International Journal of Cardiology 121 (2007) 9 – 22

www.elsevier.com/locate/ijcard

Review
Cardiovascular effects of Danshen
Tsung O. Cheng ⁎
Department of Medicine, The George Washington University Medical Center, 2150 Pennsylvania Avenue, N.W., Washington, D.C. 20037, United States
Received 25 January 2007; accepted 25 January 2007
Available online 23 March 2007

Abstract

Danshen is one of the most versatile Chinese herbal drugs that have been used for hundred of years in the treatment of numerous ailments.
Because of its properties of improving microcirculation, causing coronary vasodilatation, suppressing the formation of thromboxane,
inhibiting platelet adhesion and aggregation, and protecting against myocardial ischemia, it is widely used either alone or in combination with
other herbal ingredients for patients with coronary artery disease and other cardiovascular diseases, in both China and other countries
including the United States. This article provides an overview of its history, pharmacology, pharmacokinetics, clinical applications, side
effects, interactions with Western drugs, and future prospects in the management of cardiovascular diseases.
© 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Danshen; Salvia miltiorrhizae binge; Coronary artery disease; Hypertension; Arrhythmias; Stroke; Drug interactions; Ginseng; Traditional Chinese
medicine; Chromatography

Danshen ( ) is one of the most versatile Chinese herbal
drugs that have been used for hundred of years in the
treatment of numerous ailments including cardiovascular
diseases [1]. It is an extremely popular drug in China, either
on its own or often mixed with other herbs, where it has a
market that exceeded US$120 million in 2002 [2,3]. It has in
recent years also been widely used in the United States [4–
6]. This article provides an overview of its history, pharma-
cology, pharmacokinetics, clinical applications, side effects,
interactions with Western drugs, and future prospects in the
management of cardiovascular diseases.
1. History
Danshen is the dried root of Salvia miltiorrhizae that belongs
to the family of Labiatae [7]. Danshen has long been judged to
be highly effective in “activating circulation and dispersing
stasis or sludging of blood” [1,8–10]. Among the classic
teachings of traditional Chinese medicine, it is stated that “when
blockage is opened, pain is relieved; when blockage is not
opened, pain persists” ( ) [1,8]. This concept,
⁎ Tel.: +1 202 741 2426; fax: +1 202 741 2324.
E-mail address: tcheng@mfa.gwu.edu.
0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2007.01.004
of course, represents the modern ‘open artery hypothesis’
[11,12] in myocardial reperfusion strategies, be it pharmaco-
logical or mechanical, in the management of acute myocardial
infarction.
Yu, my schoolmate in St. John's Medical School,
University of Pennsylvania, Shanghai, China (now called the
Shanghai Second Medical University), began in 1971 the
earliest study of Danshen [1,8]. He found that oral
administration of crude powder or concoction of Danshen
was effective in the treatment of angina pectoris. Ampuls of
Danshen injected into animals produced similar favorable
results without untoward reactions. Finally, Yu himself
received an intravenous injection of the Danshen concoction,
the first instance of intravenous administration of a Chinese
herbal medicine in man [1,8]. The second intravenous
injection was administered to a junior house staff member,
who had frequent attacks of precordial distress accompanied
by T wave inversions in the precordial leads of his ECG.
Immediately after the Danshen injection, his symptoms
improved and the inverted T waves became isoelectric for
more than 8 h [1,8].
Subsequently, 11 patients with angina pectoris were
treated by intravenous injections of Danshen at the Shanghai
Third People's Hospital (which in October 1984 resumed the
10 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
former name of Ren Ji Hospital where I interned). All of
them noted symptomatic improvement within 24 h associ-
ated with T wave changes from inversion to upright or
isoelectric contour for 2–3 days [1,8]. The Shanghai Public
Health Bureau was much impressed by these findings and
called for further investigation of this drug. The Shanghai
Cooperative Group For Study of Danshen was organized in
1971 [13,14], and the supply of ampuls of Danshen
concoction for parenteral use was taken over by the 9th
Pharmaceutical Factory of Shanghai [1,8,15]. From 1972 to
1974, 311 patients with ischemic coronary heart disease were
treated with Danshen; 80% demonstrated symptomatic and
objective improvement and 50% electrocardiographic im-
provement [9]. These favorable results with Danshen
aroused great interest among the Chinese cardiologists and
led to extensive study of its action and subsequent
widespread clinical use [1,4–6,8].
2. Pharmacology
At the Shanghai Institute of Pharmacology, Academia
Sinica, many active constituents were found to exist in the
alcohol- and water-soluble extracts of Danshen [8,14,16].
The alcohol-soluble constituents, after being subjected to
aluminum oxide chromatography and re-crystallization from
methanol, yielded tanshinone I, tanshinone IIA and other
tanshinone derivatives. The water-soluble constituents con-
sisted chiefly of sodium-tanshinone IIA sulfonate, the
structural formula of which, prepared by the Shanghai
Institute of Pharmacology, is C19H17O6SNa with a molecular
weight of 396,391 (Fig. 1).
Whereas earlier studies have focused on the alcohol-
soluble constituents, more recent studies have concentrated
on hydrophilic compounds; at least 50 components have
been isolated and identified from the aqueous extracts of
Danshen [2]. Diterpene compounds are the main type of
lipophilic components from Danshen; more than 30 have
been separated and identified [2]. Phenolic acids are the main
type of hydrophilic components from Danshen; at least 15
have been separated and identified [2]. In addition to
diterpene compounds and phenolic acids, other compounds
include baicalin, β-sitosterol, ursolic acid and daucosterol
isolated from alcohol extract, and 5,3′-dihydroxy-7,4′-
dimethoxy flavanone isolated from ethyl acetate extract [2].
Fig. 1. Structural formula of sodium-tanshinone IIA sulfonate, a major
component of Danshen.
Microcirculation was observed in the nail fold of 22
coronary patients [16]. In 70%, blood flow velocity
increased after 22 weeks of Danshen concoction injection;
50% showed persistent and definite improvement, which
coincided with symptomatic and electrocardiographic T
wave improvement.
Blood rheology study showed significant improvement,
as demonstrated by reduced blood viscosity in 75% of the
patients, and reduced red blood cell electrophoresis in 93%
[16]. Another coincidental finding during observation of
blood rheologic change was the significant increase in the
number and size of new capillary networks [16]. Results of
the patients' vascular fragility tests became normal [16].
Danshen also causes coronary artery dilatation by
temporarily increasing coronary blood flow which effective-
ly improves cardiac function without increasing oxygen
consumption [16,17].
The tolerance to anoxia was much greater in Danshen
treated mice than in untreated ones [16,18]. Therefore,
Danshen was used in shock, epidemic hemorrhagic fever,
thrombolic vasculitis, and as an important adjuvant in
antibiotic treatment [16,18].
The protective effect of Danshen on myocardial ischemia
during cardiac arrest was studied during extracorporeal
circulation in 15 dogs by Zhu et al. [19]. “Protective infusion
solution” with glucose, KCl, MgCl2·6H2O, NaCl, and
CaCl2·H2O was given, immediately followed by ice packages
placed directly on the surface of the heart for rapid induction
of cardiac arrest, maintaining the temperature at 15 to 17 °C.
The ascending aorta was cross-clamped, and an infusion tube
was inserted at the root of the aorta. Dogs that had Danshen
concoction in the infusion showed no increase in serum
