The phytoestrogen ginsensoside Re activates potassium channels of vascular smooth muscle cells through PI3K/Akt and nitric oxide pathways

In vascular smooth muscle cells, large-conductance Ca2+-activated K+ channels (KCa channels) play a pivotal role in determining membrane potential, and thereby the vascular tone. Ginsenoside Re, a phytochemical from ginseng, is reported to activate this channel, but its precise mechanism is unsolved. Patch clamp studies showed that ginsenoside Re activates KCa channels in the arterial smooth muscle cell line A10 in a dose-dependent manner. The channel-opening effect of ginsenoside Re was inhibited by 1 μM L-NIO, an inhibitor of eNOS, but not by 3 μM SMTC, an inhibitor of nNOS, indicating that ginsenoside Re activated KCa channels through activation of eNOS. SH-6 (10 μM), an Akt inhibitor, and wortmannin, a PI3-kinase inhibitor, completely blocked activation of KCa channels by ginsenoside Re, indicating that it activates eNOS via a c-Src/PI3-kinase/ Akt-dependent mechanism. In addition, the ginsenoside Re-induced activation of eNOS and KCa channel was blocked by 10 μM ICI 182,780, an inhibitor of membrane estrogen receptor-α, suggesting that eNOS activation occurs via a non-genomic pathway of this receptor. In conclusion, ginsenoside Re releases NO via a membrane sex steroid receptors, resulting in KCa channel activation in vascular smooth muscle cells, promoting vasodilation and preventing severe arterial contraction.