Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a fundamental regulator of systemic blood pressure. Ginsenosides from Panax ginseng have been investigated in vitro for the molecular and biochemical mechanisms by which they stimulate NO release in vascular endothelial cells; however, little research has been done to confirm the physiological relevance of these in vitro studies. To address this research gap, the effects of a P. ginseng extract rich in ginsenosides from protopanaxatriol on spontaneously hypertensive rats (SHRs) was examined. Ginseng extract administration stimulated nongenomic Akt-mediated eNOS activation, enhanced NO production, improved vessel wall thickening, and alleviated hypertension in SHRs, confirming the physiological relevance of previous in vitro studies with ginsenosides.

The root of Panax ginseng C.A. Meyer has been shown to induce nitric oxide (NO) release resulting in a hypotensive effect. However, the main active component contributing to vascular endothelium relaxation remains uncertain. In this study, we hypothesized that multiple components of ginseng extract might have combinatory effects providing greater health benefits than a single ginsenosides. To test this hypothesis, we compared the NO-releasing and endothelial NO synthase (eNOS) activating potency of wide range of ginseng extracts (crude extract, CE; protopanaxatriol-enriched extract, TE; protopanaxadiol-enriched extract, DE) and individual ginsenosides (Rg1, Re and Rb1) in human umbilical vein endothelial cells. We found that TE had the highest potency in NO production, followed by CE, DE, and Rg1. We also observed that TE-treatment resulted in rapid activation of intracellular signaling pathways, immediate linear rise of NO, and increased eNOS activation. TE-induced activation of eNOS was abolished by pretreatment with wortmannin (inhibitor for PI3K-Akt), compound C (inhibitor for AMP activated protein kinase, AMPK) or L-NAME (inhibitor for NOS), whereas Rg1-induced eNOS phosphorylation was only partially attenuated. Further analysis revealed that TE, but not Rg1, results in AMPK phosphorylation at Thr172. These novel finding add evidence that the multiple components of Panax ginseng extract rich in protopanaxatriol offers combinatorial effects in NO production and vascular endothelium relaxation via multiple signaling pathways.