glutamic oxaloacetic transaminase content, indicating that
permeability of the myocardial cellular membrane was
fortified. Ultramicroscopic examination of specimens taken
4 h after ligation of the coronary arteries revealed that
mitochondrial damage in Danshen-infused dogs was much
less than that of dogs not receiving the infusion [19]. In a
group of 3 dogs that received CaCl2·2H2O at 11.60 mmol/l in
the protective solution without Danshen, the nucleus,
mitochondria and capillaries were severely damaged. How-
ever, one group of 4 dogs with Danshen and a similar
concentration of CaCl2·2H2O in the infusion solution
revealed only mild ultrastructural damage. Similar damage
to a mild degree was observed in dogs receiving CaCl2·2H2O
at only 2.04 mmol/l with Danshen concoction added into the
infusion solution. From the degree of damage observed, Zhu
et al. [19] concluded that Danshen exerted a protective action
on myocardial cells by blocking the influx of calcium ions
and combining the calcium into a nonionizing state at pH of
7.15 in the intracellular milieu. In the extracellular fluid
compartment where acidic metabolites accumulated during
extracorporeal circulation, calcium in a combined state was
dissociated and changed back into calcium ions. This
mechanism, in fact, protects the body from hypocalcemia.
Danshen is, therefore, a calcium antagonist. Its usefulness in
 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
treating angina pectoris (vide infra) might well be partly
attributed to this calcium antagonist action [19,20].
A recent study from Singapore [21] demonstrated for the
first time that rat hearts treated with purified S. miltior-
rhizae extract showed a much smaller size of experimental
myocardial infarction compared with saline. Another more
recent study from the same department [22] reported sig-
nificant postischemic contractile functional recovery. How-
ever, significant elevation in left ventricular end-diastolic
pressure indicative of left ventricular stiffening might
have resulted from the high dose used. The group planned
to conduct a further study on the potential therapeutic
value on prevention of ischemic heart disease with a lower
dose [22].
In a study of Danshen on the effect of release of the
vascular constricting factor of platelet, injection of a watery
extract of Danshen (10 mg/100 g of body weight) led to
suppression of the release of the vasoconstrictive factor in
rats [23]. Before injection of Danshen, 1 ml of the rat's
platelet-rich plasma and 0.1 mg/ml of adenosine 5′-
diphosphate (ADP) were dropped into the incubation fluid,
and a fresh rabbit aorta strip was placed in the solution
equivalent to 1 × 10− 7 of noradrenaline (NA). Contraction of
107 ± 26% occurred at 1 × 10− 7 NA for one and a half hours.
After Danshen injection the rat's platelet-rich plasma
induced a contraction of 38 ± 22% at 1 × 10− 7 NA for less
than 1 h. Comparing the two tests the p-value was highly
significant, being less than 0.01. On the basis of these
findings, Li et al. [23] concluded that Danshen suppressed
both the formation and the release of thromboxane A2. These
effects of Danshen, like those of persantine and aspirin, in
inhibiting prostaglandin synthesis and platelet adhesion and
aggregation, have also been demonstrated in patients with
diabetes [24].
3. Pharmacokinetics
In animal studies for both danshensu and tanshinone IIA,
which are the two major components in Danshen, they were
absorbed rapidly after oral administration [2]. In 1997, Zhao
et al. from Harbin, China [25] evaluated the pharmacoki-
netics of danshensu, one of the active components of
Danshen, by the simple high-performance liquid chromato-
graphic method. From the plasma concentration profile of
danshensu after its intravenous administration to rabbits,
they determined the half-life to be 32 min, mean residence
time to be 48 min, steady-state volume distribution to be
149 ml/kg, and total body clearance to be 3.13 ml/min/kg
[25]. Danshensu is the only compound that has been studied
in human subjects and has been found to be absorbed quickly
too [2].
The hydrolytic kinetics of lithospermic acid B, another
active component of S. miltiorrhizae, was recently studied in
China by using reversed-phase high-performance liquid
chromatography [26]. At least four degradation products
were identified: danshensu, protocatechuic aldehyde, lithos-
11
permic acid, and the isomer of lithospermic acid [26]. The
pharmacokinetics of lithospermic acid B was also investi-
gated in rats by Korean investigators [27]. Kim et al. [27],
using the Caco-2 cell monolayer system to evaluate the rate
of lithospermic acid B passage, showed low permeability
through the system and concluded that the low bioavailabil-
ity could be due to poor absorption and extensive
metabolism. The low bioavailability of lithospermic acid B
was independently confirmed by Japanese investigators [28]
who suggested that wide distribution of lithospermic acid B
besides poor absorption and extensive metabolism was also a
significant contributing factor.
It should be pointed out, however, that in all the reported
pharmacokinetic studies, the samples were obtained only
after administration of purified compounds or injections
[29]. Because most traditional Chinese medicines, including
Danshen, are administered as extracted powder or decoctions
and often in combination with other herbal drugs that may
contain multiple active substances [30], the reported
pharmacokinetics could not be used as a suitable reference
for clinical applications [29].
4. Clinical applications
4.1. Coronary artery disease
The most important and frequent clinical application of
Danshen is for various manifestations of coronary artery
disease, including angina pectoris, coronary artery spasm,
myocardial infarction, and use following percutaneous coro-
nary interventions.
4.1.1. Angina
Among all the herbal drugs, Danshen is the commonest for
treatment of angina in China [31]. Because of its properties of
improving microcirculation, causing coronary vasodilatation,
inhibiting platelet adhesion and aggregation, protecting
against myocardial ischemia, and suppressing the formation
of thromboxane [1,8], Danshen is widely used either alone or
in combination with other herbal ingredients for patients with
angina due to coronary artery disease. Its efficacy has been
recently confirmed by a systematic assessment on random-
ized controlled trials [32], by a clinical non-inferiority trial
[33], and by a meta-analysis [34]. The meta-analysis
suggested that Danshen is more effective than nitrates in
the improvement of anginal symptoms and also ECG tests
[34]. Danshen is also more suitable than isosorbide dinitrate
in long-term treatment for angina, based on Seattle Angina
Questionnaire scale and treadmill exercise test [35].
4.1.2. Coronary artery spasm
Although most patients with angina have severe athero-
sclerotic obstruction of their coronary arteries, some have
superimposed spasm of the diseased coronary arteries
causing Prinzmetal's variant angina [36]. Some of the
patients with angina may have normal coronary arteries on
12 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
coronary arteriograms but develop spasm [37–39] resulting
in a variant of the variant angina [40]. Because Danshen has
calcium antagonistic properties (vide supra), it is also
effective in relieving angina due to coronary artery spasm,
as with several other traditional Chinese aromatic and warm
herbal medicines [41].
4.1.3. Myocardial infarction
As mentioned earlier, Danshen is an important traditional
Chinese herbal medicine that is useful as a part of reper-
fusion strategies in acute myocardial infarction [1,8]. It im-
proves the opening and formation of coronary collateral
circulation and thus protects the myocardium in experimen-
tal myocardial infarction in both dogs [42] and rats [43].
Danshen has at least four beneficial effects in patients with
myocardial infarction: sedative effect, antioxidant effect,
antiplatelet effect, and improvement of coronary microcir-
culation [43]. Its cardioprotective effects in reducing the
infarct size and mortality in rats are comparable to ramipril
[43]. Its effect in improving cardiac function is comparable
to captopril in rats that developed congestive heart failure
following acute myocardial infarction [44].
4.1.4. Percutaneous coronary interventions
Geng et al. [45] studied 38 patients with acute myocardial
infarction who underwent percutaneous coronary interven-
tions. Serum levels of malondialdehyde, superoxide dis-
mutase, interleukin 6 and tumor necrosis factor alpha in
patients' venous blood were measured at different time-
points, and the integrated left ventricular ejection isometric
index was determined by echocardiogram. They found that
Danshen significantly reduced the myocardial reperfusion
injury in patients with acute myocardial infarction after
percutaneous coronary interventions [45]. Li et al. [46] found
that tanshinone, an important component of Danshen,
effectively inhibits intimal hyperplasia in mouse's carotids
and thus may play a positive role in the prevention of
restenosis after percutaneous coronary interventions.
4.2. Hyperlipidemia
4.2.1. Hypercholesterolemia
Elevated plasma cholesterol levels, especially the low-
density lipoprotein (LDL) cholesterol, predispose to coro-
nary atherosclerosis. Oxidation of LDL is related to oxygen
free radicals; oxidized LDL is involved in the development
of atherosclerosis. Both salvianolic acid A [47] and
magnesium tanshinoate B [48], two active compounds in
Danshen, inhibit LDL oxidation, resulting in a decrease in
the uptake of LDL by the macrophages [48]. Such an effect is
therapeutically relevant in protecting cells from lipid
peroxidation in vascular disorders [48]. Yang et al. [49] in
a study of 96 elderly patients with hyperlipidemia reported
that, in addition to reduction of plasma total cholesterol and
LDL, Danshen also causes a reduction in the ratio of
thromboxane B2 to 6-keto-prostaglandin F1 alpha, D-dimer
and fibrinogen, and thus improves the blood coagulation
system as well as the various endothelial functions.
4.2.2. Hypertriglyceridemia
The preventive mechanism of Danshen against experi-
mental atherosclerosis in rabbits was studied by Li and Wan
[50]. The experimental rabbit models were reproduced by
feeding high cholesterol diet. They showed that the level of
serum triglycerides in Danshen treated rabbits was signifi-
cantly lower than in the control group (p b 0.01).
4.2.3. Hyperhomocysteinemia
Hyperhomocysteinemia is an independent risk factor for
coronary artery disease [51–58]. Chan et al. [59] studied the
protective effect of Danshen against the homocysteine-
induced adverse effect on human umbilical vein endothelial
cell. They found that homocysteine not only decreased the
cell viability but also caused the disruption of capillary-like
structure formation in vitro. The protective effect of Danshen
on endothelial cell function was demonstrated through an in
vitro tube formation assay, which mimics the new blood
vessel formation. They showed that Danshen was effective in
protecting human umbilical vein endothelial cell against
homocysteine-induced injury [59].
4.3. Hypertension
Danshen has been traditionally used for treatment of
hypertension in China, Korea and Japan [60]. Its antihyper-
tensive effect is mediated through the inhibition of an
angiotensin converting enzyme, an essential regulatory
enzyme of the renin–angiotensin system [60–63]. The two
components of Danshen responsible for its antihypertensive
effect are lithospermic acid B [60] and salvianolic acid B
[62]. A recent study concluded that lithospermic acid B and
salvianolic acid B are actually the same compound with
identical chemical structures except for the configurational
assignment of the stereocenters [64].
Another antihypertensive mechanism of Danshen is its
salutary property on the rheology of erythrocytes. Cheng
et al. [65] studied 75 hypertensive patients and determined
their erythrocyte deformability and aggregation by laser
diffractometry before and after treatment with Danshen.
They found that deformability of erythrocyte was increased,
the aggregation of erythrocyte and the whole blood viscosity
were reduced, and the blood pressure was reduced. Yu et al.
[66] studied the speed of blood flow in canine mesenteric
microvasculature by Doppler's effect of laser light and found
that Danshen increased 2,3 diphosphoglyceride of red blood
cells, thus allowing red blood cells to change their shape
readily during passage through microvessels whose caliber
was smaller than the diameter of the red blood cells. Yu et al.
[66] suggested that this rheologic explanation also holds true
for Danshen's action in angina.
Danshen has also been successfully used as a comple-
mentary therapy for pregnancy-induced hypertension [67].
 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
Wang and Zhao [67] studied 60 patients and, after 10 days of
intravenous Danshen infusion, found significant reduction of
the patients' blood pressures along with obvious reduction of
blood viscosity, cholesterol and lipoprotein.
Chronic treatment with Danshen could prevent left
ventricular hypertrophy in spontaneously hypertensive rats
by inhibiting collagen composition in the left ventricle [68].
Han et al. [68] postulated the mechanism to be inhibition of
the cardiac aldosterone action. Danshen also is an effective
inhibitor of angiotensin II action and has been shown to
suppress angiotensin II-induced myocardial hypertrophy in
neonatal rats [69]. Haber et al. [70] showed that intracor-
onary angiotensin II-converting enzyme inhibition improves
diastolic function in patients with hypertensive left ventric-
ular hypertrophy and the improvement in active relaxation
is directly proportional to the severity of left ventricular
hypertrophy.
4.4. Arrhythmias
In a recent study of 120 elderly patients with unstable
angina from Shenyang, China, Danshen reduced the inci-
dence of arrhythmias from 30% to 18% [71].
Danshen has also been used in treating vasovagal
syncope; in 117 patients Danshen converted a positive tilt
table test to negative in 62.2% as compared with 14.7% in
control subjects (p b 0.01) [72].
The recent report by Fish et al. [73] that dimethyl
lithospermate B, an extract of Danshen, slows inactivation
of sodium current, leading to increased inward current during
the early phases of the action potential, suggests that this
action would suppress arrhythmogenesis associated with the
Brugada syndrome. The latter is a familial disease character-
ized by a unique pattern of ST-segment elevation in the right
precordial leads and episodes of syncope and sudden cardiac
death [74]. Until now, implantation of an ICD is the mainstay
of treatment [75,76]. Danshen may be a pharmacological
alternative to device therapy [73].
4.5. Stroke
Danshen has been used as a standard treatment for
cerebrovascular diseases, including stroke, in China, based
on both experimental [31,77,78] and clinical data [31,79,80].
However, systematic reviews on randomized controlled trials
failed to support its efficacy in disability improvement after
ischemic stroke [81,82]. It is possible that the benefits of
Danshen in stroke may sometimes be negated or outweighed
by the high bleeding complications from its antiplatelet
effect (vide supra).
4.6. Peripheral vascular disease
Danshen can improve patients' peripheral circulation
[41]. Lam et al. [83] investigated Danshen's dilating action
on rat isolated femoral artery and found that the dilating
13
action was mediated in part by the opening of tetraethy-
lammonium-sensitive K+ channels in the smooth muscle
cells. The same investigators [84] more recently studied the
mechanism of the vasorelaxant effect of Danshen in rat knee
joints and found that the knee joint blood vessels are more
sensitive to the relaxant effect of Danshen compared to blood
vessels in the general circulation. They demonstrated that
Danshen's vasorelaxant effect was partly mediated by a
calcitonin gene-related peptide released from sensory nerves,
and nitric oxide and prostaglandins also played a part [84].
Lam et al. [83,84] found no evidence to support a role for
muscarinic receptors, β-adrenoceptors or histamine recep-
tors in either rat isolated femoral artery or rat knee joint
blood vessels.
4.7. Pulmonary vascular disease
An abnormal expression of inducible heme oxygenase-1
(HO-1) and nitric oxide synthase (NOS) plays an important
role in hypoxia-induced pulmonary hypertension in rats
[85]. Danshen inhibits the increase of HO-1 and inducible
NOS and recovers their normal vasodilatation mechanism
[85]. Its action is thus similar to that of diltiazem which is
an oral calcium antagonist used in the treatment of primary
pulmonary hypertension [85]. Danshen decreases platelet
malondialdehyde levels in induced pulmonary thromboem-
bolism in mice, inhibits platelet aggregation, and increases
the activity of superoxide dismutase in platelets, thus
providing protection against pulmonary thromboembolism
[86].
Danshen can also increase right ventricular myocardial
contractility and reduce the afterload of the right ventricle
[8]. Using the method of systolic time intervals, Zhou et al.
[87] studied 26 patients with chronic cor pulmonale before
and after intravenous injection of Danshen. Right ventric-
ular function and blood rheology improved significantly as
follows: pre-ejection period (PEP) time was reduced from
0.133 ± 0.018 s to 0.118 ± 0.017 s; right ventricular ejection
time increased from 0.292 ± 0.019 s to 0.324 ± 0.020 s; and
PEP/RVET ratio decreased from 0.460 ± 0.083 to 0.395 ±
0.084. Whole blood viscosity and red blood corpuscle
electrophoresis were also significantly improved (p b 0.05).
The investigators concluded that a positive correlation
exists between PEP, whole blood viscosity and red blood
corpuscle electrophoresis, that the increase in whole blood
viscosity and hematocrit may increase the pulmonary
arterial pressure, and that Danshen by favorably influenc-
ing the PEP time, whole blood viscosity and red blood
corpuscle electrophoresis reduces the afterload of the right
ventricle, thus improving right ventricular contraction [87].
There is a long history of using herbal medicine in China to
treat chronic obstructive pulmonary disease [88], which is the
commonest cause of chronic cor pulmonale. One randomized
controlled trial [89] tested Danshen against no treatment and
found a significant improvement in forced expiratory volume
in 1 s. However, a recent systematic review of randomized
14 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
controlled trials concluded that the evidence is scarce [88].
The authors of the article concluded that “Considering the
popularity of herbal medicine among chronic obstructive
pulmonary disease patients, vigorously designed studies seem
warranted” [88].
4.8. Renal diseases
Because cardiovascular disease is the leading cause of
death among patients with chronic renal disease [90] and the
prevalence of renal disease in patients with cardiovascular
disease, specifically coronary artery disease and congestive
heart failure, ranges between 30% and 60% [90], it is
important to know how Danshen affects the patients with
renal disease. There is increasing evidence that Danshen is
renoprotective [91]. Magnesium lithospermate B, a tetramer
of caffeic acid, significantly increased the glomerular
filtration rate in rats with adenine-induced renal failure
[92] and reversed the increase of blood urea nitrogen and
serum creatinine in rats with subtotal nephrectomy [93].
Lithospermic acid B isolated from Danshen ameliorates
renal defects in rats with ischemia–reperfusion induced acute
renal failure, most likely via scavenging of reactive oxygen
species [94].
Danshen has been shown to prevent the decline of
renal cortical Na–K-ATPase activity induced by ischemia
and gentamicin [95]. Because gentamicin has often been
used in the treatment of infective endocarditis and nephro-
toxicity of gentamicin is the main concern, the use of
Danshen as a renoprotective agent has important therapeu-
tic implications.
Danshen has a protective action on hypertensive renal
lesions [96]. Cao [96] in a comparative study of 57
hypertensive patients found the therapeutic effects of
acupoint-injection of Danshen better than nifedipine with
significant differences in 24-h urinary protein, urinary β2-
microglobulin and N-acetyl-beta-D-glucosaminidase after
treatment between the two groups (p b 0.01).
Danshen is helpful for recovery of renal function in the
early stage of renal transplantation [97]. Tan et al. [97]
treated 112 patients in the early stage after renal transplan-
tation with daily injections of Danshen for 10 days and
compared with 109 patients on conventional treatment. The
urinary volume and endogenous creatinine clearance rate in
the treated group were significantly higher, but levels of
serum creatinine, incidence of renal function recovery
retardation, blood viscosity, platelet aggregation rate and
blood flow resistance in graft were significantly lower than
those in the control group (p b 0.05).
Danshen plays an important role in the treatment of
primary nephrotic syndrome in children [98]. Bao et al. [98]
randomly divided 44 patients into 20 treated with conven-
tional steroids and 24 with additional Danshen injections; the
addition of Danshen could more effectively improve the
levels of plasma endothelium level and soluble interleukin-2
receptor level.
4.9. Diabetes
Diabetes is a major cardiovascular risk factor; in fact,
diabetes is as important to the cardiologists as it is to the
endocrinologists [99]. Vascular disease is a major compli-
cation of diabetes. Danshen improves the vascular disease in
diabetic patients by reducing the activity of platelet
membrane glycoproteins in a study of 82 patients [100],
increasing the endothelium-dependent vasodilatation and
endothelial tPA and NO release in a study of 32 patients
[101], and lowering the blood viscosity and acceleration of
motor and sensory nerve conduction velocity of medium
nerve in a study of 72 patients [102]. In the last mentioned
study, the improvement was more significant in the Danshen
treated than the Western medicine treated patients [102].
Danshen can protect rats with streptozotocin diabetes from
diabetic nephropathy by suppressing the overexpressions of
transforming growth factor-β1, connective tissue growth
factor, plasminogen activator inhibitor-1 and fibronectin in
renal cortex [103].
5. Side effects
According to Zhou et al. [2], no major side effects of
Danshen have been reported. Wide clinical experiences after
many years of use in China indicate that Danshen is extremely
safe.
In theory, because of its antihypertensive effect, Danshen
may cause symptomatic hypotension and dizziness. In
theory, a chemical found in Danshen called miltirone may
cause drowsiness [104]. Some patients may experience ab-
dominal discomfort [2,104,105], decreased appetite [2,104]
or itching [104,105]. Convulsions, mental changes and
dystonia syndrome have been reported [104].
6. Interactions
Although Danshen has no major side effects, it may
interact with other drugs and cause serious complications.
6.1. Warfarin
Danshen potentiates the anticoagulant action of warfarin
[4–6,106–114]. The effects of Danshen on the pharmaco-
dynamics and pharmacokinetics of warfarin were studied
in rats by Chan et al. [115]. Their results indicated that
Danshen increases the absorption rate constant, the area
under plasma concentration time curve, maximum concen-
trations and elimination of half-lives, but decreases the
clearances and apparent volume of distribution of warfarin
[115]. That Danshen causes decreased warfarin clearance
in patients was recently reiterated by Bullington and Naffi
[116].
Warfarin is a commonly used oral anticoagulant frequent-
ly prescribed for patients with atrial fibrillation, valvular heart
disease, coronary artery disease, congestive heart failure,
 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22 15

