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Planta Med 2020; 86(04): 284-293
DOI: 10.1055/a-1099-2929
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Vasorelaxing Activity of R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol from Dalbergia tonkinensis: Involvement of Smooth Muscle CaV1.2 Channels

Nguyen Manh Cuong
1   Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
2   Graduate University of Science and Technology, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
,
Ninh The Son
3   Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
,
Ngu Truong Nhan
2   Graduate University of Science and Technology, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
4   Department of Science and Technology, Tay Nguyen University, Daklak, Vietnam
,
Pham Ngoc Khanh
1   Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
,
Tran Thu Huong
1   Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
,
Nguyen Thi Thu Tram
5   Department of Chemistry, Faculty of Science, Can Tho University of Medicine and Pharmacy, Can Tho, Vietnam
,
Giampietro Sgaragli
6   Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy
,
Amer Ahmed
6   Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy
,
Alfonso Trezza
7   Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy
,
Ottavia Spiga
7   Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy
,
Fabio Fusi
7   Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy
› Author AffiliationsSupported by: National Foundation for Science and Technology Development 104.01-2015.49
Supported by: JSPS RONPAKU Ph.D. program for FY 2017 and NAFOSTED 104.01-2015.49
Supported by: Vietnam Academy of Science and Technology QTKR 01.02/18-19
Further Information

Publication History

received 04 October 2019
revised 26 December 2019

accepted 10 January 2020

Publication Date:
28 January 2020 (online)

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Abstract

Dalbergia species heartwood, widely used in traditional medicine to treat various cardiovascular diseases, might represent a rich source of vasoactive agents. In Vietnam, Dalbergia tonkinensis is an endemic tree. Therefore, the aim of the present work was to investigate the vascular activity of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol isolated from the heartwood of D. tonkinensis and to provide circular dichroism features of its R absolute configuration. The vascular effects of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol were assessed on the in vitro mechanical activity of rat aorta rings, under isometric conditions, and on whole-cell Ba2+ currents through CaV1.2 channels (IBa1.2) recorded in single, rat tail main artery myocytes by means of the patch-clamp technique. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol showed concentration-dependent, vasorelaxant activity on both endothelium-deprived and endothelium intact rings precontracted with the α 1 receptor agonist phenylephrine. Neither the NO (nitric oxide) synthase inhibitor Nω-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin affected its spasmolytic activity. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol-induced vasorelaxation was antagonized by (S)-(−)-Bay K 8644 and unaffected by tetraethylammonium plus glibenclamide. In patch-clamp experiments, R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol inhibited IBa1.2 in a concentration-dependent manner and significantly decreased the time constant of current inactivation. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol likely stabilized the channel in its closed state, as suggested by molecular modelling and docking simulation to the CaV1.2 channel α 1c subunit. In conclusion, D. tonkinensis species may represent a source of agents potentially useful for the development of novel antihypertensive drugs.

Key words

Dalbergia tonkinensis - Fabaceae - R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol - rat aorta rings - docking simulation - CaV1.2 channel - open-chain neoflavonoid - patch clamp
 

  • References

  • 1 Laurent S. Antihypertensive drugs. Pharmacol Res 2017; 124: 116-125
    CrossrefPubMedGoogle Scholar
  • 2 Trstenjak U, Kikelj D. Multitarget cardiovascular drugs. Curr Med Chem 2011; 18: 2531-2542
    CrossrefPubMedGoogle Scholar
  • 3 Bisi A, Gobbi S, Belluti F, Rampa A. Design of multifunctional compounds for cardiovascular disease: from natural scaffolds to “classical” multitarget approach. Curr Med Chem 2013; 20: 1759-1782
    CrossrefPubMedGoogle Scholar
  • 4 Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012; 75: 311-335
    CrossrefPubMedGoogle Scholar
  • 5 Corson TW, Crews CM. Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell 2007; 130: 769-774
    CrossrefPubMedGoogle Scholar
  • 6 Banskota AH, Tezuka Y, Le Tran Q, Kadota S. Chemical constituents and biological activities of Vietnamese medicinal plants. Curr Top Med Chem 2003; 3: 227-248
    CrossrefPubMedGoogle Scholar
  • 7 Becker S, Flaws B, Casañas R. The Treatment of cardiovascular Diseases with Chinese Medicine. Boulder: Blue Poppy Press; 2005: 25-62
    Google Scholar
  • 8 Tao Y, Wang Y. Bioactive sesquiterpenes isolated from the essential oil of Dalbergia odorifera T. Chen. Fitoterapia 2010; 81: 393-396
    CrossrefPubMedGoogle Scholar
  • 9 Wang H, Dong WH, Zuo WJ, Liu S, Zhong HM, Mei WL, Dai HF. Five new sesquiterpenoids from Dalbergia odorifera . Fitoterapia 2014; 95: 16-21
    CrossrefPubMedGoogle Scholar
  • 10 Wang J, Wei N, Zhao H, Huang H, Jiang M, Bai G, Luo G. Global chemome study by LC coupled with DAD and ESI-Q-TOF MS of a composite traditional Chinese medicine Qishenyiqi dropping pills. Chromatographia 2010; 72: 431-440
    CrossrefPubMedGoogle Scholar
  • 11 Zhang XY, Huang X, Qin F, Ren P. Anti-inflammatory effect of Guan-Xin-Er-Hao via the nuclear factor-kappa B signaling pathway in rats with acute myocardial infarction. Exp Anim 2010; 59: 207-214
    CrossrefPubMedGoogle Scholar
  • 12 Zhang Y, Pan T, Zhong X, Cheng C. Tongxinluo prevents endothelial dysfunction induced by homocysteine thiolactone in vivo via suppression of oxidative stress. Evid Based Complement Alternat Med 2015; 2015: 929012
    PubMedGoogle Scholar
  • 13 Cui B, Jia L. Dalbergia odorifera-containing blood lipid-lowering composition and its preparation method. Chinese Patent 103505496 A 20140115, 2012
    PubMedGoogle Scholar
  • 14 Yang D, Xu B, Wen L, Liu S, Liu Y, Feng X, Liu Z, Jiang S. Traditional Chinese medicine composition chewable tablet for treating unstable angina pectoris and preparation method thereof. Chinese Patent CN 102755580 A 20121031, 2012
    PubMedGoogle Scholar
  • 15 He Y. Chinese medicinal plaster with effects of promoting blood circulation and removing blood stasis. Chinese Patent CN 103599402 A 20140226, 2014
    PubMedGoogle Scholar
  • 16 Fan L, Zheng Y. Application of medication composition of containing oil of Dalbergia wood in preparing medication for treating chronic insufficiency of supplying blood for brain. Chinese Patent CN1872157A, 2006
    PubMedGoogle Scholar
  • 17 Cuong NM, Nhan NT, Son NT, Nghi DH, Cuong TD. Daltonkins A and B, two new carboxyethylflavanones from the heartwood of Dalbergia tonkinensis . Bull Korean Chem Soc 2017; 38: 1511-1514
    PubMedGoogle Scholar
  • 18 Son NT, Harada K, Cuong NM, Fukuyama Y. Two new carboxyethylflavanones from the heartwood of Dalbergia tonkinensis and their antimicrobial activities. Nat Prod Commun 2017; 12: 1721-1723
