Heartwood extract of Rhus verniciflua Stokes and its active constituent fisetin attenuate vasoconstriction through calcium-dependent mechanism in rat aorta

Rhus verniciflua Stokes (RVS) exert cardiovascular protective activity by promoting blood circulation, but its active ingredients and underlying mechanism have yet to be identified. This study investigated the vascular effects of RVS, focusing on vasoconstriction and smooth muscle Ca2+ signaling. RVS heartwood extract attenuated contraction of aortic rings induced by the vasoconstrictors serotonin and phenylephrine, and inhibited the Ca2+ signaling evoked by serotonin in vascular smooth muscle cells. Subsequent activity-guided fractionation identified fisetin as an active constituent exerting a Ca2+ inhibitory effect. Fisetin could inhibit major Ca2+ mobilization pathways including extracellular Ca2+ influx mediated by the L-type voltage-gated Ca2+ channel, Ca2+ release from the intracellular store and store-operated Ca2+ entry. In accordance with Ca2+ inhibitory effect, fisetin attenuated vasoconstriction by serotonin and phenylephrine. These results suggest that the anticontractile effect, which is presumably mediated by inhibition of Ca2+ signaling, may contribute to the improvement of blood circulation by RVS. Graphical abstract Rhus verniciflua Stokes extract and its active constituent fisetin improve blood circulation by inhibiting smooth muscle Ca2+ signaling and thereby attenuating vasoconstriction.