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Research regarding the potential cardio-vascular health enhancement activity of Hydrastis canadensis (goldenseal) and/or its active compounds berberine and hydrastine
This information has been complied in order to facilitate the research efforts of health care professionals and others. These statements have not been evaluated by the Food and Drug Administration and are not intended diagnose, treat, cure, prevent, mitigate, or prevent any disease. The information is presented with the latest publications first. This is an ongoing work so check back often as we will update these pages as more information becomes available. Also see the anti-parasitic and anti-diarrhea pages. Last Updated : 08/25/2008
Identification of medicinal plant goldenseal as a natural cholesterol-lowering agent: Mechanisms of actions and new modulators of LDL receptor expression.
Abidi P, Chen W, Kraemer FB, Li H, Liu J.
J Lipid Res. 2006 Aug 2;
Our previous studies have identified berberine (BBR), an alkaloid isolated
from Chinese herb Huanglian, as a unique cholesterol-lowering drug that
upregulates hepatic LDLR expression through a mechanism of mRNA
stabilization. Here we demonstrate that the root extract of goldenseal, a
BBR-containing medicinal plant, is highly effective in upregulation of liver
LDLR expression in HepG2 cells and in reducing plasma cholesterol and LDL-cholesterol
in hyperlipidemic hamsters with greater activities than the pure compound
BBR. By conducting bioassay driven semi-purifications we demonstrate that
the higher potency of goldenseal is achieved through concerted actions of
multiple bioactive compounds in addition to BBR. We identify canadine and
two other constituents of goldenseal as new upregulators of LDLR expression.
We further show that the activity of BBR on LDLR expression is attenuated by
MDR1-mediated efflux from liver cells, whereas canadine is resistant to
MDR1. This finding defines a molecular mechanism for the higher activity of
canadine than BBR. We also provide substantial evidence to show that
goldenseal contains natural MDR1 antagonist(s) that accentuate the
upregulatory effect of BBR on LDLR mRNA expression. These new findings
identify goldenseal as a natural LDL-cholesterol lowering agent and our
studies provide a molecular basis for the mechanisms of actions.
Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway.
Huang C, Zhang Y, Gong Z, Sheng X, Li Z, Zhang W, Qin Y.
Biochem Biophys Res Commun. 2006 Jul 28;
Berberine (BBR), a compound purified from Cortidis rhizoma, reduces serum
cholesterol, triglycerides, and LDL-cholesterol of hypercholesterolemic
patients and high fat diet fed animals, and increases hepatic LDLR mRNA and
protein levels through a post-transcriptional mechanism. BBR also enhances
the hypoglycemic action of insulin in diabetic animal models. Here, we show
that BBR inhibits the differentiation of 3T3-L1 preadipocytes induced by DM
and suppresses the mitotic clonal expansion of 3T3-L1 preadipocytes in a
time- and dose-dependent manner. Gene expression analysis and Western blot
analysis reveal that the BBR inhibits the mRNA and protein levels of
adipogenesis related transcription factors PPARgamma and C/EBPalpha and
their upstream regulator, C/EBPbeta. Reporter gene assays demonstrate that
the full-length PPARgamma and alpha transcription activities are inhibited
by BBR. Using real-time PCR, we have also found that the PPAR target genes
that are involved in adipocyte differentiation, such as aP2, CD36, ACO, LPL,
and other adipocyte markers, are suppressed by BBR. These studies suggest
that BBR works on multiple molecular targets as an inhibitor of PPARgamma
and alpha, and is a potential weight reducing, hypolipidemic, and
hypoglycemic drug.
Effects of berberine on diabetes induced by alloxan and a
high-fat/high-cholesterol diet in rats.
Tang LQ, Wei W, Chen LM, Liu S.
J Ethnopharmacol. 2006 May 2;
Berberine is the major active constituent of Rhizoma coptidis. The present
study was carried out to investigate the effect of berberine on diabetes in
rats and its possible mechanisms. Diabetes was induced by tail vein
injection with alloxan in Wistar rats. The amount of alloxan administered
was 55mg/kg. Diabetic rats were fed with a high-cholesterol diet. The
fasting blood glucose, total cholesterol (TC), triglyceride (TG) and low
density lipoprotein-cholesterol (LDL-c), high density
lipoprotein-cholesterol (HDL-c), nitric oxide (NO) levels in serum and
malondialdehyde (MDA),superoxide dismutase (SOD),glutathione peroxidase (GSH-px)
contents in heart tissue were assayed by spectrophotometry. Pancreas samples
collected after 3 weeks of alloxan treatment were stained with hematoxylin-eosin
(HE) and examined under a light microscope, and scored. Intragastric
administration of berberine (100 and 200mg/kg) significantly decreased
fasting blood glucose levels, serum content of TC, TG, LDL-c, and
effectively increased HDL-c, NO level in diabetic rats. Furthermore,
berberine treatment significantly blocked the increase of MDA, increased SOD
and GSH-px levels in diabetic rats. Histopathological scores showed that
berberine had restored the damage of pancreas tissues in rats with diabetes
mellitus. The results showed berberine significantly inhibited the
progression of diabetes induced by alloxan, and the inhibitory effect of
berberine on diabetes might be associated with its hypoglycemic effect,
modulating lipids metabolic effects and its ability to scavenge free
radical.
