Eucommia Ulmoides

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The bark of Eucommia ulmoides Oliv. has been widely used as a tonic medicinal herb in the Orient, but is less well-known to the West [ 12,13]. It is used for the treatment of hypertension either as a single herb or in combination with one or two of the above-mentioned herbs in the traditional herbal prescription. According to the ancient writing of Chinese medicinal herbs [12], Eucommia ulmoides, prepared from the leaf or bark, is commonly used as a tonic for the liver and kidney, thus improving detoxification (by liver) and circulation (via kidney), respectively. The antioxidant effect of some of the chemical constituents of Eucommia leaf and bark may also contribute to its anti-inflammatory action [14]. Many studies have focused on the blood pressure-lowering effect of Eucommia leaf and bark [13, 15-19] and their chemical constituents [14], Surprisingly, little is known about its pharmacological profiles on the cardiovascular tissues. Recently, we have reported for the first time that the aqueous extracts of Eucommia leaf and bark exerted in vitro relaxation in rat aorta and dog carotid artery [20, 21], which is entirely endothelium -dependent, and mediated by nitric oxide (NO). However, these extracts do not act at the NO-releasing receptor sites, such as endothelial muscarinic receptors and appear to involve K+-channels. While this relaxant effect of Eucommia extracts may be a plausible explanation, at least in part, for its antihypertensive action, we also investigated whether such Eucommia-induced endothelium-dependent relaxation is generally applicable to other vasculature, especially the smaller muscular arteries (such as mesenteric artery), which are more important for blood pressure regulation than the large conduit elastic arteries, such as aorta and carotid artery used in our previous study [21]. Also, as blood vessels become smaller, endothelium-derived hyperpolarizing factor (EDHF) becomes functionally more active aside from NO in the endothelium-dependent relaxant events [22,23]. Therefore, we also examined whether the Eucommia extract can cause the release of EDHF in addition to NO in smaller muscular vessels, such as rat mesenteric arteries, as compared to a large artery such as rat aorta.

We found that all three types of vessel preparations elicited endothelium-derived vascular relaxation (EDVR) in response to Eucommia bark extract concentration-dependently [22] in a similar manner as the relaxant responses to carbachol (CCh). Although the NO synthase inhibitor L-NAME totally abolished the EDVR in aorta, it only partial abolished EDVR in mesenteric arteries isolated from each end, the distal end being more resistant to L-NAME. However, the residual L-NAME-resistant relaxation of the rat mesenteric arteries could be further inhibited by preincubation of the vessels with the combination of L-NAME and 15-20 mM KC1 (KC1 itself at this low concentration caused little or no contraction). Therefore, the EDVR induced by the Eucommia extract and CCh in aorta is mediated entirely by NO, and that in mesenteric arteries by NO as well as EDHF, with the EDHF component (inhibited by KC1) larger in the smaller distal end of the rat mesenteric artery. Results in our study offer a plausible mechanistic basis for the vasorelaxing action of

Eucommia ulmoides Oliv., which may account for its well documented antihypertensive action.

ELEUTHEROCOCCUS SENTICOSUS

The medicinal herb, Siberian ginseng (.Eleutherococcus senticosus Maxim or Acanthopanax senticosus Harms), is botanically different from the Korean ginseng (Panax ginseng) and North American ginseng (Panax quinquefolia), but the healing power of its roots is very similar to the root of the other two types of ginseng and has therefore been traditionally used in China as a ginseng-substitute for centuries because of its relatively lower cost. In fact, its medicinal value lies in its anti-fatigue effect following strenuous exercise and was claimed to be more superior to that of the ginseng [24], Siberian ginseng (SG) was named so, because it was naturally grown in Siberia of Russia and the earliest studies (1955-1965) of its health effects were made extensively by Russian scientists [25], Acanthopanax senticosus is also widely grown in northern China and Hokkaido, Japan. In China it is commonly referred to as "Cz-wujia " because of its thorny stem (Ci means thorny and wujia means five-petal leaf, hence Acanthopanax), whereas in Japan, it is referred to as "Ezoukogi" [14, 26].