stroke, pulmonary embolism, peripheral vascular disease and
deep vein thrombosis. Because Danshen is the most widely
used herbal medicine for cardiac patients and warfarin is one
of the most commonly used cardiac drugs in Western
medicine, this interaction becomes a very important patient-
safety issue. Because Danshen may be administered not only
orally but in a nebulizer [117] or incorporated into some
Chinese brand cigarettes (Fig. 2) [4–6,8,110,118,119], some
patients may not be aware that they are taking Danshen. Thus
it is important for every cardiologist or internist to be aware of
the possibility of such drug interactions when excessive
bleeding, unsuspected prolongation or shortening of the
prothrombin time or International Normalized Ratio (INR) or
difficulty in regulating the warfarin dosage is encountered in
any patient on warfarin therapy who has otherwise been
under good anticoagulant control.
6.2. Digoxin
Danshen has been demonstrated to show digoxin-like
immunoreactivity in vitro [120]. When patients on digoxin
therapy also receive Danshen, their sera may display a
falsely elevated (positive interference) digoxin concentration
as measured by the fluorescence polarization immunoassay
for digoxin (Abbott Laboratories, Abbott Park, IL). More
interestingly, serum digoxin concentrations were falsely
lowered (negative interference) when measured by the
microparticle enzyme immunoassay, also marketed by
Abbott Laboratories [120]. Taking advantage of poor protein
binding of digoxin (25%) and high protein binding of
digoxin-like immunoreactive components of Danshen,
Wahed and Dasgupta [120] and Dasgupta [121] demonstrat-
ed that the positive and negative interferences of Danshen in
serum digoxin measurement can be eliminated by monitor-
ing the free digoxin concentration. On the other hand, the
EMIT 2000 (Dade Behring, Deerpark, IL) [122], Randox
(Randox Labs Ltd., Antrim, UK) [122], CLIA (Bayer Diag-
nostics, Tarrytown, NY) [122], Tina-quant (Roche Diag-
nostics) [123] and Synchron LX system (Beckman) [123]
immunoassays for digoxin showed no interference from
Danshen.
Most drugs are bound to serum proteins to a various
degree, and only unbound or free drug is pharmacologically
active [121]. Danshen is moderately to strongly bound to
proteins, mainly albumin [124]. Because protein binding of
Danshen is lower in uremic patients and patients with
elevated serum bilirubin and hypoalbuminemia, a signifi-
cantly higher percentage of a free fraction of Danshen is
observed in patients with advanced renal or liver disease
[124]. Digibind (Fab fragment of polyclonal antidigoxin
antibody; Burroughs Wellcome, Research Triangle Park,
NC) binds free digoxin-like immunoreactive components of
Danshen and thus has a potential application in neutralizing
the pharmacologically active free fractions of Danshen in
case of overdosage [125].
6.3. Salicylate
As mentioned above [124], Danshen is strongly bound to
proteins (50–70%) and albumin is the major serum protein
that binds Danshen [126]. Because salicylate, a widely used
over-the-counter medicine, is also strongly bound to
albumin, it can significantly decrease free Danshen con-
centrations [126]. On the other hand, Danshen can displace

