On Cardiovascular System Are Re- Periments on the Heart of Toads, Frogs, Guinea Pigs and Rabbits in Vitro, and Showed a Cardiotonic Effect of Aco- Viewed

REVIEW Pharmacological effects of Chinese herb aconite (Fuzi) on cardiovascular system

Dandan Zhao, Jie Wang, Yanjing Cui, Xinfang Wu aa Dandan Zhao, Jie Wang, Yanjing Cui, Xinfang Wu, (Ranunculaceae). Fuzi tastes spicy and sweet, has a hot Guang'anmen Hospital, China Academy of Chinese Medical nature and toxicity, acts on the heart, kidney and Sciences, Beijing 100053, China spleen meridians and plays a role in saving yang for the Dandan Zhao, Beijing University of Traditional Chinese treatment of collapse, supplementing kidney yang, and Medicine, Beijing 100029, China eliminating cold to stop pain. Fuzi (aconite) consists of Supported by the Capital Medical Science and Technology a variety of alkaloids, such as the diester-diterpene alka- Development Program (No. SF-2007-I-04) loids, aconitine, hypaconitine, mesaconitine, and hige- Correspondence to: Prof. Jie Wang, Guang'anmen Hospi- namine. Aconite also is composed of some lipids, such tal, China Academy of Chinese Medical Sciences, Beijing as fatty acids, phosphatidate calcium, and steroids. It is 100053, China. [email protected] mainly clinically used for treatment of heart failure, Telephone: +86-10-88001381 shock and hypotension subsequent to acute myocardial Accepted: , March 1, 2012 infarction, coronary heart disease and rheumatic heart disease. Along with the repeated application of aconite in clinical practice and studies on pharmacology, its use in the cardiovascular system has been the focus of in- Abstract creasing research. In this article, aconite's pharmacological effects on the cardiovascular system are summa- Fuzi (aconite, Radix Aconiti praeparata), a widely rized. used Chinese herb, plays a significant role in the cardiovascular system. This is mainly reflected by Fuzi's cardiotonic effect, its protective effect on CARDIOTONIC EFFECT OF ACONITE myocardial cells, and its effect on heart rate and rhythm, blood pressure, and hemodynamics. In this Domestic and international research has shown that ac- article, the pharmacological effects and the corre- onite enhances cardiac contractility and also accelerates sponding mechanisms of Fuzi (aconite) and its ac- myocardial contraction frequency. Rao performed ex- tive components on cardiovascular system are re- periments on the heart of toads, frogs, guinea pigs and rabbits in vitro, and showed a cardiotonic effect of aco- viewed. nite decoction, while experiments on the heart of frogs, cats, and dogs in vivo also suggested a mildly cardioton- © 2012 JTCM. All rights reserved. ic effect of aconite. The mechanism of this action of aconite was shown to be related to calcium based on fur- Key words: Radix aconiti lateralis praeparata; Car- ther research.1 diovascular system; Pharmacologic actions Zuo et al. confirmed a "faint pulse verging on expiry" in a pathological cat model where intravenous administration of aconite water extract could gradually en- INTRODUCTION hance the heart beat. They observed that the heart in this cat model contracted more vigorously with much Fuzi (aconite, Radix Aconiti praeparata) is the pro- greater amplitude than that before drug administra- cessed tuberous root of Aconitum carmichaeli Debx tion, and repeated administration of the drug resulted

JTCM | www. journaltcm. com 308 September 15, 2012 | volume 32 | Issue 3 | Zhao DD et al. Pharmacological effects of Fuzi on cardiovascular system in a stronger effect. However, this effect was different Huang et al studied a rat model of heart failure in- according to the different states in the model. For ex- duced by adriamycin, and found that aconite decoc- ample, when the heart beat was weak and the extremi- tion could reduce Brain natriuretic peptide and Inter- ties were cold, aconite had a positive effect, but it did leukin-6 levels in serum, protect blood vessels and not show any cardiotonic function when the heart beat myocardial cells, and improve heart function. They al- was normal. Further experiments indicated that the so showed that the degree of myocardial cell injury was mechanism of effect of aconite may be related to 1 re- significantly less in the aconite decoction group than ceptor and receptor activation in the heart.2 β that in the heart failure model group which was not Xu et al.3 reportedα that aconite decoction can antago- given any drug after the heart failure model is success- nize the inhibition of phenobarbital, chloral hydrate fully made.9 Fang, et al reported that hypaconitine at and other drugs on the heart of the toad, and it an appropriate concentration of 250 ng/mL reduces showed a significant cardiotonic