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 Ca(2+)-activated K(+) channels (K(Ca) 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 K(Ca) 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 microM L-NIO, an inhibitor of eNOS, but not by 3 microM SMTC, an inhibitor of nNOS, indicating that ginsenoside Re activated K(Ca) channels through activation of eNOS. SH-6 (10 microM), an Akt inhibitor, and wortmannin, a PI3-kinase inhibitor, completely blocked activation of K(Ca) 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 K(Ca) channel was blocked by 10 microM ICI 182, 780, an inhibitor of membrane estrogen receptor-alpha, 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 K(Ca) channel activation in vascular smooth muscle cells, promoting vasodilation and preventing severe arterial contraction.
Nakaya
Yutaka
Y
Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Mawatari
Kazuaki
K
Takahashi
Akira
A
Harada
Nagakatsu
N
Hata
Akiko
A
Yasui
Sonoko
S
D000818:Animals; D002460:Cell Line; D036145:Ginsenosides / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048789:Phytoestrogens / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D036145:Ginsenosides; D048789:Phytoestrogens; D024681:Potassium Channels, Calcium-Activated; D009569:Nitric Oxide; C049864:ginsenoside Re; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt