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Kaempferol stimulates large conductance Ca 2+ ‐activated K + (BK Ca ) channels in human umbilical vein endothelial cells via a cAMP/PKA‐dependent pathway
Author(s) -
Xu Y C,
Leung G P H,
Wong P Y D,
Vanhoutte P M,
Man R Y K
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.194
Subject(s) - iberiotoxin , charybdotoxin , chemistry , apamin , hyperpolarization (physics) , patch clamp , channel blocker , biophysics , kaempferol , adenylyl cyclase , pharmacology , membrane potential , potassium channel , biochemistry , signal transduction , biology , stereochemistry , receptor , calcium , flavonoid , organic chemistry , antioxidant , nuclear magnetic resonance spectroscopy
Background and purpose: Kaempferol has been shown to possess a vasodilator effect but its mechanism of action remains unclear. In this study, experiments were carried out to study the effect of kaempferol on K + channels in endothelial cells. Experimental approach: K + channel activities in human umbilical vein endothelial cells (HUVECs) were studied by conventional whole cell and cell‐attached patch‐clamp electrophysiology. Key results: Kaempferol stimulated an outward‐rectifying current in HUVECs in a dose‐dependent manner with an EC 50 value of 2.5±0.02 μ M . This kaempferol‐induced current was abolished by large conductance Ca 2+ ‐activated K + (BK Ca ) channel blockers, such as iberiotoxin (IbTX) and charybdotoxin (ChTX), whereas the small conductance Ca 2+ ‐activated K + (SK Ca ) channel blocker, apamin, and the voltage‐dependent K + (K V ) channel blocker, 4‐aminopyridine, had no effect. Cell‐attached patches demonstrated that kaempferol increased the open probability of Bk Ca channels in HUVECs. Clamping intracellular Ca 2+ did not prevent kaempferol‐induced increases in outward current. In addition, the kaempferol‐induced current was diminished by the adenylyl cyclase inhibitor SQ22536, the cAMP antagonist Rp‐8‐Br‐cAMP and the PKA inhibitor KT5720, but was not affected by the guanylyl cyclase inhibitor ODQ, the cGMP antagonist Rp‐8‐Br‐cGMP and the PKG inhibitor KT5823. The activation of BK Ca channels by kaempferol caused membrane hyperpolarization of HUVECs. Conclusion and implications: These results demonstrate that kaempferol activates the opening of BK Ca channels in HUVECs via a cAMP/PKA‐dependent pathway, resulting in membrane hyperpolarization. This mechanism may partly account for the vasodilator effects of kaempferol. British Journal of Pharmacology (2008) 154 , 1247–1253; doi: 10.1038/bjp.2008.194 ; published online 19 May 2008