Many plant flavonoids possess cardiac and vascular protective properties. Yet, their mechanism of action is not well known. We hypothesized that quercetin modulates arterial contractility by affecting smooth muscle cell calcium homeostasis. Responses of rat tail arteries were determined using wire-myography and FURA-2 fluorimetry. Quercetin relaxed serotonin-precontracted vessels with a pD2 of 5.09. Removal of the endothelium did not alter the effect of quercetin. Further, quercetin reduced the intracellular calcium concentration ([Ca]i). At 10mM quercetin, [Ca]i in the cytosol and in calcium stores was decreased by 89% and 84%, respectively. This effect of quercetin on cytosolic and stored [Ca]i was not mimicked by extracellular EGTA, 2-APB or CPA. However, the quercetin-induced change in cytosolic and stored [Ca]i was inhibited partly by KB-R7943, an inhibitor of Na/Ca-exchange, but not by 2-APB+ryanodine. In addition, the quercetin-induced relaxation was reduced considerably by Rp-8- Br-PET-cGMPS, a PKG-inhibitor, but not by inhibitors of PKA and guanylate cyclase. These data show that quercetin relaxes rat tail arteries and that this effect is endothelium-independent, mediated partly by Na/Ca-exchange and PKG.