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Planta Med 2019; 85(09/10): 738-744
DOI: 10.1055/a-0942-4502
DOI: 10.1055/a-0942-4502
Biological and Pharmacological Activity
Original Papers
Higenamine, a Dual Agonist for β 1- and β 2-Adrenergic Receptors Identified by Screening a Traditional Chinese Medicine Library
Further Information
Publication History
received 24 October 2018
revised 18 May 2019
accepted 23 May 2019
Publication Date:
11 June 2019 (online)
Abstract
Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of β 2-adrenergic receptor signaling in combination with the presently preferred β 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for β-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent β-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both β 1-adrenergic receptor and β 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a β 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for β 1/β 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in β 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.
Supporting Information
- Supporting Information
The establishment and verification of the screen assay using isoproterenol are provided as Supporting Information.
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References
- 1 Liew CC, Dzau VJ. Molecular genetics and genomics of heart failure. Nat Rev Genet 2004; 5: 811-825
- 2 Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975; 37: 1022-1036
- 3 Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there?. Nat Rev Drug Discov 2006; 5: 993-996
- 4 Klabunde T, Hessler G. Drug design strategies for targeting G-protein-coupled receptors. Chembiochem 2002; 3: 928-944
- 5 Xiao RP, Ji X, Lakatta EG. Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol 1995; 47: 322-329
- 6 Woo AY, Xiao RP. beta-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin 2012; 33: 335-341
- 7 Patterson AJ, Zhu W, Chow A, Agrawal R, Kosek J, Xiao RP, Kobilka B. Protecting the myocardium: a role for the beta2 adrenergic receptor in the heart. Crit Care Med 2004; 32: 1041-1048
- 8 Zhu WZ, Wang SQ, Chakir K, Yang D, Zhang T, Brown JH, Devic E, Kobilka BK, Cheng H, Xiao RP. Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J Clin Invest 2003; 111: 617-625
- 9 Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A 2001; 98: 1607-1612
- 10 Wang W, Zhu W, Wang S, Yang D, Crow MT, Xiao RP, Cheng H. Sustained beta1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circ Res 2004; 95: 798-806
- 11 Mangmool S, Shukla AK, Rockman HA. Rbeta-Arrestin-dependent activation of Ca(2+)/calmodulin kinase II after beta(1)-adrenergic receptor stimulation. J Cell Biol 2010; 189: 573-587
- 12 Chesley A, Lundberg MS, Asai T, Xiao RP, Ohtani S, Lakatta EG, Crow MT. The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3′-kinase. Circ Res 2000; 87: 1172-1179
- 13 Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, DeGeorge jr. BR, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn 2nd GW, Koch WJ. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 2008; 103: 413-422
- 14 Zhu W, Petrashevskaya N, Ren S, Zhao A, Chakir K, Gao E, Chuprun JK, Wang Y, Talan M, Dorn 2nd GW, Lakatta EG, Koch WJ, Feldman AM, Xiao RP. Gi-biased beta2AR signaling links GRK2 upregulation to heart failure. Circ Res 2012; 110: 265-274
- 15 Ahmet I, Krawczyk M, Zhu W, Woo AY, Morrell C, Poosala S, Xiao RP, Lakatta EG, Talan MI. Cardioprotective and survival benefits of long-term combined therapy with beta2 adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction. J Pharmacol Exp Ther 2008; 325: 491-499
- 16 Ahmet I, Morrell C, Lakatta EG, Talan MI. Therapeutic efficacy of a combination of a beta1-adrenoreceptor (AR) blocker and beta2-AR agonist in a rat model of postmyocardial infarction dilated heart failure exceeds that of a beta1-AR blocker plus angiotensin-converting enzyme inhibitor. J Pharmacol Exp Ther 2009; 331: 178-185
- 17 Gao H, Wang Z, Li Y, Qian Z. Overview of the quality standard research of traditional Chinese medicine. Front Med 2011; 5: 195-202
- 18 Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M, Yum J, Kim YJ, Lee HK, Cortese JF, Wirth DF, Dignam JD, Rao A, Yeo CY, Mazitschek R, Whitman M. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol 2012; 8: 311-317
- 19 Sham TT, Chan CO, Wang YH, Yang JM, Mok DK, Chan SW. A review on the traditional Chinese medicinal herbs and formulae with hypolipidemic effect. Biomed Res Int 2014; 2014: 925302
