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Introduction: Euphorbia humifusa Willd.(EH) is an important traditional Chinese medicine that has commonly been used for the treatment of dysentery and diuresis in many Asian countries for thousands of years.EH has a wide variety of pharmacological actions such as antioxidative and hypotensive effects and anti-HBV activity.However, the mechanisms involved are to be defined.The aim of the present study was to define the effect of EH extracts on vascular tension and responsible mechanisms in rat thoracic aortic rings.Methods: Methanol extract of EH (MEH) and ethyl acetate fraction of the MEH (EEH) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta.Results: MEH and EEH induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner.Endothelium-denudation abolished EEH-induced vasorelaxation.Pretreatment of the endothelium-intact aortic rings with NG-nitro-L-arginine methylester (L-NAME) and 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ) significantly inhibited EEH-induced vasorelaxation.Inhibition of Ca2+ entry via L-type Ca2+ channels failed to block the EEH-induced vasorelaxation.Extracellular Ca2+ depletion significantly attenuated EEH-induced vasorelaxation.Modulators of the store-operated Ca2+ entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate (2-APB) and Gd3+, and an inhibitor of Akt, wortmannin, markedly attenuated the EEH-induced vasorelaxation.EEH increased cGMP levels of the aortic rings in a concentration-dependent manner and the effect was blocked by L-NAME or ODQ.Furthermore, the EEH-induced vasorelaxation was significantly attenuated by tetraethylammonium (TEA), but not by glibenclamide, indomethacin, atropine, and propranolol.In addition, the EEH-induced relaxant responses were attenuated by the treatment with charybdotoxin and iberiotoxin, but not by apamin.Conclusions: The present study demonstrates that EEH induces vascular relaxation via endothelium-dependent and mediated by Akt-and SOCE-eNOS-cGMP pathways, at least in part, through the activation of BKCa channels.