Pharmalogical of xanthones as cardiovascular

Pharmacological Effects of Xanthonesas Cardiovascular Protective Agents

De-Jian Jiang, Zhong Dai, Yuan-Jian Li

Department of Pharmacology, School of Pharmaceutical Sciences,

Central South University, Changsha, China

Keywords: Atherosclerosis — Cardioprotection — Endogenous NO synthase

inhibitor — Endothelial dysfunction — Low-density lipoproteins — Nitric

oxide (NO) — Xanthones.

ABSTRACT

Many epidemiological studies indicate that consumption of dietary polyphenolic com-

pounds is beneficial in the prevention of cardiovascular diseases. Xanthones are a class of

polyphenolic compounds that commonly occur in plants and have been shown to have ex-

tensive biological and pharmacological activities. Recently, the pharmacological prop-

erties of xanthones in the cardiovascular system have attracted great interest. Xanthones

and xanthone derivatives have been shown to have beneficial effects on some cardiovas-

cular diseases, including ischemic heart disease, atherosclerosis, hypertension and throm-

bosis. The protective effects of xanthones in the cardiovascular system may be due to their

antioxidant, antiinflammatory, platelet aggregation inhibitory, antithrombotic and�or

vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide synthase

inhibitors by xanthones may represent the basis for improved endothelial function and for

reduction of events associated with atherosclerosis.

INTRODUCTION

A number of epidemiological studies indicate that consumption of dietary polyphenolic

compounds is beneficial in the prevention of cardiovascular diseases. The “French

Paradox” is the best example of such a benefit (26,27,70). French consume higher fat

91

Cardiovascular Drug ReviewsVol. 22, No. 2, pp. 91–102© 2004 Neva Press, Branford, Connecticut

Address correspondence and reprint requests to: Yuan-Jian Li, MD, Dept. of Pharmacology, School of Phar-

maceutical Sciences, Central South University, Xiang-Ya Road #90, Changsha 410078, China.

Tel: +86 (731) 235-5078; Fax: +86 (731) 265–0442; E-mail: [email protected]

mailto:[email protected]

diets, exercise less, and smoke more than Americans. However, their mortality from

cardiovascular diseases is much lower than in the USA or in most other Western societies.

Polyphenolic constituents in red wine have been found to be cardioprotective and their

consumption is likely to explain the “French Paradox” (17). Among many polyphenolic

compounds, flavonoids received the most attention and their pharmacology was studied

extensively. However, a large number of studies also involved other naturally occurring

polyphenolic compounds, such as xanthones.

Xanthones are polyphenolic compounds that commonly occur in Chinese herbs such as

Swertia davidi Franch (Gentianceae), which has been used in the treatment of inflamma-

tion, allergy or hepatitis (77). Nowadays, xanthones and xanthone derivatives are isolated

from plants or are chemically synthesized. A substantial number of studies demonstrated

that xanthones and xanthone derivatives have extensive biological and pharmacological

activities such as antiinflammatory, antihepatotoxic, antitumor and antimicrobial activities

(67). Recently, cardiovascular effects of xanthones attracted considerable interest. Xan-

thones and xanthone derivatives have been shown to have beneficial effects in the

treatment of cardiovascular diseases, including ischemic heart disease, atherosclerosis, hy-

pertension and thrombosis. This review focuses on the protective effects and the mecha-

nisms of action of xanthones and xanthone derivatives in the cardiovascular system.

CHEMISTRY

As Figure 1A shows, xanthene-9-one is the basic skeleton of xanthone. The carbons

have been numbered according to the biosynthetic convention: carbons 1–4 are assigned

to the acetate-derived ring A and carbons 5–8 to the sikimin-derived ring B (67). The

xanthones isolated so far may be classified into five major groups: simple oxygenated

xanthones, xanthone glycosides, prenylated and related xanthones, xanthonolignoids and

miscellaneous xanthones. Xanthones have been found in some familiar fruits such as man-

go and mangosteen, and in some medicinal plant families such as Gentianceae and

Polygalaceae. Chemical structures of several xanthone compounds are shown in Fig. 1B.

PHARMACOKINETICS AND TOXICITY

Recently the pharmacokinetics of mangiferin, a xanthone glycoside isolated from the

herbal root of Anemarrhena asphodeloides, in the rat was reported (46). The pharmacoki-

netics of mangiferin at doses of 10–30 mg�kg reveal a linear relation, while doses at

30–100 mg�kg magniferin shows a nonlinear pharmacokinetic phenomenon. Mangiferin

was undetectable in brain dialysate.

There are only a few studies on the toxicity of xanthones. Although in some studies

xanthones were found to be cytotoxic in tumor cell lines (57,72), they are generally con-

sidered to have low toxicity to normal cells and tissues. In an acute toxicity study in mice,

the maximal tolerated dose of 1,6-dihydroxy-3,5-dimethoxyxanthone, isolated from Cans-

cora lucidissima, was 300 mg�kg, i.p. (85).

Cardiovascular Drug Reviews, Vol. 22, No. 2, 2004

92 JIANG DJ ET AL.

CARDIOPROTECTIVE EFFECTS OF XANTHONES

There is a great deal of evidence in animals that xanthones prevent damage of cardiac

tissue induced by various means. The three xanthones isolated from Canscora lucidissi-

ma, significantly decreased myocardial ischemia-reperfusion-induced arrhythmias in vivo.

They also increased the survival rate and decreased the release of lactate dehydrogenase

(LDH) in cultured cardiomyocytes subjected to anoxia�reoxygenation (23,25). In our

recent study we found that the xanthone extracted from Swertia davidi Franch, as well as


XANTHONES 93

H CO3

OCH3

OCH3

AB

1

2

3

5 4O

O

6

7

8

A

B

O

O OH

CH O3

HO OH

Mangostin

O

O OH

OH

OH

OH

O

O OH

OHHO

HO

Norathyriol

O

O OHOH

Daviditin A

OH

HO

OH

CH OH2

O

OH

OH

O

O

HOOH

Mangiferin

Demethylbellidifolin

FIG. 1. A, the basic skeleton of xanthone; B, chemical structures of several xanthone derivatives.

demethylbellidifolin, an isolated xanthone, significantly improved the recovery of cardiac

function (coronary flow, left ventricular pressure and its first derivatives) during reperfu-

sion, the decreased the release of creatine kinase (CK) in isolated rat hearts, and markedly

decreased myocardial infarct size in vivo (40,41). Mangiferin, isolated from Rhizoma ane-

marhenea, has been shown to inhibit apoptosis induced by hypoxia�reoxygenation in cul-

tured cardiomyocytes (73). Other studies have shown that some xanthones protect against

the cardiac injury induced by streptozotocin or epinephrine (60,62).

Gentiana kochiana Perr. et Song. (Gentianaceae) is a plant used in traditional Italian

medicine as an antihypertensive remedy (3). Recently, gentiacaulein and gentiakochianin,

two xanthone compounds isolated from the root of this plant, were found to relax isolated

rat aortic strips, this effect may explain the antihypertensive property of Gentiana kochia-

na (12). Moreover, a series of synthetic xanthones and xanthone derivatives had also

hypotensive acitivity in rats (83).

THE ROLE OF ANTIOXIDANT, ANTIINFLAMMATORY,

ANTITHROMBOTIC AND VASODILATOR ACTIVITIES

IN THE CARDIOPROTECTIVE EFFECTS OF XANTHONES

Free Radical Scavenging and Antioxidant Activities

The generation of oxygen free radicals is strongly implicated as an important patho-

physiological mechanism mediating myocardial ischemia-reperfusion injury (34). Mole-

cules involved in the free radical reactions include superoxide anion, hydroxyl radical, hy-

drogen peroxide, peroxynitrite and hypochlorous acid. Free radicals contain an unpaired

electron and are accordingly highly reactive. Reintroduction of abundant oxygen at the

very onset of reperfusion evokes a burst of free radicals as demonstrated in experimental

animal models as well as in humans with acute myocardial infarction undergoing throm-

bolysis or percutaneous transluminal coronary angioplasty. The release of free radicals, in

combination with the ischemia-induced decrease in antioxidant activity, renders the myo-

cardium extremely vulnerable. Oxygen radicals react readily with cellular phospholipids

and proteins, causing lipid peroxidation and oxidation of thiol groups with subsequent al-

teration of membrane ultrastructure and dysfunction of various cellular proteins. The anti-

oxidants are known to interfere with the free radical formation, and antioxidant reserve

and enzyme capacity are significantly reduced following ischemia and reperfusion. The

loss of key antioxidant enzymes and antioxidant status downregulates the overall antiox-

idant reserve of the myocardium, and makes the heart susceptible to injury induced by

ischemia reperfusion. The reduced antioxidant defense cannot provide protection against

increased activities of free radicals and oxidative stress.

It has been reported that some free radical scavengers and antioxidants prevent arrhyth-

mias and cardiac injury induced by myocardial ischemia-reperfusion (18). Xanthones

have been described as strong scavengers of free radicals and antioxidants. They exhibit

concentration-dependent scavenging activity toward superoxide anions, hydroxyl and

peroxyl radicals (24,49,87). Our recent study, as well as studies by others, showed that

some xanthones scavenge 1,1-diphenyl-2-picrylhydracyl (DPPH) radicals in a concen-

tration-dependent manner (13,38). It has been also shown that xanthones inhibit the pro-

duction of lipid peroxides in normal brain, hepatic and myocardial tissues and elevate the

production of lipid peroxides induced by FeSO4 + cysteine, FeCl2 + ascorbic acid or


94 JIANG DJ ET AL.

CCl4 + NADPH mixtures in rat liver homogenates (24,39). There is also direct evidence

that xanthones scavenge free radicals and inhibit oxidative stress in post-ischemic myo-

cardium. Addition of xanthine�xanthine oxidase or Fe2+�H2O2 to the reperfusion solution

has been found to increase the production of oxygen free radicals and to aggravate injury

induced by ischemia-reperfusion. Magniferin has been shown to attenuate this effect. As

demonstrated by electron spin resonance and chemiluminescence techniques the pro-

tective effect of mangiferin can be correlated with the reduction of oxygen free radicals in

myocardium (87). Furthermore, the oxidative stress in myocardial tissue has been as-

sessed by the levels of malondialdehyde (MDA), reflecting level of lipid peroxidation.

During reperfusion myocardial MDA levels were significantly increased and this increase

was reduced by xanthones in vivo and in vitro (25,40,41). In addition to directly scav-

enging free radicals and inhibiting oxidative stress, xanthones attenuated the

reperfusion-induced inhibition of antioxidant enzymes such as superoxide dismutase,

which increases the antioxidant capacity of myocardium (25).

Apoptosis may be the major initial form of ischemic myocardial cell death occurring

within the first 2 or 3 h after an ischemic episode (9). Active oxygen species may trigger

apoptotic process by adjusting the apoptosis related genes, such as bcl-2 and p53, in myo-

cardial ischemia-reperfusion injury (1). It is well known that bcl-2 and p53 are involved in

the regulation of apoptotic process. The function of bcl-2 as a survival gene is to inhibit

cell death by acting as an antioxidant, triggering enhanced expression of cellular antiox-

idant defense and directly inhibiting the generation of oxygen radicals. As a pro-apoptotic

transcription factor, p53 gene suppresses the anti-death gene bcl-2 and enhances bax in-

duction, playing a critical role in triggering the apoptotic program of cells in hypoxia-me-

diated cellular apoptosis. The inhibitory effect of mangiferin on apoptosis of cardiomyo-

cytes in hypoxia�reoxygenation process has been observed. As demonstrated by DNA

electrophoresis on agarose gel mangiferin reduced the apoptosis in cardiomyocytes in-

duced by 24-h hypoxia and 4-h reoxygenation (73). Moreover, the downregulation of

bcl-2 and the upregulation of p53 in cardiomyocytes induced by hypoxia�reoxygenation

were significantly attenuated by pretreantment with mangiferin (73).

Low-density lipoprotein (LDL) oxidation plays a causative role in the early atheroge-

nesis and the oxidatively modified LDL (ox-LDL) has been shown to exist in atheroscle-

rotic lesions (45). There is evidence that intake of polyphenolic compounds is inversely

related to the morbidity and mortality from coronary heart disease, and that this phe-

nomenon is associated with the inhibition of LDL oxidation (26,35). Some xanthone com-

pounds have been found to inhibit oxidation of LDL in vitro and in vivo (38,39,59,84).

Mangostin, a prenylated xantone, prolonged in a dose-dependent manner, the lag time to

either metal ion dependent (Cu2+) or independent (aqueous peroxyl radicals) oxidation of

LDL. This effect has been monitored by the formation of conjugated dienes at 234 nm and

by the levels of thiobarbituric reactive substances generated in LDL (84). Moreover, man-

gostin significantly inhibited the consumption of alpha-tocopherol in the LDL during

Cu2+-induced LDL oxidation (84). More recently, we also showed that some xanthones, at

low concentrations, inhibit Cu2+-induced LDL oxidation (38,39). These results suggest

that xanthones can act as potent inhibitors of LDL oxidation via several mechanisms by:

1) scavenging free radicals by acting as hydrogen atom donating molecules or singlet

oxygen quenchers; 2) reducing the capacity of metal to generate free radicals via chelation

of transition metal ions; and 3) inhibiting the consumption of antioxidants such as á-toco-

pherol in the LDL particles.


XANTHONES 95

Inhibition of Inflammatory Response

Myocardial reperfusion injury has recently been considered to involve a type of inflam-

matory response, and myocardial infarction has been associated with the coordinated acti-

vation of a series of inflammatory responses, including complement activation, an in-

crease in the expression of cytokines and adhesion molecules, as well as neutrophil

infiltration and recruitment (21). The cytokine cascade in the infarcted myocardium is

triggered by a number of agents, including cytokines (such as TNF-á and IL-1â) and by

free radicals. It has been recently reported that mast cell is an important source of pre-

formed and newly synthesized cytokines, chemokines and growth factors, and that TNF-á,

released by degranulation of cardiac mast cell following myocardial ischemia, may be an

upstream cytokine responsible for initiation of the inflammatory cascade (20). Elevation

of inflammation factors and increase of vascular permeability have been thought to play a

crucial role in recruiting neutrophils in the ischemic and reperfused myocardium (43). Re-

cruited neutrophils exert potent cytotoxic effects through the release of proteolytic en-

zymes and the adhesion to the intercellular adhesion molecule-1 (ICAM-1) that is ex-

pressed in the endothelial cells and cardiomyocytes (43). It has been suggested that

adherence to CD11b�CD18-ICAM-1 activates the neutrophil respiratory burst, resulting

in a highly compartmented iron-dependent oxidative injury of cardiomyocytes (19).

Xanthones have been shown to have a strong antiinflammatory activity, such as inhi-

bition of allergy, decrease of histamine release and reduction of some prostanoids syn-

thesis via inhibition of cyclooxygenase (COX) activity (63,64,71). Norathyriol has antiin-

flammatory effects mediated partly through suppression of mast cell degranulation (51).

Moreover, it has been reported that norathyriol attenuates the increased permeability

of heart endothelial cells and the “respiratory burst” of neutrophils induced by some in-

flammatory agonists by inhibiting the activation of protein kinase C or phospholipase C

(29,47). Some synthetic xanthones have been shown to inhibit the increased expression of

ICAM-1 induced by TNF-á in cultured endothelial cells (58). More recently, we have

shown that, in isolated rat hearts subjected to 20 min of global ischemia, followed by

40 min of reperfusion, 3,4,5,6-tetrahydroxyxanthone attenuates the inhibition of cardiac

function, the increase in the release of CK in the coronary effluent, as well as the increased

levels of TNF-á in myocardium (16). The same compound also markedly decreased the

infarct size and the release of CK and TNF-á in myocardium induced by coronary artery

occlusion for 60 min, followed by 180 min of reperfusion in vivo (16). These results

suggest that the protective effects of xanthones in myocardial ischemia�reperfusion injury

may be related to inhibition of inflammatory response in myocardial infarction, especially

a reduction of TNF-á production.