Fig. 2. Danshen cigarettes advertisement (left lower) in the back cover of Chinese Journal of Integrated Traditional and Western Medicine. The caption in
Chinese described this special Danshen formula contained in the cigarettes as follows: “Whereas smoking ordinary cigarettes is injurious to the health, smoking
this specially medicated cigarettes can diminish the risk…. Dating from the Tang Dynasty, the ingredients contained in Danshen are capable of activating
circulation, dispersing stasis or sludging of blood, improving the circulation, and protecting against cardiac and cerebrovascular diseases, etc.”
16 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22

salicylate from protein binding, thereby increasing the free
salicylate concentration [126,127].
6.4. Diazepam
Danshen stimulates the enzyme activity of liver microsom-
al cytochrome P450 (CYP) in rats [128]. Thus, if Danshen is
administered with drugs that are substrates of CYP, such as
diazepam, the latter may be rapidly metabolized. Further
systematic studies are needed to reveal the mechanism of
stimulation and to identify the active compounds in Danshen
that affect the activity of CYP [128].
they are combined in the formulation of some patent
traditional Chinese medicine, e.g. the “Cardiotonic Pill”,
also known as Danshen Dripping Pill [134], or fu fang dan
shen di wan in Chinese ( ), in which Danshen and
Panax notoginseng, one variety of Ginseng [135], are com-
bined with borneol in a fixed ratio using modern techniques
of pharmaceutical preparation [136] (Fig. 5).
8. Future prospects
One third of all modern drugs are derived from herbs [137].
Typical examples are aspirin (from white willow and