    PubMedGoogle Scholar
  • 19 Son NT, Oda M, Hayashi N, Yamaguchi D, Kawagishi Y, Takahashi F, Harada K, Cuong NM, Fukuyama Y. Antimicrobial activity of the constituents of Dalbergia tonkinensis and structural-bioactive highlights. Nat Prod Commun 2018; 13: 157-161
    PubMedGoogle Scholar
  • 20 Nguyen VB, Wang SL, Nhan NT, Nguyen TH, Nguyen NPD, Nghi DH, Cuong NM. New records of potent in-vitro antidiabetic properties of Dalbergia tonkinensis heartwood and the bioactivity-guided isolation of active compounds. Molecules 2018; 23: E1589
    CrossrefPubMedGoogle Scholar
  • 21 Nhan NT, Son NT, Dao Cuong TD, Nguyen PDN, Khanh PN, Huong TT, Cuong NM. Further study on chemical constituents from the heartwood of Dalbergia tonkinensis collected on Daklak province. Vietnam J Sci Tech 2018; 56: 252-258
    PubMedGoogle Scholar
  • 22 Son NT, Kamiji M, Huong TT, Kubo M, Cuong NM, Fukuyama Y. Chemical constituents of the Vietnamese plants Dalbergia tonkinensis Prain and Cratoxylum formosum (Jack) Dyer in Hook and their DPPH radical scavenging activities. Med Chem Res 2019; 28: 1441-1447
    CrossrefPubMedGoogle Scholar
  • 23 Son NT, Suenaga M, Matsunaga Y, Chinh LV, Kubo M, Harada K, Cuong NM, Fukuyama Y. Serine protease inhibitors and activators from Dalbergia tonkinensis species. J Nat Med 2020; 74: 257-263
    CrossrefPubMedGoogle Scholar
  • 24 Son NT, Cuong NM, Fukuyama Y. Chemical constituents of the heartwood of Dalbergia tonkinensis . Chem Nat Compd 2019; 5: 735-736
    PubMedGoogle Scholar
  • 25 Ollis WD. The neoflavonoids, a new class of natural products. Experientia 1966; 22: 777-783
    CrossrefPubMedGoogle Scholar
  • 26 Shiuh-Chuan C, Yuan-Shiun C, Sheng-Chu K. Neoflavonoids from Dalbergia odorifera . Phytochemistry 1997; 46: 947-949
    CrossrefPubMedGoogle Scholar
  • 27 Donnelly DMX, Nangle BJ, Hulbert PB, Klyne W, Swan RJ. Optical rotatory dispersion. Part XLVIII. Some 3,3-diarylprop-1-enes and related quinones: The absolute configuration of latifolin. J Chem Soc (C) 1967; 2450-2452
    PubMedGoogle Scholar
  • 28 Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 268: C799-C822
    PubMedGoogle Scholar
  • 29 Gurney AM. Mechanisms of drug-induced vasodilation. J Pharm Pharmacol 1994; 46: 242-251
    CrossrefPubMedGoogle Scholar
  • 30 Kuga T, Sadoshima J, Tomoike H, Kanaide H, Akaike N, Nakamura M. Actions of Ca2+ antagonists on two types of Ca2+ channels in rat aorta smooth muscle cells in primary culture. Circ Res 1990; 67: 469-480
    CrossrefPubMedGoogle Scholar
  • 31 Timin EN, Berjukow S, Hering S. Concepts of State-Dependent Pharmacology of Calcium Channels. In: McDonough SI. ed. Calcium Channel Pharmacology. New York: Kluwer Academic/Plenum Publishers; 2004: 1-19
    CrossrefGoogle Scholar
  • 32 Yu SM, Cheng ZJ, Kuo SC. Endothelium-dependent relaxation of rat aorta by butein, a novel cyclic AMP-specific phosphodiesterase inhibitor. Eur J Pharmacol 1995; 280: 69-77
    PubMedGoogle Scholar
  • 33 Yu SM, Kuo SC. Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta. Br J Pharmacol 1995; 114: 1587-1594
    CrossrefPubMedGoogle Scholar
  • 34 Fusi F, Spiga O, Trezza A, Sgaragli G, Saponara S. The surge of flavonoids as novel, fine regulators of cardiovascular CaV channels. Eur J Pharmacol 2017; 796: 158-174