The antiinflammatory roles of xanthones may also be of particular interest with respect

to atherosclerosis, which is being increasingly viewed as a disease with complex in-

flammatory responses (50). The earliest stages of atherogenesis are associated with the

enhanced expression of pro-inflammatory cytokines such as TNF-á. Numerous patho-

physiological phenomena may stimulate cytokine release, including ox-LDL, free rad-

icals, hemodynamic stress, hypertension, or infectious organisms. Many of the early athe-

rogenic processes, triggered by inflammatory cytokines, alter endothelial function,

enhance the expression of leukocyte adhesion molecules and chemokines, promote mono-

cyte and T-cell recruitment, and foster formation of monocyte- and smooth muscle cell-

derived foam cells.


96 JIANG DJ ET AL.

As mentioned above, xanthones significantly inhibit TNF-á-induced increase of

ICAM-1 expression in cultured endothelial cells (58). Our study showed that xanthones

significantly inhibit the increased adhesion of monocytes to endothelial cells and attenuate

the increased levels of TNF-á and monocyte chemoattractant protein (MCP-1) induced by

ox-LDL in cultured endothelial cells (36,39). Recently, it has been shown that mangiferin

decreases TNF-á mRNA levels in rat macrophages stimulated in vivo with 3% thiogly-

collate and in vitro with 100 ng�mL lipopolysaccharide (49). These antiinflammatory ef-

fects of xanthones may contribute to their protection against atherogenesis.

Inhibition of Platelet Aggregation and Antithrombotic Effects

Intravascular thrombosis is involved in the pathogenesis of several cardiovascular dis-

eases. The initiation of intraluminal thrombosis is believed to involve platelet adherence

and aggregation. In the normal circulation, platelets do not aggregate in the absence of

stimulation. When a blood vessel is damaged, platelets adhere to the disrupted surface and

then release several biologically active mediators such as platelet-activating factor (PAF)

that promotes platelet aggregation (61). Platelet aggregation plays probably a crucial role

in the development of an atherosclerotic lesion, unstable angina, or acute myocardial in-

farction (14,22).

The effects of natural or synthetic xanthones and xanthone derivatives on platelet ag-

gregation have been evaluated in washed rabbit platelets or human platelet-rich plasma.

Xanthones and xanthone derivatives inhibited platelet aggregation and ATP release in-

duced by a variety of agonists, including ADP, arachidonic acid, PAF, collagen, ionophore

A23187 and thrombin (10,52–54,56,69,79). The inhibitory effect of xanthones and xan-

thone derivatives on platelet aggregation may be related to the reduction of phosphoinosi-

tide breakdown and�or decrease of thromboxane formation via inhibition of COX

(10,52,69,79). Moreover, some xanthones block the PAF receptor and inhibit PAF binding

to rabbit platelets in vitro (32,33). Jacarelhyperols A and B, two new bisxanthones ex-

tracted from Hypericum japonicum, showed significant inhibitory effects against PAF-in-

duced hypotension (30). In vivo, at 30 min after intraperitoneal administration of norathy-

riol, tail-bleeding time of mice was markedly prolonged in a dose-dependent manner (78).

In endotoxin-induced experimental disseminated intravascular coagulation in rats, nor-

athyriol prevented the decrease in platelet counts and fibrinogen, and the prolongation of

plasma prothrombin time (78). However, norathyriol could not prevent acute thromboem-

bolic death in mice.

Vasorelaxant Actions

The vasorelaxant actions of several xanthones have been examined in rat thoracic aorta

(3,11,12,44). The norepinephrine (NE)- and high K+-induced vasoconstriction was in-

hibited concentration-dependently in aorta pretreated with xanthone or norathyriol

(11,44). This relaxant effect of xanthone and norathyriol persisted in endothelium-de-

nuded aorta, suggesting that the relaxation induced by xanthones is endothelium-inde-

pendent. The 45Ca2+ influx caused by either NE or high-K+ was inhibited by xanthone or

norathyriol in a concentration-dependent manner, suggesting that xanthones might act as

blockers of both receptor-operated and voltage-dependent Ca2+ channels. Moreover, the

relaxant effect of norathyriol was not antagonized by methylene blue or indomethacin.

These data suggested that the mechanism of xanthone-induced vasorelaxation might in-


XANTHONES 97

volve the block of Ca2+ channels. However, although xanthone caused an increase in the

levels of intracellular cyclic adenosine 3�,5�-monophosphate (cAMP) but not cyclic gua-

nosine 3�,5�-monophosphate (cGMP), norathyriol (at a high concentration of 400 ìM) in-

creased cGMP but not cAMP levels.

EFFECTS OF XANTHONES ON ENDOTHELIAL FUNCTION

AND ON THE LEVELS OF ENDOGENOUS NITRIC OXIDE

SYNTHASE INHIBITOR

Endothelial Dysfunction and Endogenous Nitric Oxide Synthase Inhibitors

It has been shown that endothelium-dependent vasodilation is attenuated in many risk

factors of atherosclerosis, such as hypercholesterolemia, hypertension, and diabetes melli-

tus, and endothelial dysfunction is recognized as an early event in the pathogenesis of

atherosclerosis (68). Nitric oxide (NO), synthesized from L-arginine by NO synthase

(NOS) in endothelial cells, has been thought to play a key role in the maintenance of vas-

cular tone and structure. NO possesses complex cardiovascular actions such as protection

of endothelial cells, decrease of the endothelial adhesiveness and inhibition of the adhe-

sion of monocytes to endothelial cells, and it is generally described as an “endogenous

anti-atherosclerotic molecule” (65).