6.5. Aminoglycosides

Danshen inhibits gentamicin-dependent lipid peroxida-

tion (formation of conjugated dienes from arachidonic acid)
as well as the gentamicin-catalyzed formation of superoxide
(in a lucigenin-based chemiluminescence assay) and hy-
droxyl radicals (oxidation of N,N-dimethyl-p-nitrosoaniline)
[129]. Because of the nephrotoxicity and ototoxicity, the use
of aminoglycosides, which are probably the most commonly
used antibiotics worldwide, has been largely replaced by
newer, less toxic, alternative antibiotics. In developing
countries, however, aminoglycosides remain the antibiotics
of choice, because of their efficacy, low cost, and easy
availability [129]. Danshen may serve as an inexpensive and
effective prophylactic agent against aminoglycoside-induced
nephrotoxicity and ototoxicity.

6.6. Alcohol

Danshen has been shown to reduce voluntary alcohol

intake in selectively bred Sardinian alcohol-preferring rats
[130]. It has been further shown that miltirone is the likely
active constituent of Danshen that is responsible [131]. Pure
miltirone reduces alcohol intake in alcohol-experienced rats,
delays acquisition of alcohol-drinking behavior in alcohol-
naive rats, hampers alcohol absorption from the gastrointes-
tinal tract, and does not affect the severity of alcohol with-
drawal syndrome in alcohol-dependent rats [131]. This
reducing effect of Danshen may not only serve as an effective
hangover remedy but also be a promising therapy against
alcoholism [132].