    CrossrefPubMedGoogle Scholar
  • 35 Tikhonov DB, Zhorov BS. Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem 2009; 284: 19006-19017
    CrossrefPubMedGoogle Scholar
  • 36 Fusi F, Trezza A, Spiga O, Sgaragli G, Bova S. Ca(v)1.2 channel current block by the PKA inhibitor H-89 in rat tail artery myocytes via a PKA-independent mechanism: Electrophysiological, functional, and molecular docking studies. Biochem Pharmacol 2017; 140: 53-63
    CrossrefPubMedGoogle Scholar
  • 37 Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Morgan KG. Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharmacol Rev 2016; 68: 476-532
    CrossrefPubMedGoogle Scholar
  • 38 Sonkusare S, Palade PT, Marsh JD, Telemaque S, Pesic A, Rusch NJ. Vascular calcium channels and high blood pressure: pathophysiology and therapeutic implications. Vascul Pharmacol 2006; 44: 131-142
    CrossrefPubMedGoogle Scholar
  • 39 Cuong NM, Khanh PN, Huyen PT, Duc HV, Huong TT, Ha VT, Durante M, Sgaragli G, Fusi F. Vascular L-type Ca2+ channel blocking activity of sulphur-containing indole alkaloids from Glycosmis petelotii . J Nat Prod 2014; 77: 1586-1593
    CrossrefPubMedGoogle Scholar
  • 40 Fusi F, Saponara S, Sgaragli G, Cargnelli G, Bova S. Ca2+ entry blocking and contractility promoting actions of norbormide in single rat caudal artery myocytes. Br J Pharmacol 2002; 137: 323-328
    CrossrefPubMedGoogle Scholar
  • 41 Fusi F, Sgaragli G, Saponara S. Mechanism of myricetin stimulation of vascular L-type Ca2+ current. J Pharmacol Exp Ther 2005; 313: 790-797
    CrossrefPubMedGoogle Scholar
  • 42 Mugnai P, Durante M, Sgaragli G, Saponara S, Paliuri G, Bova S, Fusi F. L-type Ca2+ channel current characteristics are preserved in rat tail artery myocytes after one-day storage. Acta Physiol 2014; 211: 334-345
    CrossrefPubMedGoogle Scholar
  • 43 Budriesi R, Cosimelli B, Ioan P, Ugenti MP, Carosati E, Frosini M, Fusi F, Saponara S, Cruciani G, Novellino E, Spinelli D, Chiarini A. L-Type calcium channel blockers: from diltiazem to 1,2,4-oxadiazol-5-ones via thiazinooxadiazol-3-one derivatives. J Med Chem 2009; 52: 2352-2362
    CrossrefPubMedGoogle Scholar
  • 44 Magnon M, Calderone V, Floch A, Cavero I. Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings. Naunyn Schmiedebergs Arch Pharmacol 1998; 358: 452-463
    CrossrefPubMedGoogle Scholar
  • 45 Fusi F, Durante M, Spiga O, Trezza A, Frosini M, Floriddia E, Teodori E, Dei S, Saponara S. In vitro and in silico analysis of the vascular effects of asymmetrical N,N-bis(alkanol) amine aryl esters, novel multidrug resistance-reverting agents. Naunyn Schmiedebergs Arch Pharmacol 2016; 389: 1033-1043
    CrossrefPubMedGoogle Scholar
  • 46 Available at. http://blog.molview.org/posts/2017/02/26/images-and-copyright Accessed December 26, 2019
    PubMedGoogle Scholar
  • 47 Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004; 25: 1605-1612
    CrossrefPubMedGoogle Scholar
  • 48 Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009; 16: 2785-2791
    PubMedGoogle Scholar
  • 49 Koebel MR, Schmadeke G, Posner RG, Sirimulla S. AutoDock VinaXB: implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina. J Cheminform 2016; 8: 27
    CrossrefPubMedGoogle Scholar
  • 50 Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res 2015; 43: W443-W447
    CrossrefPubMedGoogle Scholar