Recently, it has been found that L-arginine analogs such as asymmetric dimethylargi-

nine (ADMA), which is present in the blood of both humans and animals, can inhibit NOS

in vivo and in vitro (81,82). ADMA has been shown to concentration-dependently inhibit

vasodilator responses to acetylcholine in isolated aortic rings, upregulate expression of

MCP-1 and enhance adhesion of monocytes in cultured endothelial cells (2,6). There is

growing evidence that endothelial dysfunction in some cardiovascular diseases, such as

hypercholesterolemia, heart failure and hypertension, is associated with elevation of

ADMA levels, and that its levels could predict endothelial dysfunction (15,74,80,86).

Xanthones Protect against Endothelial Dysfunction by Reducing

the Levels of Endogenous Nitric Oxide Synthase Inhibitors

Vasodilator responses to acetylcholine in rings of the isolated thoracic aorta have been

shown to be impaired in the presence of lysophosphatidylcholine (LPC), a major com-

ponent of ox-LDL. Daviditin A significantly attenuated inhibition of endothelium-de-

pendent relaxation by LPC (38). Previous observations and our recent studies have shown

that a single injection of native LDL causes a rapid accumulation and oxidation of LDL in

the arterial wall. This effect is followed by an acute inflammatory response, such as an in-

crease of ICAM-1 expression at 6 to 12 h after injection of LDL, which leads to endo-

thelial dysfunction concomitantly with an elevation of ADMA level (8,42). Pretreatment

with xanthones attenuated the endothelial dysfunction and the elevation of ADMA level

elicited by injection of LDL in vivo (37). Moreover, in cultured endothelial cells xan-

thones inhibited the increase in the release of LDH, the upregulation of MCP-1 expression

and the enhancement of monocytes adhesion concomitantly with a reduction of ADMA

levels (36,39). These findings suggest that xanthones protect against endothelial damage

induced by high-lipid levels, and that the protective effect of xanthones on the endo-

thelium is related to a reduction of ADMA concentration.


98 JIANG DJ ET AL.

Mechanism of the Inhibitory Effect of Xanthones on ADMA Levels

ADMA is synthesized by protein arginine methyltransferases (PRMTs), which utilize

S-adenosylmethionine as methyl group donor, and is degraded by dimethylarginine dime-

thylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethyl-

amine (7, 66). Two different isoforms of DDAH are known, DDAH-1 and DDAH-2.

DDAH-1 is typically found in tissues expressing neuronal NOS, whereas DDAH-2 pre-

dominates in tissues containing the endothelial isoform of NOS (48). There is evidence

that lipid-induced dysregulation of DDAH may be an important factor contributing to the

elevation of ADMA in hypercholesterelemia and hyperhomocysteinemia (5,75). Others

have reported that in cultured endothelial cells treated with ox-LDL or TNFá the elevated

content of ADMA is also related to the decreased activity of DDAH, but not to its protein

expression (31). DDAH has been thought to be an oxidant-sensitive enzyme that has

sulfhydryl groups in its structure. Though it is not yet understood in detail, oxidative stress

induced by lipid and�or inflammation factors may contribute to the decrease of DDAH

activity (4). Some antioxidants have been shown to attenuate homocysteine- or high glu-

cose-induced ADMA accumulation by reversing the decrease in DDAH activity (55,76).

Our results in cultured endothelial cells treated with LDL, ox-LDL or LPC also showed

that xanthones significantly decreased the level of ADMA concomitantly with an im-

provement in DDAH activity (36–39). As mentioned above, xanthones can significantly

attenuate the levels of lipid peroxides and of TNF-á induced by ox-LDL (36–39). These

findings suggest that xanthones-induced decreased level of ADMA is related to an in-

crease of DDAH activity due to inhibition of oxidative stress via antioxidant and�or anti-

inflammatory activities.

SUMMARY

There is substantial evidence to suggest that xanthones and xanthone derivatives may

be potentially useful as pharmacological agents in the treatment or prevention of cardio-

vascular diseases, including ischemic heart disease, atherosclerosis and hypertension. The

protective effects of xanthones in the cardiovascular system may be due to their antiox-

idant, anti-inflammatory, platelet aggregation inhibitory, antithrombotic and�or vasore-

laxant activities. In particular, the antagonism of endogenous NOS inhibitors by xanthones

may represent the basis for improved endothelial function and for reduction of events as-

sociated with atherosclerosis. However, the precise effects of xanthones need to be further

elucidated in animal experiments in vivo and in humans. Moreover, pharmacokinetics,

toxicity and structural optimization of xanthones should also be explored.

Acknowledgments. This study was supported by a grant from the Provincial Natural Science

Foundation of Hunan, China, No. 02jjy2046.

REFERENCES

1. Ajstura J, Cheng W, Reiss K, et al. Apoptosis and necrotic myocyte cell deaths are independent contributing

variables of infarct size in rats. Lab Invest 1996;74:86–107.

2. Azuma H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors

for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharma-

col 1995;115:1001–1004.