7. Danshen vs Ginseng

Danshen ( ) shares the same last name as Ginseng

( ).
Ginseng was also discovered by the Chinese and used as a
revitalizing agent and a sovereign remedy for almost all
diseases since time immemorial [133]. Because of their
identical last name, many Chinese take Danshen as if it is the
Fig. 3. A, Salvia miltiorrhizae Bunge (courtesy of Guangdong Science and
same as Ginseng. Except for superficial resemblance in Technology Press, Guangzhou, China). B, Danshen (courtesy of Fu Zhou
appearances of Danshen (Fig. 3) and Ginseng (Fig. 4), there Corona Science and Technology Development Co. Ltd., FuZhou, Fujian,
is little in common between the two. Sometimes, however, China. www.fzrm.com).
 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22
Fig. 4. Ginseng ( ). Note the semblance of a human face, thus the
Chinese name of meaning a person.
wintergreen leaves), atropine (from belladonna), digitalis
(from foxglove), ephedrine (from Ma Huang), reserpine
(from Rauwolfia serpentina), scopolamine (from Datura
fastuosa), taxol (from Taxus brevifolia), and vincristine
Fig. 5. A full page advertisement of Danshen in the December 2004 issue of
Chinese Journal of Cardiology, showing graphically how and why it is the
key to the “treatment of coronary heart disease and angina by virtue of its
properties of improving microcirculation, causing coronary vasodilatation,
suppressing thromboxane formation and lowering cholesterol levels in the
blood” (English translation of the Chinese text to which the key is pointed).
17
(from Catharanthus roseus) [138]. Some herbs have been
extensively studied such as aspirin, digitalis, and taxol, but
others have not. The contemporary problem with most of the
herbal drugs is that the exact chemistry and composition are
often not well known. Thus, their pharmacology and pharma-
cokinetics remain a mystery.
Although Danshen has been widely used not only in
China (officially listed in the Chinese pharmacopoeia [139])
but also around the world, its chemical composition is still
not fully understood. Modern research into Danshen had
continued in China for four decades [140]. Fingerprint
technique was introduced in early 1990s by the World Health
Organization as a powerful tool for identification and quality
control of multi-component herbal medicines [141]. With the
recent introduction of high-performance liquid chromato-
graphic technique of fingerprinting, it is now possible to
identify most of the components in Danshen. Recently Ma
et al. [142] and Liu et al. [143], using this new technique,
isolated and reported the identification of 25 (Fig. 6) and 34
components (Fig. 7A and B) of Danshen, respectively.
Undoubtedly, more and more different components will be
identified — more than 70 so far (Guo DA, personal com-
munication, September 25, 2006). These elegant chemical and
biological studies will continue to increase our understanding
about a scientific basis for the clinical use of Danshen and can
also contribute to the development of new drug candidates
[144].
The greatest hindrance to date to -the acceptance of
traditional Chinese medicine in the Western world is the
Fig. 6. Chemical structures of 7 main components of the 25 components
from Danshen (from Ref. [142] with permission).
18 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22

attitude toward the need for scientific evaluation [145]. For
advocates, if the treatment works, there is no necessity for
further evaluation. For skeptics, traditional Chinese medicine
is either a placebo or quackery, so evaluation is a waste of
time and money. Accurate identification of the various
components of Danshen as recently reported will go a long
way in advancing the validity and convincing the doubting
Thomases of the efficacy of Danshen in the treatment of not
only cardiovascular diseases but also other conditions
[143,144,146,147].
 T.O. Cheng / International Journal of Cardiology 121 (2007) 9–22 19

Fig. 7. A, The chemical structures of 34 components identified in Danshen: (1) danshensu; (2) procatechuic acid; (3) procatechualdehyde; (4) vanillic acid; (5)
caffeic acid; (6) ferulic acid; (7) salvianolic acid D; (8) salvianolic acid E, (9) rosmarimic acid; (10) lithospermic acid; (11) salvianolic acid B; (12) salvianolic
acid A; (13) tanshindiol C; (14) tanshindiol B; (15) salvianolic acid C; (16) tanshinone II-B; (17) praewa tanshinone A; (18) dihydrotanshinone I; (19)
methyltanshinonate; (20) cryptotanshinone; (21) tanshinone I, (22) dehydromiltirone; (23) tanshinone IIA; (24) salvianolic acid F; (25) salvianolic acid I; (26)
isosalvianolic acid B; (27) salvianolic acid L; (28) royleanone-4; (29) 7α-hydroxyallyl-royleanone; (30) trijuganone; (31) neocryptotanshinone; (32) trijuganone
A; (33) methylenetanshinone; (34) miltirone. B, The chromatograms of three Danshen preparations: standard compounds (A), Danshen crude drug (B) and
Fufang Danshen tablets (C). The number of each component peak corresponds to that in A. Both A and B, courtesy of Dr. De-An Guo, Shanghai Research Center
for TCM Modernization, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai and the
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.

Benjamin Franklin said in 1738 in Poor Richard's Almanac
that “Time is an herb that cures all diseases” [148]. Danshen
may be an herb that can cure almost all diseases, and more
patients with cardiovascular diseases around the world are
expected to receive Danshen therapy in the near future.
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