effect on the heart of apoptosis of myocardial cells induced by H2O2. They the reserpinized cat model in vivo or in vitro. They con- speculated that its mechanism may be related to a de- cluded that the cardiotonic effect of drugs of this type crease in expression of the apoptosis proteins, caspases is not caused by catecholamine release, but by a direct 3 and 9, and an increase in cell proliferation activity.10 contribution on the heart. Lee et al showed that higenamine protects myocardial Therefore, based on previous findings, aconite has obvi- cells from ischemia reperfusion injury, and therefore, it ous cardiotonic effects on the heart in vitro and in vi- significantly reduces myocardial infarct size. They vo, as well as in the normal and exhausted heart. The found that administration of higenamine 1 hour prior effective components of aconite include higenamine, to ischemic-reperfusion (I/R)-injury greatly decreased salsoline, methyl chloride dopamine, and aconite glyco- the release of cytochrome C, caspase-3 activity, and sides,3~6 and it is likely that there are other undiscov- Bax expression, but it up-regulated the expression of ered components. Bcl-2 and HO-1, as well as HO enzyme activity in the With regard to the mechanism of the cardiotonic effect left ventricle. These changes could be inhibited by of aconite, different explanations have been provided. ZnPP IX, an enzyme inhibitor of HO-1. As a result, Aconite achieve this effect through some substances they considered that HO-1 plays an important role in contained in it functions as receptor and receptor the protective action of higenamine in I/R-induced α β agonists, and increases intracellular calcium concentra- myocardial injury.11 + tions by activating sodium channels and increasing Na It has also been suggested that the mechanism of the + 2+ 1,2,7 influx, thereby stimulating reverse Na /Ca exchange. above function may be due to blocking sodium chan- A slight decrease in serumTumor Necrosis Factor – nels,12 or protecting the mitochondria of the cells.13 A α (TNF- ) and Nitric oxide (NO) levels of adriamy- previous study investigated the effect of aconite on the α cin-induced heart failure in rats by aconite decoction vascular extracellular matrix of the aorta in a cardiac hy- has been shown, suggesting another mechanism of car- pertrophy rat model induced by thyroxine, and found 8 diotonic function. that the mechanism whereby aconite prevented cardio- Aconite is widely used in the treatment of heart failure vascular hypertrophy could be attributed to inhibition and shock subsequent to acute myocardial infarction, of collagen synthesis.14 especially for symptoms, such as yang debilitation, a Combined administration with ginger in a heart failure cold body and extremities, and a faint pulse verging on model in the rat, aconite causes a decrease in the epi- expiry, which also suggest that aconite has cardiotonic nephrine, atrial natriuretic peptide, and endothelin lev- and anti-shock effects. Although the purified chemical els in plasma. Furthermore, on the one hand, a de- composition from Fuzi has strong cardiotonic and an- crease in epinephrine levels can prevent or reduce the ti-shock effects, the herb, Fuzi, itself hasn't been used toxicity of catecholamines on the heart, reduce myocar- as a cardiotonic drug in research and in the clinical set- dial energy demand and curb excessive adrenergic de- ting. This may be because of the effect of one the compensation during heart failure, and on the other herb's ingredients, aconitine, which can cause rapid ar- hand, a decrease in epinephrine levels can also inhibit rhythmia and ventricular fibrillation. renin release.15 In addition, the active ingredients of aconite have anti-inflammatory and antioxidant effects, which both PROTECTIVE EFFECT OF ACONITE play important roles in a variety of cardiovascular dis- ON MYOCARDIAL CELLS eases. For example, an increased expression of adhesion It has previously been shown that aconite and its ex- molecules and inflammatory-induced cytokines was tract can conserve myocardial cells of animal models found in the myocardial tissues of patients with cardio- and clinical patients with heart failure, myocardial in- vascular disease, indicating that local inflammation of farction, cardiac hypertrophy and other cardiovascular microvascular and myocardial cells is important in the diseases. The explanation of the mechanism of action pathological changes of cardiovascular diseases.16~18 This varies because of different viewpoints. also provides a theoretical basis for the protective effect