XANTHONES 99

3. Baragatti B, Calderone V, Testai L, Martinotti E, Chericoni S, Morelli I. Vasodilator activity of crude metha-

nolic extract of Gentiana kokiana Perr. et Song. (Gentianaceae). J Ethnopharmacol 2002;79:369–372.

4. Böger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardio-

vasc Res 2003;59:824–833.

5. Böger RH, Bode-Böger SM, Szuba A, et al. Asymmetric dimethylarginine: A novel risk factor for endo-

thelial dysfunction: Its role in hypercholesterolemia. Circulation 1998;98:1842–1847.

6. Böger RH, Bode-Böger SM, Tsao PS, Lin PS, Chan JR, Cooke JP. An endogenous inhibitor of nitric oxide

synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol 2000;36:2287–95.

7. Böger RH, Sydow K, Borlak J, et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylargi-

nine in human endothelial cells: Involvement of S-adenosylmethionine-dependent methyltransferases. Circ

Res 2000;87:99–105.

8. Calara F, Dimayuga P, Niemann A, et al. An animal model to study local oxidation of LDL and its biological

effects in the arterial wall. Arterioscler Thromb Vasc Biol 1998;18:884–893.

9. Chang CH, Lin CC, Hattori M, Namba T. Effects on anti-lipid peroxidation of Cudrania cochinchinensis

var. gerontogea. J Ethnopharmacol 1994;44:79–85.

10. Chen WY, Ko FN, Lin CN, Teng CM. The effect of 3-[2–(cyclopropylamino) ethoxy]xanthone on platelet

thromboxane formation. Thromb Res 1994;75:81–90.

11. Cheng YW, Kang JJ. Mechanism of vasorelaxation of thoracic aorta caused by xanthone. Eur J Pharmacol

1997;336:23–28.

12. Chericoni S, Testai L, Calderone V, et al. The xanthones: Gentiacaulein and gentiakochianin are responsible

for the vasodilator action of the roots of Gentiana kochiana. Planta Med 2003;69:770–772.

13. Chiang YM, Kuo YH, Oota S, Fukuyama Y. Xanthones and benzophenones from the sems of Garcinia

multiflora. J Nat Prod 2003;66:1070–1073.

14. Cohn PF. Role of antiplatelet agents in cardioprotection. Am J Manag Care 2002;8(Suppl 9):38–39.

15. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000;20:2032–2037.

16. Dai Z, Jiang DJ, Hu GY, et al. 3,4,5,6-tetrahydroxyxanthone protects against myocardial ischemia-reperfu-

sion injury in rats. Cardiovasc Drug Ther 2004; In press.

17. Das DK, Sato M, Ray PS, et al. Cardioprotection of red wine: Role of polyphenolic antioxidants. Drugs Exp

Clin Res 1999;25:115–120.

18. Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion

injury. Cardiovasc Res 2000;47:446–456.

19. Entman ML, Youker K, Shoji T, et al. Neutrophil induced oxidative injury of cardiac myocytes. A com-

partmented system requiring CD11b�CD18-ICAM-1 adherence. J Clin Invest 1992;4:1335–1345.

20. Frangogiannis NG, Lindsey ML, Michael LH, et al. Resident cardiac mast cells degranulate and release pre-

formed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia�reperfusion.

Circulation 1998;7:699–710.

21. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardio-

vasc Res 2002;53:31–47.

22. Gomes ME, Verheugt FW. Platelet aggregation inhibitors in prevention and treatment of coronary throm-

bosis. Neth J Med 2003;61:185–192.

23. He QH, He L, Xu SB, Deng Q. Effect of xanthone from Canscora lucidissima on cultured myocytes

anoxia-reoxygenation injuries. Zhong Yao Cai 2000;23:399–401.

24. He QH, Xu SB. Effects of canscora lucidissima xanthones on antioxidation in vitro. Chin Pharmacol Bull

1998;14:130–132.

25. He QH, Xu SB, Peng B. Mechanism of Canscora lucidissima xanthones against arrhythmia induced by

myocardial ischemia-reperfusion in rats. Zhongguo Zhong Yao Za Zhi 1998;23:556–557.

26. Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease

and cancer in the seven countries study. Arch Intern Med 1995;155:381–386.

27. Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D. Dietary antioxidant flavonoids and

risk of coronary heart disease: The Zutphen Elderly Study. Lancet 1993;342:1007–1011.

28. Hertog MGL, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease

and cancer in the seven countries study. Arch Intern Med 1995;155:381–386.

29. Hsu MF, Raung SL, Tsao LT, Lin CN, Wang JP. Examination of the inhibitory effect of norathyriol in for-

mylmethionyl-leucyl-phenylalanine-induced respiratory burst in rat neutrophils. Free Radic Biol Med

1997;23:1035–1045.

30. Ishiguro K, Nagata S, Oku H, Yamaki M. Bisxanthones from Hypericum japonicum: Inhibitors of PAF-in-

duced hypotension. Planta Med 2002;68:258–261.

31. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dys-

function: Dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99:3092–3095.


100 JIANG DJ ET AL.

32. Jantan I, Juriyati J, Warif NA. Inhibitory effects of xanthones on platelet activating factor receptor binding in

vitro. J Ethnopharmacol 2001;75:287–290.

33. Jantan I, Pisar MM, Idris MS, Taher M, Ali RM. In vitro inhibitory effect of rubraxanthone isolated from

Garcinia parvifolia on platelet-activating factor receptor binding. Planta Med 2002;68:1133–1134.