Inhibition of lipid synthesis through activation of AMP-kinase:
An additional mechanism for the hypolipidemic effects of Berberine.
Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y,
Issandou M.
J Lipid Res. 2006 Feb 28;
The alkaloid drug Berberine (BBR) was recently described to decrease plasma
cholesterol and triglycerides in hypercholesterolemic patients by increasing
expression of the hepatic LDL receptor. Using HepG2 human hepatoma cells, we
found that BBR inhibits cholesterol and triglyceride synthesis in a similar
fashion to the AMP-activated protein kinase (AMPK) activator,
5-aminoimidazole-4-carboxamide 1--ribofuranoside (AICAR). A significant
increase in AMPK phosphorylation as well as in AMPK activity was observed
when the cells were incubated with BBR. Activation of AMPK was also
demonstrated by measuring the phosphorylation of acetyl CoA carboxylase, a
substrate of AMPK, correlated with a subsequent increase in fatty acid
oxidation. All these effects were abolished by the mitogen-activated protein
kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters
with BBR decreased plasma LDL cholesterol and strongly reduced fat storage
in the liver. These findings indicate that BBR, in addition to
up-regulating the LDL receptor, inhibits lipid synthesis in human
hepatocytes through activation of AMPK. These effects could account for
the strong reduction of plasma triglycerides observed with this drug in
clinical trials.
Extracellular Signal-Regulated Kinase-Dependent
Stabilization of Hepatic Low-Density Lipoprotein Receptor mRNA by Herbal
Medicine Berberine
Abidi P. Zhou Y, Jaing JG, Liu J.
Arterioscler Thromb Vasc Biol.
2005 Aug 11;
OBJECTIVE: Our recent studies identified berberine (BBR) as a novel
cholesterol-lowering drug that upregulates low-density lipoprotein (LDL)
receptor expression through mRNA stabilization. Here, we investigated
mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR)
messenger. METHODS AND RESULTS: We show that the extracellular
signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to
attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter
constructs, we demonstrate that BBR affects LDLR mRNA stability entirely
through 3' untranslated region (UTR) in an ERK-dependent manner, and this
stabilizing effect is more prominent in liver-derived cells than nonhepatic
cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid
CDCA is mediated through the LDLR coding sequence, whereas the 5'UTR, 3'UTR,
and the coding sequence of LDLR mRNA are all implicated in the action of
phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE,
we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind
to the LDLR 3'UTR in BBR-inducible and ERK-dependent manners. CONCLUSIONS:
These new findings demonstrate that the BBR-induced stabilization of LDLR
mRNA is mediated by the ERK signaling pathway through interactions of cis-regulatory
sequences of 3'UTR and mRNA binding proteins that are downstream effectors
of this signaling cascade.
Berberine--a novel approach to cholesterol lowering.
Doggrel, S.A.
Expert Opin Investig Drugs. 2005
May;14(5):683-5.
Although low-density lipoprotein (LDL)-cholesterol lowering with the statins
reduces the mortality and morbidity associated with coronary artery disease,
considerable mortality and morbidity remains. Berberine upregulates the LDL
receptor (LDLR) by a mechanism distinct from that of the statins, which
involves stabilising the LDLR mRNA. In hamsters fed a high-fat and
high-cholesterol diet for 2 weeks, the oral administration of berberine 100
mg/kg for 10 days reduced total serum cholesterol from approximately 4.8 to
2.7 mmol/l, and LDL-cholesterol from approximately 2.5 to 1.4 mmol/l. In
subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d.
for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any
effect on high-density lipoprotein-cholesterol. Berberine also caused a
reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and
statins both upregulate LDLR, their lipid-lowering profiles are similar.
Thus, this mechanism is unlikely to make berberine an attractive alternative
to statins for lipid lowering in most circumstances. However, the other
effects of berberine (antihypertensive, inotropic and class III
antiarrhythmic properties) may make it a useful agent in the treatment of
cardiovascular disease.
Protective effect of berberine on cardiac hypertrophy induced by L-thyroxine in rats.