JTCM | www. journaltcm. com 309 September 15, 2012 | volume 32 | Issue 3 | Zhao DD et al. Pharmacological effects of Fuzi on cardiovascular system of aconite on myocardial cells. showing neither synergy nor antagonism with isopro- The effect of Yi Qi Wen Yang Huo Xue Fang (tonify terenol (ISO), suggesting that its up-regulation of myo- Qi, warm yang, and promote blood circulation formu- cardial -AR function may also achieved by affecting la) on bone marrow stem cells in patients with myocar- the pharmacokineticsβ of the receptor, subtypes chang- dial infarction was investigated, and it was found that es, and gene expression.23 Ameri reported that anti-ar- it can mobilize stem cells, which can reduce myocardial rhythmia may depend on chemical composition of infarct size, suppress left ventricular remodeling, and Fuzi (aconite) having different affinities to various sub- improve cardiac function.19 types of the alpha-subunit of the Na + channel in the As well as the protective effect of aconite on myocardi- brain and heart.24 al cells, including inhibiting injury of these cells, it can The dual pharmacological effect of aconite and its ex- also mobilize bone marrow stem cells that may migrate tract on heart rate and rhythm determines its different into the ischemic myocardium, differentiate into myo- clinical applications. According to the effect of hige- cardial cells in the myocardial microenvironment to in- namine on bradyarrhythmia, it is clinically used to crease the number of myocardial cells directly, and alter treat sinus bradycardia, sinoatrial block and atrioven- necrosis of the myocardium. tricular block, with satisfactory results. Guanfu base A, an active extract ingredient from white aconite, has shown great value in antagonizing supraventricular ar- EFFECT OF ACONITE ON HEART rhythmia, improving myocardial ischemia and anti-an- gina. RATE AND RHYTHM In spite of the antiarrhythmic effect of aconite, it is al- Aconite can increase heart rate, mentioned as positive so reported that aconite can induce arrhythmia, in chronotropic action, and it also acts on the rhythm of which ventricular arrhythmia, sinus tachycardia or bra- the heart, which antagonizes arrhythmia and results in dycardia are common,25,26 but bundle branch block is an arrhythmogenic effect. This may lie in the fact that rare.27 Aconite is often used to create anti-arrhythmic different components of aconite have different pharma- animal models in research because of its arrhythmogen- cological effects. The effects of aconite on heart rate ic pharmacological property.28 and rhythm vary between studies because of different Diterpenoid alkaloids contained in aconite can induce origins, processing methods, extract compositions, ani- arrhythmia. Two mechanisms are involved: 1) they mal models, and how individual body reacts upon spe- have a direct effect on the myocardium causing sodium cial circumstances. An aconite decoction can speed up ion channels in the myocardial cells to open, accelerat- the contraction frequency of the mammalian heart in ing the influx of sodium ions, leading to membrane de- vitro. However, a large dose of aconite inhibits the polarization, increasing automaticity of fast responsive heart by slowing the heart rate, which suggests that the cells, and leading to arrhythmia; and 2) they cause va- effect of aconite on heart rate is dose-related.1 Another gus nerve stimulation, resulting in arrhythmia, such as study reported that an aqueous solution of aconite in bradycardia.29 different doses can accelerate the heart rate in a cat model of heart failure, but it did not significantly affect the heart rate of normal anesthetized dogs and cats.6 EFFECT OF ACONITE ON BLOOD Zhang, et al. showed that butanol extract, ethanol extract and aqueous extract of aconite all have a preven- PRESSURE tive effect on ventricular fibrillation induced by chloro- Reports of aconite's effects on blood pressure are var- form in mice, especially the aqueous extract.20 Wang et ied, including some reports that it lowers blood pres- al. administrated hypaconitine intravenously to anes- sure, some studies have shown that it elevates blood thetized rats and observed its effect on electrocardio- pressure initially and then lowers blood pressure later, gram and experimental arrhythmia. They found that a and some studies consider that it has no significant ef- small dose (0.5 mg kg-1 intraperitoneal injection) of fect on blood pressure.3 The reason for this discrepancy hypaconitine caused· anti-arrhythmic effects. Hypaconi- between studies may be because blood pressure-increas- tine could antagonize aconitine-induced arrhythmia. ing substances, such as chloride methyldopamine and Therefore, hypaconitine serves as a natural compound salsolinol, and blood pressure-decreasing substances, type I anti-arrhythmic.21 such as higenamine, coexist in aconite. Therefore, dif- With regard