34. Jeroudi MO, Hartley CJ, Bolli R. Myocardial reperfusion injury: Role of oxygen radicals and potential

therapy with antioxidants. Am J Cardiol 1994;73:2B-7B.

35. Jialal I, Devaraj S. The role of oxidized low-density lipoprotein in atherogenesis. J Nutr 1996;126(Suppl 4):

1053S–1057S.

36. Jiang DJ, Hu GY, Jiang JL, Xiang HL, Deng HW, Li YJ. Relationship between protective effect of xanthone

on endothelial cells and endogenous nitric oxide synthase inhibitors. Bioorg Med Chem 2003;11:5171–5177.

37. Jiang DJ, Jiang JL, Zhu HQ, et al. Demethylbellidifolin preserves endothelial function by reduction of the

endogenous nitric oxide synthase inhibitor level. J Ethnopharmacol 2004; In press.

38. Jiang DJ, Jiang JL, Tan GS, Du YH, Xu KP, Li YJ. Protective effects of daviditin A against endothelial

damage induced by lysophosphatidylcholine. Naunyn Schmideberg’s Arch Pharmacol 2003;367:600–606.

39. Jiang DJ, Jiang JL, Tan GS, Huang ZZ, Deng HW, Li YJ. Demethylbellidifolin inhibits adhesion of mono-

cytes to endothelial cells via reduction of endogenous nitric oxide synthase inhibitor level. Planta Med 2003;

69:1150–1152.

40. Jiang DJ, Tan GS, Ye F, Du YH, Xu KP, Li YJ. Protective effects of xanthones against myocardial ische-

mia-reperfusion injury in rats. Acta Pharmacol Sin 2003;24:175–180.

41. Jiang DJ, Tan GS, Zhou ZH, Xu KP, Ye F, Li YJ. Protective effects of demethylbellidifolin on myocardial

ischemia-reperfusion injury in rats. Planta Med 2002;68:710–713.

42. Jiang JL, Li NS, Li YJ, Deng HW. Probucol preserves endothelial function by reduction of the endogenous

nitric oxide synthase inhibitor level. Br J Pharmacol 2002;135:1175–1182.

43. Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury.

Cardiovasc Res 1999;43:860–878.

44. Ko FN, Lin CN, Liou SS, Huang TF, Teng CM. Vasorelaxation of rat thoracic aorta caused by norathyriol

isolated from Gentianaceae. Eur J Pharmacol 1991; 192:133–139.

45. Kumar D, Lou H, Singal PK. Oxidative stress and apoptosis in heart dysfunction. Herz 2002;27:662–668.

46. Lai L, Lin LC, Lin JH, Tsai TH. Pharmacokinetic study of free mangiferin in rats by microdialysis coupled

with microbore high-performance liquid chromatography and tandem mass spectrometry. J Chromatogr A

2003;987:367–374.

47. Lee HZ, Lin WC, Yeh FT, Lin CN, Wu CH. Decreased protein kinase C activation mediates inhibitory effect

of norathyriol on serotonin-mediated endothelial permeability. Eur J Pharmacol 1998;353:303–313.

48. Leiper JM, Santa Maria J, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohyd-

rolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999;

343:209–214.

49. Leiro JM, Alvarez E, Arranz JA, Siso IG, Orallo F. In vitro effects of mangiferin on superoxide concentra-

tions and expression of the inducible nitric oxide synthase, tumour necrosis factor-alpha and transforming

growth factor-beta genes. Biochem Pharmacol 2003;65:1361–1371.

50. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–874.

51. Lin CN, Chung MI, Liou SJ, Lee TH, Wang JP. Synthesis and anti-inflammatory effects of xanthone deriva-

tives. J Pharm Pharmacol 1996;48:532–538.

52. Lin CN, Hsieh HK, Liou SJ, et al. Synthesis and antithrombotic effect of xanthone derivatives. J Pharm

Pharmacol 1996;48:887–890.

53. Lin CN, Liou SS, Ko FN, Teng CM. Gamma-Pyrone compounds. IV: Synthesis and antiplatelet effects of

mono- and dioxygenated xanthones and xanthonoxypropanolamine. J Pharm Sci 1993;82:11–16.

54. Lin CN, Liou SS, Ko FN, Teng CM. Gamma-pyrone compounds. II: Synthesis and antiplatelet effects of te-

traoxygenated xanthones. J Pharm Sci 1992;81:1109–1112.

55. Lin KY, Ito A, Asagami T, Tsao PS, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: Role

of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002;106:

987–992.

56. Liou SS, Teng CM, Ko FN, Lin CN. Gamma-Pyrone compounds. 5. Synthesis and antiplatelet effects of

xanthonoxypropanolamines and related compounds. J Pharm Sci 1994;83:391–395.

57. Liu HS, Lin CN, Won SJ. Antitumor effect of 2,6-di(2,3-epoxypropoxy)xanthone on tumor cell lines. Anti-

cancer Res 1997;17:1107–1114.

58. Madan B, Singh I, Kumar A, et al. Xanthones as inhibitors of microsomal lipid peroxidation and TNF-alpha

induced ICAM-1 expression on human umbilical vein endothelial cells (HUVECs). Bioorg Med Chem

2002;10:3431–3436.

59. Mahabusarakam W, Proudfoot J, Taylor W, Croft K. Inhibition of lipoprotein oxidation by prenylated

xanthones derived from mangostin. Free Radic Res 2000;33:643–659.