Yang J, Zhou ZY, Xu JG.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2004 Mar;35(2):223-5.
OBJECTIVE: To assess the effects of berberine on cardiac hypertrophy induceded by L-thyroxine(L-Thy) in rats. METHODS: A cardiac hypertrophy model was produced by intraperitoneal (i.p.) injection of L-thyroxine 0.5 mg/(kg.d) x 10 d. 24 SD rats were divided into three groups: 1. control (normal saline); 2. L-Thy; 3. i.p. L-Thy + berberine gastrogavage 30 mg/(kg.d) x 10 d. Then the cardiac indexes, Na(+)-K(+)-ATPase activity, Ca(2+)-ATPase activity, the cardiac nitric oxide (NO) content, and the CaN activity were measured. RESULTS: Compared with the measurements in the control group, the cardiac indexes and the CaN activity were remarkably increased in the hypertrophy group (P < 0.01), but the cardiac NO content, Na(+)-K(+)-ATPase activity and Ca(2+)-ATPase activity in myocardium were significantly decreased (P < 0.01). Further comparison between the hypertrophy group and the L-Thy + berberine group showed that berberine 30 mg/(kg.d) x 10 d prevented the ventricular hypertrophy induced by L-Thy and decreased the cardiac indexes and CaN activity (P < 0.01); berberine elevated the cardiac NO content, Na(+)-K(+)-ATPase activity and Ca(2+)-ATPase activity (P < 0.01). CONCLUSION: Berberine can prevent the cardiac hypertrophy induced by L-thyroxine in rats.
Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
Zeng XH, Zeng XJ, Li YY.
Am J Cardiol. 2003 Jul 15;92(2):173-6.
This study was designed to assess the efficacy and safety of berberine for chronic congestive heart failure (CHF). One hundred fifty-six patients with CHF and >90 ventricular premature complexes (VPCs) and/or nonsustained ventricular tachycardia (VT) on 24-hour Holter monitoring were randomly divided into 2 groups. All patients were given conventional therapy for CHF, consisting of angiotensin-converting enzyme inhibitors, digoxin, diuretics, and nitrates. Patients in the treatment group (n = 79) were also given berberine 1.2 to 2.0 g/day. The remaining 77 patients were given placebo. Symptoms, a 6-minute walk test, left ventricular (LV) ejection fraction (EF), frequency and complexity of VPCs, and quality of life were assessed after 8 weeks of treatment and during a mean 24-month follow-up. After treatment with berberine, there was a significantly greater increase in LVEF, exercise capacity, improvement of the dyspnea-fatigue index, and a decrease of frequency and complexity of VPCs compared with the control group. There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up (7 patients receiving treatment died vs 13 on placebo, p <0.02). Proarrhythmia was not observed, and there were no apparent side effects. Thus, berberine improved quality of life and decreased VPCs and mortality in patients with CHF.
Protective effect of berberine on cardiac myocyte injured
by ischemia-reperfusion
Zheng L, Zhou Z, Tao D, Lan T.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2003 Jul;34(3):452-4.
OBJECTIVE: To observe the protective effect of berberine on cardiac myocyte injured by ischemia-reperfusion(I/R) in neonatal rats. METHODS: Cardiac myocytes from neonatal SD rat were cultured and pretreated with berberine in three different concentrations, 1.5 x 10(-6) mol/L, 1.5 x 10(-5) mol/L and 1.5 x 10(-4) mol/L, before exposure to hypoxia (95% N2-5% CO2) for 24 h and reoxygenation (95% air-5% CO2) for 1 h to create cell model of ischemia-reperfusion. Then lactate dehydrogenase (LDH) release, methylenedioxyamphetamine (MDA) release superoxide dismutase (SOD) activity were measured, and cell apoptosis was detected. RESULTS: Compared with the measurements taken in normal group, the LDH and MDA in the supernatant of the cells in ischemia and reperfusion group increased highly (P < 0.01), SOD activity decreased sharply (P < 0.01), and apoptosis of cells in ischemia groups and reperfusion groups increased highly (P < 0.01). Pretreatment of myocytes with berberine resulted in reduction in LDH and MDA release (P < 0.01) in I/R groups, attenuation of apoptosis in ischemia and reperfusion groups (P < 0.01). When the concentration of berberine was increased, these effects were getting obvious. Especially when the myocytes were pretreated with berberine at 1.5 x 10(-5) mmol/L, the cell apoptosis rates were 14.4% and 20% in ischemia group and reperfusion group, which were lower than the rates of 17.4% and 41% before pretreatment, respectively. CONCLUSION: Berberine alleviates I/R injury and attenuates apoptosis in myocytes exposed to I/R. These effects partly depend on the concentration of berberine.
Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy.
Hong Y, Hui SS, Chan BT, Hou J.
Life Sci. 2003 Apr 18;72(22):2499-507.
The aim of this study is to investigate the effect of berberine on catecholamine level (adrenaline and noradrenaline) in rats with experimental cardiac hypertrophy. Cardiac hypertrophy(CH) was induced by suprarenal abdominal aorta constriction, and the drugs were administered for 8 weeks starting from 4 weeks after surgery. The degree of cardiac hypertrophy was determined by heart and left ventricular weight. The level of adrenaline(AD) and noradrenaline(NA) was detected by HPLC. The data showed that in the CH model rats, the level of plasma and left ventricular tissue AD, and the level of NA in plasma were higher than that of the age-matched controls(indicating increased "total" sympathetic activity). The level of NA in left ventricular tissue of CH model rats was however lower than the age-matched controls. Berberine and captopril showed significant effect on inhibiting the development of cardiac hypertrophy. Berberine decreased plasma NA level and the AD level both in plasma and left ventricular tissue, but had no effect on improving the cardiac NA depletion. Captopril showed significant effect on increasing the depleted cardiac NA and in reducing the elevated plasma NA level. These findings show the efficacy of berberine on modulating the sympathetic nervous activity of rats with experimental cardiac hypertrophy, and reflect the therapeutic potentials of berberine in patients with cardiac hypertrophy and chronic heart failure.
Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels.
Kang DG, Sohn EJ, Kwon EK, Han JH, Oh H, Lee HS.
Vascul Pharmacol. 2002 Dec;39(6):281-6.
The present study was designed to examine the relaxant and anticonstrictive effects of berberine in the isolated thoracic aorta in rats. Intravenous injection of berberine lowered the mean arterial pressure (MAP) of anesthesized rats in a dose-dependent manner. The angiotensin-converting enzyme (ACE) activities were inhibited significantly by the addition of berberine in a dose-dependent manner of which the IC50 value of berberine for ACE was 42 micrograms/ml (125 microM). In the endothelium-intact rings, angiotensin I-induced contraction was markedly attenuated by prior exposure of aortic rings to berberine. Treatment of the intact aortic rings with berberine (10 micrograms/ml) increased the NOx and cGMP productions relative to the vehicle-treated group. Berberine induced a dose-dependent relaxation in phenylephrine-precontracted aortic rings, but NG-nitro-L-arginine methyl ester (L-NAME)-pretreated intact aortic rings or functional removal of the endothelium attenuated the berberine-induced relaxation without an effect on maximum response. These results suggest that berberine has a hypotensive effect, at least in part, via the inhibition of ACE and direct release of NO/cGMP in the vascular tissues.
Effect of berberine on arachidonic acid metabolism in rabbit platelets and endothelial cells.
Huang CG, Chu ZL, Wei SJ, Jiang H, Jiao BH.
Thromb Res. 2002 May 15;106(4-5):223-7.
The antiplatelet effect of berberine has been demonstrated in both laboratory research and clinical trials. In the present study, we show ex vivo that berberine significantly inhibited rabbit platelet aggregation induced by adenosine diphosphate, arachidonic acid, collagen or calcium ionophore A23187. The most potent inhibition was observed in collagen-induced platelet aggregation. Using radioimmunoassay, we show in vitro that berberine significantly inhibited synthesis of thromboxane A(2) in rabbit platelets induced by adenosine diphosphate, arachidonic acid or collagen in which collagen-induced thromboxane A(2) synthesis was also most potently inhibited. In our in vivo study using radioimmunoassay, the plasma prostacyclin level was reduced by 34.6% during a 30-min period after intravenous administration of 50 mg/kg of berberine. These results suggest that berberine might inhibit arachidonic acid metabolism in rabbit platelets and endothelial cells at two or more sites: cyclooxygenase in the arachidonic acid cascade and possibly the enzyme(s) for arachidonic acid liberation from membrane phospholipid(s).
Effect of berberine on regression of pressure-overload induced cardiac hypertrophy in rats.
Hong Y, Hui SC, Chan TY, Hou JY.
Am J Chin Med. 2002;30(4):589-99.