- 20 Dondorp A, Nosten F, Stepniewska K, Day N, White N. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717-725
- 21 Chan TY. Aconitum alkaloid content and the high toxicity of aconite tincture. Forensic Sci Int 2012; 222: 1-3
- 22 Wen-Ting S, Fa-Feng C, Li X, Cheng-Ren L, Jian-Xun L. Chinese medicine shenfu injection for heart failure: a systematic review and meta-analysis. Evid Based Complement Alternat Med 2012; 2012: 713149
- 23 Shao MJ, Wang SR, Zhao MJ, Lv XL, Xu H, Li L, Gu H, Zhang JL, Li G, Cui XN, Huang L. The effects of velvet antler of deer on cardiac functions of rats with heart failure following myocardial infarction. Evid Based Complement Alternat Med 2012; 2012: 825056
- 24 Song YH, Wang SR, Zhao MJ, Lv XL, Xu H, Li L, Gu H, Zhang JL, Li G, Cui XN, Huang L. Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure. Int J Mol Med 2008; 21: 117-124
- 25 Kimura I, Makino M, Takamura Y, Islam MA, Kimura M. Positive chronotropic and inotropic effects of higenamine and its enhancing action on the aconitine-induced tachyarrhythmia in isolated murine atria. Jpn J Pharmacol 1994; 66: 75-80
- 26 Liu WH, Zhou YP, Zeng GY. [Effects of DL-demethylcoclaurine on experimental heart failure]. Yao Xue Xue Bao 1988; 23: 81-85
- 27 Fung FY, Linn YC. Developing traditional chinese medicine in the era of evidence-based medicine: current evidences and challenges. Evid Based Complement Alternat Med 2015; 2015: 425037
- 28 Curran PK, Fishman PH. Endogenous beta 3- but not beta 1-adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells. Cell Signal 1996; 8: 355-364
- 29 Mangmool S, Kurose H. G(i/o) protein-dependent and -independent actions of Pertussis Toxin (PTX). Toxins (Basel) 2011; 3: 884-899
- 30 Pyo MK, Kim JM, Jin JL, Chang KC, Lee DH, Yun-Choi HS. Effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on platelet TXA2 synthesis and aggregation. Thromb Res 2007; 120: 81-86
- 31 Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK. Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody. Nature 2013; 502: 575-579
- 32 Kosuge T, Yokota M. Letter: Studies on cardiac principle of aconite root. Chem Pharm Bull (Tokyo) 1976; 24: 176-178
- 33 Zhang N, Lian Z, Peng X, Li Z, Zhu H. Applications of Higenamine in pharmacology and medicine. J Ethnopharmacol 2017; 196: 242-252
- 34 Chen SP, Ng SW, Poon WT, Lai CK, Ngan TM, Tse ML, Chan TY, Chan AY, Mak TW. Aconite poisoning over 5 years: a case series in Hong Kong and lessons towards herbal safety. Drug Saf 2012; 35: 575-587
- 35 Chan TY. Aconite poisoning. Clin Toxicol (Phila) 2009; 47: 279-285
- 36 Park CW, Chang KC, Lim JK. Effects of higenamine on isolated heart adrenoceptor of rabbit. Arch Int Pharmacodyn Ther 1984; 267: 279-288
- 37 Chen SJ, Zhou GB, Zhang XW, Mao JH, de Thé H, Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood 2011; 117: 6425-6437
- 38 Fu M, Wu M, Wang JF, Qiao YJ, Wang Z. Disruption of the intracellular Ca2+ homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes. Biochem Biophys Res Commun 2007; 354: 929-936
- 39 Ahmet I, Krawczyk M, Heller P, Moon C, Lakatta EG, Talan MI. Beneficial effects of chronic pharmacological manipulation of beta-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy. Circulation 2004; 110: 1083-1090
- 40 Feng S, Jiang J, Hu P, Zhang JY, Liu T, Zhao Q, Li BL. A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacol Sin 2012; 33: 1353-1358
- 41 Woo AY, Wang TB, Zeng X, Zhu W, Abernethy DR, Wainer IW, Xiao RP. Stereochemistry of an agonist determines coupling preference of beta2-adrenoceptor to different G proteins in cardiomyocytes. Mol Pharmacol 2009; 75: 158-165
- 42 Zhou YY, Wang SQ, Zhu WZ, Chruscinski A, Kobilka BK, Ziman B, Wang S, Lakatta EG, Cheng H, Xiao RP. Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiology. Am J Physiol Heart Circ Physiol 2000; 279: H429-H436
- 43 Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 2008; 16: 897-905
- 44 Chemical Computing Group. Molecular operating environment (MOE), version 2012.10. Montreal, Quebec, Canada: 2012. Available at http://www.chemcomp.com/ Accessed April 10, 2019
- 45 Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF. Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 2008; 454: 486-491
- 46 DeLano WL. The PyMOL molecular graphics system. Palo Alto, CA: DeLano Scientific; 2002