Ginsenoside-Rd a new voltage-independent Ca2+ entry blocker reverses basilar hypertrophic remodeling in stroke-prone renovascular hypertensive rats

Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
European journal of pharmacology (Impact Factor: 2.53). 02/2009; 606(1-3):142-9. DOI: 10.1016/j.ejphar.2009.01.033
Source: PubMed


The total saponins of Panax notoginseng have been clinically used for the treatment of cardiovascular diseases and stroke in China. Our recent study has identified ginsenoside-Rd, a purified component of total saponins of P. notoginseng, as an inhibitor to remarkably inhibit voltage-independent Ca(2+) entry. We deduced a hypothesis that the inhibition of voltage-independent Ca(2+) entry might contribute to its cerebrovascular benefits. Ginsenoside-Rd was administered to two-kidney, two-clip (2k2c) stroke-prone hypertensive rats to examine its effects on blood pressure, cerebrovascular remodeling and Ca(2+) entry in freshly isolated basilar arterial vascular smooth muscle cells (BAVSMCs). Its effects on endothelin-1 induced Ca(2+) entry and cellular proliferation were assessed in cultured BAVSMCs. The results showed that, in vivo, ginsenoside-Rd treatment attenuated basilar hypertrophic inward remodeling in 2k2c hypertensive rats without affecting systemic blood pressure.During the development of hypertension, there were time-dependent increases in receptor-operated Ca(2+) channel (ROCC)-, store-operated Ca(2+) channel (SOCC)- and voltage dependent Ca(2+) channel (VDCC)-mediated Ca(2+) entries in freshly isolated BAVSMCs. Ginsenoside-Rd reversed the increase in SOCC- or ROCC- but not VDCC-mediated Ca(2+) entry. In vitro, ginsenoside-Rd concentration-dependently inhibited endothelin-1 induced BAVSMC proliferation and Mn(2+) quenching rate within the same concentration range as required for inhibition of increased SOCC- or ROCC-mediated Ca(2+) entries during hypertension. These results provide in vivo evidence showing attenuation of hypertensive cerebrovascular remodeling after ginsenoside-Rd treatment. The underlying mechanism might be associated with inhibitory effects of ginsenoside-Rd on voltage-independent Ca(2+) entry and BAVSMC proliferation, but not with VDCC-mediated Ca(2+) entry.

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    • "Chemical structure of 20(S)-protopanaxatriol (PPT). improved pharmacokinetic characteristics [2] [8]. Intestinal bacterial metabolites, including compound C-K, PPD, and PPT, were found to have been easily absorbed and observed in the plasma after oral administration of Rb1, Re, and Rg1 [20] [21] [22] [23]. "
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    ABSTRACT: 20(S)-Protopanaxatriol (PPT), one of the aglycones of ginsenosides, has been shown to exert cardioprotective effects against myocardial ischemic injury. However, studies on PPT metabolism have rarely been reported. This study is the first to investigate the in vivo metabolism of PPT following oral administration by ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy. The structures of the metabolites were identified based on the characteristics of their MS data, MS(2) data, and chromatographic retention times. A total of 22 metabolites, including 17 phase I and 5 phase II metabolites, were found and tentatively identified by comparing their mass spectrometry profiles with those of PPT. Two new monooxygenation metabolites, (20S,24S)-epoxy-dammarane-3,6,12,25-tetraol and (20S,24R)-epoxy-dammarane-3,6,12,25-tetraol, were chemicallly synthesized and unambiguously characterized according to the NMR spectroscopic data. The metabolic pathways of PPT were proposed accordingly for the first time. Results revealed that oxidation of (1) double bonds at Δ((24,25)) to form 24,25-epoxides, followed by rearrangement to yield 20,24-oxide forms; and (2) vinyl-methyl at C-26/27 to form corresponding carboxylic acid were the predominant metabolic pathways. Phase II metabolic pathways were proven for the first time to consist of glucuronidation and cysteine conjugation. This study provides valuable and new information on the metabolism of PPT, which is indispensable for understanding the safety and efficacy of PPT, as well as its corresponding ginsenosides.
    Journal of pharmaceutical and biomedical analysis 10/2013; 88C:497-508. DOI:10.1016/j.jpba.2013.09.031 · 2.98 Impact Factor
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    • "Several studies have shown that ginseng and ginsenosides have beneficial effects on the cardiovascular system and that increases in endothelial NO production due to ginseng saponins are crucial for this activity (Wang et al., 2008; Cai et al., 2009; Deng et al., 2009). In this sense, Rg3 is the most attractive ginsenoside, since the compound potently relaxes vascular arteries via NO production (Kim et al., 1999) and is easily extracted from red ginseng by a steaming and drying process (Park et al., 2002). "

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    • "Ginsenoside Rb1 inhibits cardiac hypertrophy in a rat model [27]. Ginsenoside Rd reverses basilar hypertrophic remodeling in stroke-prone renovascular hypertensive rats as a new voltage-independent Ca2+ entry blocker [28]. Also, the effect of sugar position in ginsenosides on inhibitory potency of Na+/K+-ATPase activity has been described [29]. "
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    ABSTRACT: Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginseng may also be potentially valuable in treating cardiovascular diseases. Research concerning cardiovascular disease is focusing on purified individual ginsenoside constituents of ginseng to reveal specific mechanisms instead of using whole ginseng extracts. The most commonly studied ginsenosides are Rb1, Rg1, Rg3, Rh1, Re, and Rd. The molecular mechanisms and medical applications of ginsenosides in the treatment of cardiovascular disease have attracted much attention and been the subject of numerous publications. Here, we review the current literature on the myriad pharmacological functions and the potential benefits of ginseng in this area. In vitro investigations using cell cultures and in vivo animal models have indicated ginseng's potential cardiovascular benefits through diverse mechanisms that include antioxidation, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, and improving lipid profiles. Some 40 ginsenosides have been identified. Each may have different effects in pharmacology and mechanisms due to their different chemical structures. This review also summarizes results of relevant clinical trials regarding the cardiovascular effects of ginseng, particularly in the management of hypertension and improving cardiovascular function.
    Journal of ginseng research 01/2012; 36(1):16-26. DOI:10.5142/jgr.2012.36.1.16 · 2.82 Impact Factor
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