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Planta Med 2020; 86(10): 708-716
DOI: 10.1055/a-1158-9422
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Biochanin A, the Most Potent of 16 Isoflavones, Induces Relaxation of the Coronary Artery Through the Calcium Channel and cGMP-dependent Pathway

Thomas Migkos
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
,
Jana Pourová
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
,
Marie Vopršalová
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
,
Cyril Auger
2   INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
,
Valérie Schini-Kerth
2   INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
,
Přemysl Mladěnka
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
› Author AffiliationsSupported by: EFSA-CDN project CZ.02.1.01/0.0/0.0/16_019/0000841
Supported by: Univerzita Karlova v Praze SVV 260 414
Further Information

Publication History

received 03 February 2020
revised 02 April 2020

accepted 13 April 2020

Publication Date:
14 May 2020 (online)

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Abstract

The dietary intake of flavonoids seems to be inversely related to cardiovascular mortality. The consumption of isoflavonoids is increasing in the general population, especially due to the use of food supplements and a variety of isoflavonoid-rich foods. However, detailed studies on the vascular influence of individual pure isoflavonoids are mostly missing. For this study, 16 isoflavonoids were initially screened for their vasorelaxant properties on rat aortas. The 2 most potent of them, biochanin A and glycitein, were further tested for the mechanism of action on porcine coronary arteries. They both induced an endothelium independent vascular relaxation, with EC50 below 6 and 17 µM, respectively. Biochanin A, but not glycitein, was able to block the vasoconstriction caused by KCl, CaCl2, serotonin, and U46619 in a dose-dependent manner. Another series of experiments suggested that the major mechanism of action of biochanin A was the inhibition of L-type calcium channels. Moreover, biochanin A in relatively small concentrations (2 – 4 µM) interfered with the cGMP, but not cAMP, pathway in isolated coronary arteries. These results indicate that some isoflavonoids, in particular biochanin A, are able to have vasodilatory effects in micromolar concentrations, which is of potential clinical interest for the management of cardiovascular pathologies.

