reversed with KT-5823 (a PKG inhibitor) or anti-Kv1.5antibody treatment of cells.Sildenafil restored hypoxia-induced decrease in I(Kv) combined with depolarization of Em.Then administration with anti-Kv1.5 antibody in pipettes during whole cell configuration of patch clamp abolished the increase in I(Kv) and inhibition of depolarization of Em in PASMCs pretreated with sildenafil under hypoxia.Moreover, we found that I(Kv) also diminished in PASMCs pretreatment with KT-5823 or anti-Kv1.5 antibody in the presence of sildenafil under hypoxia.Conclusion: The results from this present study suggest that sildenafil inhibits hypoxia-induced proliferation involvement of rescuing Kv1.5 channel in PASMCs, potentially by decreasing [Ca2+]cyt.