Berberine is the basic chemical component of a Chinese herb, Coptis chinensis Franch (coptis), considered to be useful in treating some diseases of the cardiovascular system, such as hypertension and chronic heart failure (CHF). In this study, we investigate the inhibitory effect of berberine on experimental cardiac hypertrophy, which is regarded as a risk factor of CHF and other heart diseases. Forty-two male SD rats were divided into four groups: age-matched control, aortic banding model, berberine-treated group and captopril-treated group. Cardiac hypertrophy was induced by suprarenal abdominal aorta constriction (banding). The drugs were orally administered for 8 weeks starting from 4 weeks after surgery at dosage of berberine 10 mg/kg and captopril 50 mg/kg. Blood pressure (BP) was measured four times during the period of the experiment, and hemodynamic parameters, cardiac index, cell size of left ventricular myocardium and total protein of left ventricular tissue were detected 8 weeks after treatment with drugs. The data from the present study showed that: (1) The BP of the aorta banded rats was increased compared with those of the normal (p < 0.001) and the age-matched control rats (p < 0.001), and berberine showed no significant effect on it. (2) After 8 weeks of treatment with berberine, the elevated left ventricular end diastolic pressure (LVEDP) was slightly decreased compared with the aortic banded rats. Meanwhile, the maximum rates of contraction and relaxation (+/- dp/dtmax) was increased (p < 0.05) and the time to reach the point of maximum rate from beginning of contraction (t-dp/dt) was shortened (p < 0.01), indicating that the functions of heart, both contraction and relaxation, were improved. (3) Cardiac growth was inhibited by treatment with berberine. Both whole heart and left ventricular weight were notably decreased compared with the banded rats (p < 0.05 and p < 0.01). (4) The cell size of left ventricular myocardium was significantly reduced (p < 0.001) and the total protein of left ventricular tissue was slightly down-regulated by treatment with berberine. These data suggest that berberine can improve abnormal cardiac function and can prevent the development of left ventricular hypertrophy induced by pressure-overload. This indicates that it may have therapeutic potential in the treatment of CHF.
Cardiovascular actions of berberine.
Lau CW, Yao XQ, Chen ZY, Ko WH, Huang Y.
Cardiovasc Drug Rev. 2001 Fall;19(3):234-44.
Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.
Protective effect of berberine on isolated perfused heart in heart failure
Zhou Z, Xu J, Lan T.
Hua Xi Yi Ke Da Xue Xue Bao. 2001 Sep;32(3):417-8.
OBJECTIVE: To examine the protective action of berberine against the development of heart failure. METHODS: Wister rats were divided into two groups. The Langendorff perfusion of isolated heart was performed and Verapamil was used to bring about acute heart failure. The experiment group was given berberine (10(-6) mol/L) before the use of Verapamil, but the control group was not given the berberine. A comparison was made on the degree of heart failure between the two group. RESULTS: The degree of heart failure in the experiment group was significantly less severe than that in the control group (P < 0.001). CONCLUSION: Berberine has the protective action against development of heart failure.
Inhibitory effects of berberine on IK1, IK, and HERG channels of cardiac myocytes.
Li BX, Yang BF, Zhou J, Xu CQ, Li YR.
Acta Pharmacol Sin. 2001 Feb;22(2):125-31.
AIM: To study the effects of berberine on inward rectifier potassium current (IK1) and outward delayed rectifier potassium current (IK) of guinea pig ventricular myocytes, and on human ether-a-go-go related gene (HERG) channel expressed in Xenopus oocytes. METHODS: Whole cell patch-clamp and geneclamp techniques were used to record ionic currents. RESULTS: Berberine prolonged action potential duration (APD) and inhibited IK1 and IK in a concentration-dependent manner. Berberine 100 micromol/L increased APD90 from (450 +\- 48) ms to (888 +\- 90) ms (n = 6, P < 0.01), and inhibited IK1 by 65 % +\- 7 % (n = 6, P < 0.01). Berberine 50 micromol/L inhibited IK by 57 % +\- 6 %, IKtail by 53 % +\- 6 % (n = 6, P < 0.01). Berberine produced a voltage-dependent block on IK that increased with stronger depolarization, and once all channels were activated, there was no further block at positive potentials. Berberine blocked the HERG channels potently with an IC50 value of approximately 75 micromol/L. This block was voltage-dependent, suggesting that it probably bind to either open or inactivated HERG channels. CONCLUSION: Berberine prolonged APD and possessed blocking effect on IK1, IK, and HERG channel expressed in Xenopus oocytes. The antiarrhythmic mechanism of berberine is related to its inhibitory effects on IK1, IK, and HERG channel.
Vasorelaxant and antiproliferative effects of berberine.
Ko WH, Yao XQ, Lau CW, Law WI, Chen ZY, Kwok W, Ho K, Huang Y
Eur J Pharmacol. 2000 Jul 7;399(2-3):187-96.