XANTHONES 101

60. Marona H, Pekala E, Filipek B, Maciag D, Szneler E. Pharmacological properties of some aminoalkanolic

derivatives of xanthone. Pharmazie 2001;56:567–572.

61. Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathophysiology.

Physiol Rev 2000;80:1669–1699.

62. Muruganandan S, Gupta S, Kataria M, Lal J, Gupta PK. Mangiferin protects the streptozotocin-induced oxi-

dative damage to cardiac and renal tissues in rats. Toxicology 2002;176:165–173.

63. Nakatani K, Atsuml M, Arakawa T, et al. Inhibitions of histamine release and prostaglandin E2 synthesis by

mangosteen, a Thai medicinal plant. Biol Pharm Bull 2002;25:1137–1141.

64. Nakatani K, Nakahata N, Arakawa T, Yasuda H, Ohizumi Y. Inhibition of cyclooxygenase and prostaglandin

E2 synthesis by gamma-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. Biochem

Pharmacol 2002;63:73–79.

65. Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric Oxide 2001;5:88–97.

66. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalysing the direct conversion of Ng,Ng-di-

methyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun 1987;148:671–677.

67. Peres V, Nagem TJ, De Oliveira FF. Tetraoxygenated naturally occurring xanthones. Phytochemistry 2000;

55:683–710.

68. Poredos P. Endothelial dysfunction in the pathogenesis of atherosclerosis. Int Angiol 2002;21:109–116.

69. Rajtar G, Zolkowska D, Kleinrok Z, Marona H. Antiplatelets activity of some xanthone derivatives. Acta Pol

Pharm 1999;56:319–324.

70. Rimm EB, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Relation between intake of flavonoids and

risk for coronary heart disease in male health professionals. Ann Intern Med 1996;125:384–389.

71. Sayah M, Cechinel-Filho V, Pinheiro TR, Yunes RA, Calixto JB. In vitro effect of the extract and the 1,7-di-

hydroxy-2,3-dimethoxyxanthone from Polygala cyparissias on the contractions induced by inflammatory

mediators and ovalbumin in normal and actively sensitised trachea from guinea pig. Inflamm Res 1999;48:

218–223.

72. Seo EK, Kim NC, Wani MC, et al. Cytotoxic prenylated xanthones and the unusual compounds anthraquino-

benzophenones from Cratoxylum sumatranum. J Nat Prod 2002;65:299–305.

73. Shen JG, Quo XS, Jiang B, Li M, Xin W, Zhao BL. Chinonin, a novel drug against cardiomyocyte apoptosis

induced by hypoxia and reoxygenation. Biochim Biophys Acta 2000;1500:217–226.

74. Surdacki A, Nowicki M, Sandmann J. Reduced urinary excretion of nitric oxide metabolites and increased

plasma levels of asymmetrical dimethylarginine in men with essential hypertension. J Cardiovasc Pharma-

col 1999;33:652–658.

75. Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide

synthase pathway: Role of asymmetric dimethylarginine. Circulation 2001;104:2569–2575.

76. Stuhlinger MC, Tsao PS, Kimoto M, Cooke JP. Homocysteine induced accumulation of asymmetric

dimethylarginine: Role of DDAH and effect of antioxidants. Circulation 2000;102(Suppl):AI-177.

77. Tan GS, Xu KP, Xu PS, Hu GY, Li YJ. Studies of the chemical constituents of Swertia davidi Franch. Yao

Xue Xue Bao 2002;37:630–632.

78. Teng CM, Ko FN, Wang JP, et al. Antihaemostatic and antithrombotic effect of some antiplatelet agents iso-

lated from Chinese herbs. J Pharm Pharmacol 1991;43:667–669.

79. Teng CM, Lin CN, Ko FN, Cheng KL, Huang TF. Novel inhibitory actions on platelet thromboxane and ino-

sitolphosphate formation by xanthones and their glycosides. Biochem Pharmacol 1989;38:3791–3795.

80. Usui M, Matsuoka H, Miyazaki H, et al. Increased endogenous nitric oxide synthase inhibitor in patients

with congestive heart failure. Life Sci 1998;62:2425–2430.

81. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of NO syn-

thesis in chronic renal failure. Lancet 1992;339:572–575.

82. Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous dimethylarginine as an inhibitor of nitric

oxide synthesis. J Cardiovasc Pharmacol 1992;20(Suppl 12):S60–S62.

83. Wang LW, Kang JJ, Chen IJ, Teng CM, Lin CN. Antihypertensive and vasorelaxing activities of synthetic

xanthone derivatives. Bioorg Med Chem 2002;10:567–572.

84. Williams P, Ongsakul M, Proudfoot J, Croft K, Beilin L. Mangostin inhibits the oxidative modification of

human low density lipoprotein. Free Radic Res 1995;23:175–184.

85. Yang DM and Xu SB. The primary studies of Canscora lucidissima xanthones on anti-inflammation and

toxicity. Acad J GuangDong Coll Pharm 2001;7:33–35.

86. Yu XJ, Li YJ, Xiong Y. Increase of an endogenous inhibitor of nitric oxide synthesis in serum of high choles-

terol fed rabbits. Life Sci 1994;54:753–758.

87. Zhao B, Shen J, Li M, Li M, Wan Q, Xin W. Scavenging effect of Chinonin on NO and oxygen free radicals

and its protective effect on the myocardium from the injury of ischemia-reperfusion. Biochim Biophys Acta

1996;1315:131–137.


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