KMUP-1 Prevents Serotonin-Induced K+ Channel Proteins Inhibition and Vasoconstriction in Pulmonary Artery

• Main Authors: Yu-Wei Liu, 劉祐瑋
• Other Authors: Bin-Nan Wu
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/61480891723332029622

碩士 === 高雄醫學大學 === 藥理學研究所 === 98 === Serotonin (5-hydroxytryptamine, 5-HT) is a potent pulmonary vasoconstrictor and promotes pulmonary arterial smooth muscle cells (PASMCs) proliferation. K+ channels play an essential role in regulating resting membrane potential and contraction of vascular smooth muscle. Serotonin-induced inhibition of K+ channels could increase the intracellular Ca2+ concentration ([Ca2+]i) in PASMCs and could be a major trigger for pulmonary vasoconstriction and development of pulmonary arterial hypertension (PAH). In this study, we examined the mechanism of action by which KMUP-1 could attenuate the pulmonary vasoconstriction in isolated pulmonary arteries (PAs) and prevent the serotonin-induced K+ channel inhibitory activity in PASMCs. PASMCs were primary cultured from Spraque-Dawley rats and placed in the incubator. PASMCs from passage 3 to 6 were used in this study. Cells were incubated with serotonin (10 μM), KMUP-1 (1 μM) or test agents in the same medium for 24 h. Stimulation of isolated PAs with serotonin induced a significant contractile response and KMUP-1 could prevent it. The various K+ channel inhibitors blocked the effect of vasodilatation of KMUP-1. We suggest that the prevention of KMUP-1 on serotonin-induced contraction might via activation of K+ channels. Additionally, serotonin caused decreases the protein expression and activity of voltage-gated K+ (Kv1.5 and Kv2.1) and large-conductance Ca2+-activated K+ (BKCa) channels in PASMCs. KMUP-1 avoided serotonin-induced decreases in K+ channel proteins. Serotonin-inhibited K+ channel proteins were attenuated by the PKA activator 8-Br-cAMP (100 μM). And a PKC inhibitor chelerythrine (1 μM) enhanced serotonin-inhibited K+ channel proteins. These results indicate that serotonin-inhibited K+ channel might involve the PKA inhibition and PKC activation. In conclusion, KMUP-1 could be used to prevent serotonin-induced K+ channels inhibition and vasoconstriction, which promote the development of PAH.