The present study was intended to examine the relaxant effects of berberine in rat isolated mesenteric arteries. Berberine produced a rightward shift of the concentration-response curve to phenylephrine and significantly reduced the maximal contractile response to phenylephrine. Berberine (10(-7)-3x10(-5) M) also relaxed the phenylephrine- and 9,11-dideoxy-11alpha, 9alpha-epoxy-methanoprostaglandin F(2alpha)-precontracted arteries with respective IC(50) values of 1.48+/-0.16x10(-6) and 2.23+/-0. 22x10(-6) M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC(50): 4.73+/-0. 32x10(-6) M) without affecting the maximum relaxant response. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue reduced the relaxant effect of berberine, and L-arginine (10(-3) M) partially antagonized the effect of L-NAME. In contrast, pretreatment with 10(-6) M glibenclamide or 10(-5) M indomethacin had no effect. Berberine (10(-5) M) reduced over by 50% the transient contraction induced by caffeine or phenylephrine in endothelium-denuded rings bathed in Ca(2+)-free Krebs solution. Pretreatment with putative K(+) channel blockers, such as tetrapentylammonium ions (1-3x10(-6) M), 4-aminopyridine (10(-3) M), or Ba(2+) (3x10(-4) M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3x10(-3) M), charybdotoxin (10(-7) M) or glibenclamide (10(-6) M) were without effect. Berberine reduced the high-K(+)-induced sustained contraction and the relaxant response to berberine was greater in rings with endothelium (IC(50): 4.41+/-0.47x10(-6) M) than in those without endothelium (IC(50): 8.73+/-0.74x10(-6) M). However, berberine (10(-6)-10(-4) M) did not affect the high-K(+)-induced increase of intracellular [Ca(2+)] in cultured aortic smooth muscle cells. Berberine did not affect active phorbol ester-induced contraction in Ca(2+)-free Krebs solution. In addition, berberine inhibited proliferation of cultured rat aortic smooth muscle cells with an IC(50) of 2.3+/-0.43x10(-5) M. These findings suggest that berberine could act at both endothelium and the underlying vascular smooth muscle to induce relaxation. Nitric oxide from endothelium may account primarily for the berberine-induced endothelium-dependent relaxation, while activation of tetrapentylammonium-, 4-aminopyridine- and Ba(2+)-sensitive K(+) channels, inhibition of intracellular Ca(2+) release from caffeine-sensitive pools, or a direct relaxant effect, is likely responsible for the berberine-induced endothelium-independent relaxation. Mechanisms related to either Ca(2+) influx or protein kinase C activation may not be involved. Both vasorelaxant and antiproliferative effects may contribute to a long-term benefit of berberine in the vascular system.
Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration in plasma studied by HPLC.
Zeng X, Zeng X. Biomed Chromatogr. 1999 Nov;13(7):442-4.
It has been reported that berberine is valuable for long-term treatment of ventricular premature beats (VPBs) and leads to a decrease in mortality for patients with congestive heart failure (CHF). In order to improve its therapeutic value and reduce its side effects, it is necessary to study the relationship between its activity and plasma concentration in patients with CHF. Patients with CHF were treated with conventional therapy for 2 weeks. Immediately after the data from a dynamic electrocardiogram (DCG) and left ventricular ejection fraction (LVEF) were obtained, 1.2 g/day of oral berberine was given. After 2 weeks of berberine therapy, the DCG data and LVEF were reassessed and the plasma berberine concentration was measured by HPLC. Plasma samples were pretreated by extraction with chloroform. Berberine in all samples was determined using a mu Bondapak C(18) column, a mobile phase of acetonitrile:0.02 mol/L phosphoric acid (45:55, v/v), and a UV detector at 346 nm. The mean recovery was 96.5%. The linear range was 40-1600 ng/mL. The detection limit for berberine in plasma was 0. 4 ng. The decrease in frequency and complexity of VPBs and the increase in LVEF in patients with plasma berberine concentrations higher than 0.11 mg/L (n = 31, group B) were more significant than at concentrations lower than 0.11 mg/L (p < 0.01 vs p < 0.05).
Ionic mechanism responsible for prolongation of cardiac action-potential duration by berberine.
Wang YX, Zheng YM.
J Cardiovasc Pharmacol. 1997 Aug;30(2):214-22.