to the mechanism, it could be related to ferent origins and processing methods of aconite may higenamine up regulating the Adrenergic beta-receptor lead to different levels of these components, which ( -AR)22,23 and electrophysiological properties and ion then results in varied effects on blood pressure. In addi- channelsβ of myocardial cell membranes.12 A previous tion, aconite's effect on blood pressure is also related to study suggested that higenamine increases the respon- dose. sivity of cAMP in plasma, and affects heart rate Gu et al.30 reported the effect of water extract from Si- through the receptor-G protein-cAMP complex.22 chuan aconite on blood pressure of anesthetized cats. Large doses of higenamine act directly on the -AR, They found that it decreased Blood Pressure (BP) at a β JTCM | www. journaltcm. com 310 September 15, 2012 | volume 32 | Issue 3 | Zhao DD et al. Pharmacological effects of Fuzi on cardiovascular system

35 low dose (12.5-50 mg/kg), but showed a three-phase ef- blocking 2-adrenergic receptors. Higenamine has in- fect at a higher dose(400 mg/kg), with a temporary inhibitory effectsα on amino acid (AA)-induced platelet crease in BP, then an immediate increase in BP, fol- aggregation, partly by inhibiting the production of lowed by a final decrease in BP. The mechanism is as thromboxane A2 from AA, and partly by directly follows: the effect of increasing BP depends on the di- blocking the thromboxane A2 receptor, in addition to rect excitement of receptors in blood vessels; and the previously reported effects on the 2-adrenergic recep- effect of decreasingα BP is related to excitement of M re- tor, mostly by directly blocking theα thromboxane A2 ceptors and 2 receptors. Furthermore the effects of ac- receptor.36 onite on BPβ also indicates the involvement of nervous The effect of higenamine on DIC was investigated by system, as well as unknown active substances of the car- using an experimental DIC rat model. The oral admin- diovascular system contained in aconite preparations. istration of higenamine significantly ameliorated a de- The water soluble part of aconite can increase femoral crease in fibrinogen levels in plasma, an increase in fi- arterial blood flow, decrease the pressure of blood ves- brinogen/fibrin degradation product levels, and prolon- sels, and show mild expansion of coronary vessels.6 gation of prothrombin time induced by the intrave- Chong et al.31 created a vasoconstriction model of rats nous infusion of lipopolysaccharide (LPS). Prolonga- using phenylephrine or KCl, and they observed a relax- tion of activated partial thrombin time and a decrease ing effect on rat aorta from aconitine, and additionally in platelet count were also suppressed with hige- found that the relaxing effect was concentration-depen- namine. Additionally, an increase in serum aspartate dent. Niu et al.32 found that the relaxing effect of aco- transaminaseand blood urea nitrogen levels was pre- nite decoction on aorta is endothelium-dependent, and vented with higenamine.37 These data strongly suggest related to NO released by the endothelium, instead of that higenamine suppresses NO products and induced receptor-dependent Ca2+ channels in cell membranes of nitric oxide synthase expression in the experimental smooth muscle or voltage-dependent Ca2 + . Results of DIC model, prevents platelet aggregation, inhibits the these experiments showed that aconite had a dilatory formation of intravascular fibrin deposition or throm- effect on peripheral blood vessels, and its decoction can bosis, and improves blood supply to organs. This indi- significantly expand blood vessels of the hind limb in cates that aconitine can protect the heart, platelets and anesthetized dogs and cats, and increase blood flow.Af- vascular smooth muscle in the DIC rat model induced ter intravenous administration of aconite, BP of the by LPS.38 Previous studies have shown that higenamine "faint pulse verging on expiry" pathological model cat up-regulates the -AR, increases responsivity of cAMP rose, but this function was significantly weakened by in plasma, and actsβ directly on the -AR at a large -receptor blockers. According to the above results, ac- dose.23 β oniteα may play a role in the increase of BP as an re- In addition, aconite polyose extracted from aconite in- ceptor stimulant.2 α creases hepatic low density lipoprotein receptor and cytochrome P450 7alpha-1expression and decreases 3-hy- droxy-3-methyl glutaryl (HMG)-CoA expression, and EFFECTS OF ACONITE ON lowers cholesterol levels,39 which are significant factors HEMODYNAMICS in the prevention of cardiovascular diseases. The effect of aconite on hemodynamics is mainly due In conclusion, aconite has been used for the treatment