According to ancient Chinese medical writings [12], Ciwujia root is traditionally used in China to fight against ailments due to stagnation of blood circulation and other body fluids and help clear excessive fluid cumulated in the body (as in edema). These ailments range from indigestion, urinary stagnation, general fatigue, arthritis, mild hyperglycemia to hypertension. Russian scientists reported that Siberian ginseng (SG) improves red blood cell production and perfusion of tissues, and thus efficient oxygen delivery and consumption [25], These effects of SG on circulation noted by people in different cultures conceivably would contribute collectively to its well-known anti-fatigue effect, which has also been confirmed in animal studies of physical endurance by scientists in Hokkaido [14,26], Accordingly, SG has been widely used by athletes and people involved in stressful activities. Despite its wide and huge global consumption of SG as a health food, reports on its pharmacologic profile on vascular system are scanty. PubMed search indicated that the general study of SG represents a very small portion (<1%) of the large body of studies on ginseng.

Although the health effect of SQ like that of the Panax ginseng ox Panax notoginseng, may be attributed to a general improvement of body circulation [ 12], probably via vasodilatory effect elicited by its active ingredients [27-29], direct in vitro studies of SG or its extracts on vascular function are so far not available. On the other hand, in both Panax ginseng and Panax notoginseng, the total glycosidic saponins (also referred to as ginsenosides) are the major active substances known to cause vascular relaxation by endothelium-dependent [7-8, 28] and endothelium-independent [27, 29] mechanisms, respectively. SG, however, does not contain these vasodilatory ginsenosides [14] and a direct vasodilatory effect of SG has not been experimentally demonstrated despite historical claims suggesting vasodilatation as exerting its health effect. We therefore investigated the in vitro vasorelaxant effect of the aqueous extract of the roots of SG (Eleutherococcus senticosus Maxim) using several vascular rings prepared from dog carotid artery, rat aorta and rat mesenteric artery. SG extract (0.04-0.8 mg/ml) caused concentration-dependent relaxation in dog carotid arterial rings pre-contracted with 100 jiM phenylephrine (PE), and the relaxation was primarily endothelium-dependent. Treatment with 100 jlM L-NOARG (a nitric oxide synthase inhibitor) either prevented or reverted SG-induced relaxation suggesting that the endothelium-dependent relaxation was mediated by NO. Similar endothelium-dependent vascular relaxant responses were also obtained with rat aortic and mesenteric arterial rings, except that it occurred over a relatively higher concentration range of SG (0.5-2.0 mg/ml). When tested in the presence of 300 ]oM L-NAME, the vasorelaxant effect of SG was inhibited totally in rat aorta but only partially in rat mesenteric artery. The relaxation to SG that was insensitive to L-NAME in rat mesenteric arterial rings was eliminated when the rings (both proximal and distal ends) were pre-treated with a combination of 300 jlM L-NAME and 15 mM KC1 indicating the involvement of endothelium-derived hyperpolarizing factor (EDHF). This vasorelaxant response of the SG extract was inhibited partially by atropine (1 jiM), completely by TEA (5 mM), butnotbyindomethacin(l |iM) or propranolol (10 |iM). SQupto 2 mg/ml, had no effect on KCl-induced contraction in any of the vascular rings studied. When compared with CCh-induced relaxation, SG resembles CCh in that the sensitivity to L-NAME inhibition is dependent on vascular size, i.e. aorta > proximal end of mesenteric artery > distal end of mesenteric artery. However, SG exhibited different potencies for relaxation while CCh showed similar potency (EC50 of about 0.2 |iM) in all three vascular segments. These studies have demonstrated that the vascular effect of SG is endothelium-dependent and mediated by NO and/or EDHF depending on the vessel size. Other vasorelaxation pathways, such as inhibition of K+-channels and activation of muscarinic receptors, may also be involved.

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