This study was designed to investigate the effects of berberine on membrane currents forming the repolarization phase of action potentials in isolated guinea pig ventricular myocytes by using the patch-clamp technique. Application of berberine (3-30 microM) to the current-clamped myocytes produced a significant prolongation of action-potential duration (APD), which was concentration dependent. However, this agent (3-30 microM) did not affect the resting potential and action-potential amplitude. The prolongation of APD caused by berberine was not attenuated by tetrodotoxin (TTX, 10 microM), and TTX (10 microM) failed to shorten APD in cells pretreated with 30 microM berberine. Under the voltage-clamp conditions, berberine (3-30 microM) inhibited the delayed rectifier K+ currents (I(K)). Under conditions in which the rapidly activating components (I(Kr)) and slowly activating component (I(Ks)) were dissected out, berberine was shown to block I(Ks) without affecting I(Kr). Application of berberine (3-30 microM) increased the Na+-Ca2+ exchange currents, which were completely abolished by 5 mM NiCl. The L-type Ca2+ currents (I(Ca)) also were increased by 3-30 microM berberine, but the threshold potential, the potential at which I(Ca) was maximal, and the apparent reversal potential remained unchanged. Berberine at either 3 or 30 microM did not affect the inward rectifier K+ currents. This study suggests that the prolongation of cardiac repolarization by berberine is mainly caused by the inhibition of I(Ks) and increase of I(Ca).
Effects of berberine on platelet aggregation and plasma levels of TXB2 and 6-keto-PGF1 alpha in rats with reversible middle cerebral artery occlusion
Wu JF, Liu TP.
Yao Xue Xue Bao. 1995;30(2):98-102.
Berberine (Ber) 20 mg.kg-1.d-1 for 1, 3, or 5 d inhibited platelet aggregation induced by ADP, arachidonic acid (AA) and collagen (Coll) in rats with 24 h reversible middle cerebral artery occlusion (MCAO), and the platelet adhesiveness was inhibited as well. Using radioimmunoassay method, the thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) contents in rat plasma were measured 24 h after MCAO. The results indicate that the TXB2 levels after drug treatment were lower than those in ischemia control rats, but the 6-keto-PGF1 alpha levels showed no obvious difference between the two groups. The same dose of Ber was also shown to inhibit thrombosis formation. This suggests that the decline of platelet aggregation and decrease of TXB2 content may be one of the important factors involved in the anti-cerebral ischemia effect of Ber.
Effects of berberine on delayed afterdepolarizations in ventricular muscles in vitro and in vivo.
Wang YX, Yao XJ, Tan YH.
J Cardiovasc Pharmacol. 1994 May;23(5):716-22.
The effects of berberine on delayed afterdepolarizations in ventricular muscles in vitro and in vivo were investigated to help explain the mechanisms for its antiarrhythmic action. Berberine 3 mumol reduced the amplitude of delayed afterdepolarizations induced by ouabain or posthypoxic reoxygenation and abolished subsequent triggered activity in isolated guinea pig right ventricular papillary muscles. At 30 mumol, it decreased the incidence of delayed afterdepolarizations, associated with a further decrease in the amplitude of delayed afterdepolarizations. In rabbit left ventricular (LV) muscles in vivo, berberine 1 mg/kg intravenously (i.v.) decreased the amplitude of delayed afterdepolarizations evoked by ouabain and calcium gluconate from 9.6 +/- 1.9 to 6.8 +/- 0.8 mV and left stellate ganglion stimulation from 9.4 +/- 2.1 to 6.2 +/- 0.7 mV and blocked ventricular arrhythmias. After a 4-mg/kg i.v. bolus, the drug inhibited and even completely abolished development of delayed afterdepolarizations, yet still reduced maximal velocity of depolarization in isolated and in vivo ventricular muscles. Therefore, one of the important mechanisms for antiarrhythmic action of berberine may be suppression of delayed afterdepolarizations, which may be attributable in part to a decrease in Na+ influx.
Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit.
Riccioppo Neto F.
Br J Pharmacol. 1993 Feb;108(2):534-7.
1. Conventional microelectrode techniques were used for intracellular recordings of the transmembrane electrical potentials, the effects of berberine were studied on canine cardiac Purkinje and ventricular muscle fibres and on rabbit atrial fibres. 2. Berberine (3-30 microM) increased in a concentration-dependent manner, the action potential duration (APD) in canine Purkinje and ventricular muscle without affecting other parameters of the action potential. 3. The berberine-induced enlargement of the APD showed reverse use-dependence, so that the effect was greater at lower rates of stimulation. 4. Preparations perfused with berberine (30 microM) and driven at rates below 0.5 Hz exhibited early after depolarizations which persisted 3-4 h after washing. 5. The early afterdepolarizations were reversibly abolished by perfusion with lignocaine (3 microM) or by the increase in the rate of stimulation. 6. The effective refractory period (ERP) of Purkinje fibres was greatly increased by berberine (30 microM); however, the ratio ERP/APD was not significantly affected. 7. Berberine (10-100 microM) decreased in a concentration-dependent manner the spontaneous frequency of rabbit sinoatrial cells. The decrease in frequency was accompanied by a depression of the phase 4 depolarization, without significant changes in other parameters of the nodal action potential. 8. Atropine (2.5 microM) did not affect the bradycardic effect of berberine. On the other hand, berberine (30 microM) did not alter the chronotropic effect of isoprenaline. 9. Berberine (30 microM) also increased the duration of slow responses in K-depolarized rabbit atrial muscle fibres, other parameters being unaffected. 10. It is suggested that berberine exerts Class III antiarrhythmic and proarrhythmic actions in cardiac muscle of the dog in vitro.