to anticoagulant and anti-thrombosis effects, and the of many types of diseases, and is especially well known active component is mainly higenamine. Aconite has for its pharmacological effects on the cardiovascular sys- shown therapeutic potential for disseminated intravas- tem, such as improving heart function, easing ischemia cular coagulation (DIC) and/or accompanying multi- reperfusion injury, resisting arrhythmia, stretching of ple organ failure. Studies have shown that aconite de- the arteria coronaria, stabilizing blood pressure, and an- coction can extend the time for thrombosis, which in- tagonizing coagulation and thrombosis. These effects dicates that it can inhibit blood clotting and antago- are able to be used to treat heart failure, shock due to nize thrombosis.33 Higenamine shows inhibitory activi- myocardial infarcts, arrhythmia, DIC state and multi- ty in both human and rat platelet aggregation induced ple organ failure. by ADP, collagen and epinephrine. And higenamine However, most of the pharmacological effects of aco- had the strongest inhibitory effect on epinephrine-in- nite are dual, such as the effects on cardiac rhythm and duced aggregation. Anti-thrombotic effects of hige- blood pressure, which are closely related to the various namine have also been observed in both an acute active components contained in Chinese herbs. The ba- mouse thrombosis model and rat arterio-venous shunt sis of the above-mentioned pharmacological effects of (AV-shunt) model. The oral administration of hige- aconite are mostly concerned with the regulation of the namine increases the rate of recovery from an acute neuroendocrine system. For example, aconite acts as an thrombotic challenge in mice and decreases the weight agonist of different subtypes of and receptors, as of thrombus formed inside the AV-shunt tube in rats.34 well as affects sodium and calciumα ionβ channels. Fur- Higenamine possibly exerts antithrombotic effects by thermore, studies on signal transduction involving NO

JTCM | www. journaltcm. com 311 September 15, 2012 | volume 32 | Issue 3 | Zhao DD et al. Pharmacological effects of Fuzi on cardiovascular system and cAMP are also carried out supplementarily. rats model. Shan Xi Zhong Yi 2009; 30(6): 745-746. By reviewing the literature in this field, we realized that 10 Fang K, Li ZH, Li GH, Shao XT. Protection of hypaconi- the following two points should be emphasized. First, tine on H2O2-induced myocardial apoptosis in rats. because of the close relationship between the pharma- Zhongguo Zhong Yi Yao Ke Ji 2010; 17(4): 315-318. cological effects of aconite and the category and dosage 11 Lee YS, Kang YJ, Kim HJ, et al. Higenamine reduces of the active components, it is unwise to prescribe aco- apoptotic cell death by induction of heme oxygenase-1 in nite alone in clinical application with a large dose. It is rat myocardial ischemia-reperfusion injury. Apoptosis highly recommended that aconite is applied when com- 2006; 11(7): 1091-1100. patible with other herbs, such as ginseng, ginger, ramu- 12 Luo J, Min S, Wei K, Cao J. Ion channel mechanism and lus cinnamomi, atractylodes macrocephala, tuckahoe, ingredient bases of Shenfu Decoction’s cardiac electro- gypsum, and berberine, to ensure clinical safety, and physiological effects. J Ethnopharmacol 2008; 117(3): 439-445. play an efficient role in its pharmacological effects. If a 13 Cao J, Zhang CD, Zhang GX, Zhang YJ, Min S. Protec- high dose of aconite is required, attention should be tive injured by effect of Shenfu injection on myocardial paid to observing adverse reactions, so that any adverse mitochondria ischemia reperfusion in rabbits. Chin effects can be dealt with in a timely manner. Other- 一 Med J (Engl) 2005; 118(6): 505-507. wise, it is a good choice to use an extract of an effective 14 Meng HL, Cao T. Study on the influence of aconite on monomer aimed at the corresponding pathological re- aorta vascular extracellular matrix of cardiac hypertrophy sponse. Second, research on cardiac protection of aco- rat model induced by thyroxine. Ya Tai Chuan Tong Yi nite is still insufficient. Development of science and Yao 2009; 5(2): 32-34. technology, in particular, intervention technologies, 15 Zhan HX, Peng C. Influence of combination aconite and has led to an increasing number of patients surviving ginger on heart failure rats in epinephrine, angiotensin from myocardial infarction, which leads to another aldosterone, and ANP, NT level in plasma. Zhong Yao YaoⅡ, problem of ischemia reperfusion injury. As a result, fur- Li Yu Lin Chuang 2006; 22(2): 12-14. ther research on the protective effect and application of 16 Campian ME, Hardziyenka M, Bruin K, et al. 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