Beneficial effects of berberine on hemodynamics during acute ischemic left ventricular failure in dogs.
Huang WM, Yan H, Jin JM, Yu C, Zhang H.
Chin Med J (Engl). 1992 Dec;105(12):1014-9.
In 18 dogs ischemic left ventricular failure characterized by a 30 percent reduction in peak rate of rise of left ventricular pressure (+dp/dt) and elevation of left ventricular end-diastolic pressure (LVEDP) to 15 mmHg or more was produced by ligation of the proximal left anterior descending coronary artery followed by serial occlusions of the distal left circumflex coronary artery. In 10 days, administration of berberine in an intravenous bolus injection (1 mg/kg, within 3 minutes) followed by a constant infusion (0.2 mg/kg/min, 30 minutes) increased the cardiac output (CO) from 1.25 +/- 0.12 to 1.61 +/- 0.17 L/min (P < 0.05), and +dp/dt from 810 +/- 85 to 1021 +/- 130 mmHg/s (P < 0.01), and decreased LVEDP from 16.5 +/- 1.3 to 12.0 +/- 1.0 mmHg (P < 0.05), diastolic blood pressure from 94 +/- 6 to 84 +/- 5 mmHg (P < 0.01), systemic vascular resistance from 7303 +/- 278 to 5442 +/- 231 dynes.x/cm5 (P < 0.01), but did not affect the heart rate. Injection of 5% glucose with the same volume did not improve CO and dp/dt (P > 0.05) but increased the LVEDP from 17.1 +/- 1.4 to 17.8 +/- 1.6 mmHg (P < 0.01) in 8 dogs. The levels of plasma concentration of berberine was determined with high-performance liquid chromatography. The changes in plasma drug level were found parallel to hemodynamic effects of berberine. The results of this study showed that berberine was able to improve the impaired left ventricular function by its positive inotropic effect and mild systemic vasodilatation.
Ventricular tachyarrhythmias treated with berberine
Huang W.
Zhonghua Xin Xue Guan Bing Za Zhi. 1990 Jun;18(3):155-6, 190.
The effects of berberine on 100 cases with ventricular tachyarrhythmias observed with 24 to 48 hour ambulatory monitoring were reported. The results showed that 62% of patients had 50% or greater, and 38% of patients had 90% or greater VPC suppression. The mean value of VPCs in whole group was significantly decreased by berberine from 452 +/- 421.8 beats per hour to 271 +/- 352.7 beats per hour (P less than 0.001). These results revealed that berberine is effective for ventricular tachyarrhythmias.
Cardiovascular effects of berberine in patients with severe congestive heart failure.
Marin-Neto JA, Maciel BC, Secches AL, Gallo Junior L.
Clin Cardiol. 1988 Apr;11(4):253-60.
Berberine, an alkaloid of the protoberberine family, has been shown to have strong positive inotropic and peripheral resistance-lowering effects in dogs with and without heart failure. To determine the acute cardiovascular effects of berberine in humans, 12 patients with refractory congestive heart failure were studied before and during berberine intravenous infusion at rates of 0.02 and 0.2 mg/kg per min for 30 minutes. The lower infusion dose produced no significant circulatory changes, apart from a reduction in heart rate (14%). The 0.2 mg/kg per min dose elicited several significant changes: (a) Decreases in systemic (48%, p less than 0.01) and pulmonary vascular resistance (41%, p less than 0.01), and in right atrium (28%, p less than 0.05) and left ventricular end-diastolic pressures (32%, p less than 0.01). (b) Increases in cardiac index (45%, p less than 0.01), stroke index (45%, p less than 0.01), and LV ejection fraction measured by contrast angiography (56%, p less than 0.01). (c) Increases in hemodynamic and echocardiographic indices of LV performance: peak measured velocity of shortening (45%, p less than 0.01), peak shortening velocity at zero load (41%, p less than 0.01), rate of development of pressure at developed isovolumic pressure of 40 mmHg (20%, p less than 0.01), percent fractional shortening (50%, p less than 0.01), and the mean velocity of circumferential fiber shortening (54%, p less than 0.01). (d) Decrease of arteriovenous oxygen difference (28%, p less than 0.05) with no changes in total body oxygen uptake, arterial oxygen tension, or hemoglobin dissociation properties.
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