Key words

blood vessels - cardiovascular - ex vivo - glycitein - isoflavonoid

Supporting Information

    Detailed description of the experimental procedures, as well as the graphs depicting the effect of the isoflavonoids of lower potency and the mechanism of action tested in rat aorta are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Kokubo Y, Iso H, Ishihara J, Okada K, Inoue M, Tsugane S, Group JS. Association of dietary intake of soy, beans, and isoflavones with risk of cerebral and myocardial infarctions in Japanese populations: the Japan Public Health Center-based (JPHC) study cohort I. Circulation 2007; 116: 2553-2562
    CrossrefPubMedGoogle Scholar
  • 2 Pase MP, Grima NA, Sarris J. The effects of dietary and nutrient interventions on arterial stiffness: a systematic review. Am J Clin Nutr 2011; 93: 446-454
    CrossrefPubMedGoogle Scholar
  • 3 Sagara M, Kanda T, NJelekera M, Teramoto T, Armitage L, Birt N, Birt C, Yamori Y. Effects of dietary intake of soy protein and isoflavones on cardiovascular disease risk factors in high risk, middle-aged men in Scotland. J Am Coll Nutr 2004; 23: 85-91
    CrossrefPubMedGoogle Scholar
  • 4 Setchell KD. Soy isoflavones – benefits and risks from natureʼs selective estrogen receptor modulators (SERMs). J Am Coll Nutr 2001; 20: 354S-362S discussion 381S–383S
    CrossrefPubMedGoogle Scholar
  • 5 Li T, Zhong Y, Tang T, Luo J, Cui H, Fan R, Wang Y, Wang D. Formononetin induces vasorelaxation in rat thoracic aorta via regulation of the PI3K/PTEN/Akt signaling pathway. Drug Des Devel Ther 2018; 12: 3675-3684
    CrossrefPubMedGoogle Scholar
  • 6 Tseng HH, Vong CT, Leung GP, Seto SW, Kwan YW, Lee SM, Hoi MP. Calycosin and formononetin induce endothelium-dependent vasodilation by the activation of large-conductance Ca(2+)-activated K(+) channels (BKCa). Evid Based Complement Alternat Med 2016; 2016: 5272531
    PubMedGoogle Scholar
  • 7 Yeung DK, Leung SW, Xu YC, Vanhoutte PM, Man RY. Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery. Eur J Pharmacol 2006; 552: 105-111
    CrossrefPubMedGoogle Scholar
  • 8 Choi S, Jung WS, Cho NS, Ryu KH, Jun JY, Shin BC, Chung JH, Yeum CH. Mechanisms of phytoestrogen biochanin A-induced vasorelaxation in renovascular hypertensive rats. Kidney Res Clin Pract 2014; 33: 181-186
    CrossrefPubMedGoogle Scholar
  • 9 Socas-Rodriguez B, Herrera-Herrera AV, Hernandez-Borges J, Rodriguez-Delgado MA. Multiresidue determination of estrogens in different dairy products by ultra-high-performance liquid chromatography triple quadrupole mass spectrometry. J Chromatogr A 2017; 1496: 58-67
    CrossrefPubMedGoogle Scholar
  • 10 Krizova L, Vesely A, Trinacty J, Schulzova V, Hurajova A, Hajslova J, Kvasnickova E, Havlikova S. Changes in isoflavones concentrations in cheese during processing and ripening. Acta Univ Agric Silvic Mendelianae Brun 2011; 59: 153-162
    PubMedGoogle Scholar
  • 11 Torregrosa G, Burguete MC, Perez-Asensio FJ, Salom JB, Gil JV, Alborch E. Pharmacological profile of phytoestrogens in cerebral vessels: in vitro study with rabbit basilar artery. Eur J Pharmacol 2003; 482: 227-234
    CrossrefPubMedGoogle Scholar
  • 12 Teede HJ, McGrath BP, DeSilva L, Cehun M, Fassoulakis A, Nestel PJ. Isoflavones reduce arterial stiffness: a placebo-controlled study in men and postmenopausal women. Arterioscler Thromb Vasc Biol 2003; 23: 1066-1071
    CrossrefPubMedGoogle Scholar
  • 13 Wu JH, Li Q, Wu MY, Guo DJ, Chen HL, Chen SL, Seto SW, Au AL, Poon CC, Leung GP, Lee SM, Kwan YW, Chan SW. Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways. J Nutr Biochem 2010; 21: 613-620
    CrossrefPubMedGoogle Scholar
  • 14 Sun XH, Ding JP, Li H, Pan N, Gan L, Yang XL, Xu HB. Activation of large-conductance calcium-activated potassium channels by puerarin: the underlying mechanism of puerarin-mediated vasodilation. J Pharmacol Exp Ther 2007; 323: 391-397
    CrossrefPubMedGoogle Scholar
  • 15 Figtree GA, Griffiths H, Lu YQ, Webb CM, MacLeod K, Collins P. Plant-derived estrogens relax coronary arteries in vitro by a calcium antagonistic mechanism. J Am Coll Cardiol 2000; 35: 1977-1985
    CrossrefPubMedGoogle Scholar
  • 16 Lee MY, Leung SW, Vanhoutte PM, Man RY. Genistein reduces agonist-induced contractions of porcine coronary arterial smooth muscle in a cyclic AMP-dependent manner. Eur J Pharmacol 2004; 503: 165-172
    CrossrefPubMedGoogle Scholar
  • 17 Xu YC, Leung SW, Yeung DK, Hu LH, Chen GH, Che CM, Man RY. Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery. Phytochemistry 2007; 68: 1179-1188
    CrossrefPubMedGoogle Scholar
  • 18 Lelovas PP, Kostomitsopoulos NG, Xanthos TT. A comparative anatomic and physiologic overview of the porcine heart. J Am Assoc Lab Anim Sci 2014; 53: 432-438
    PubMedGoogle Scholar
  • 19 Kim B, Jo C, Choi HY, Lee K. Prunetin relaxed isolated rat aortic rings by blocking calcium channels. Molecules 2018; 23: 2372
    CrossrefPubMedGoogle Scholar
  • 20 Mishra SK, Abbot SE, Choudhury Z, Cheng M, Khatab N, Maycock NJ, Zavery A, Aaronson PI. Endothelium-dependent relaxation of rat aorta and main pulmonary artery by the phytoestrogens genistein and daidzein. Cardiovasc Res 2000; 46: 539-546
    CrossrefPubMedGoogle Scholar
  • 21 Sun T, Liu R, Cao YX. Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms. Acta Pharmacol Sin 2011; 32: 1009-1018
    CrossrefPubMedGoogle Scholar
  • 22 Wu XL, Wang YY, Cheng J, Zhao YY. Calcium channel blocking activity of calycosin, a major active component of Astragali radix, on rat aorta. Acta Pharmacol Sin 2006; 27: 1007-1012
    CrossrefPubMedGoogle Scholar
  • 23 Wijetunge S, Aalkjaer C, Schachter M, Hughes AD. Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells. Biochem Biophys Res Commun 1992; 189: 1620-1623
    CrossrefPubMedGoogle Scholar
  • 24 Yamaguchi K, Honda H, Wakisaka C, Tohei A, Kogo H. Effects of phytoestrogens on acetylcholine- and isoprenaline-induced vasodilation in rat aorta. Jpn J Pharmacol 2001; 87: 67-73
    CrossrefPubMedGoogle Scholar
  • 25 Wang HP, Gao Q, Mei RH, Zhao MH, Lu Y, Li XY, Bruce IC, Xia Q. Mechanisms underlying biochanin A-induced relaxation of the aorta differ between normotensive and hypertensive rats. Clin Exp Pharmacol Physiol 2006; 33: 802-807
    CrossrefPubMedGoogle Scholar
  • 26 Nobe K, Paul RJ. Distinct pathways of Ca(2+) sensitization in porcine coronary artery: effects of Rho-related kinase and protein kinase C inhibition on force and intracellular Ca(2+). Circ Res 2001; 88: 1283-1290
    CrossrefPubMedGoogle Scholar
  • 27 Miyata K, Shimokawa H, Higo T, Yamawaki T, Katsumata N, Kandabashi T, Tanaka E, Takamura Y, Yogo K, Egashira K, Takeshita A. Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model. J Cardiovasc Pharmacol 2000; 35: 294-301
    CrossrefPubMedGoogle Scholar
  • 28 White RE, Darkow DJ, Lang JL. Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ Res 1995; 77: 936-942
    CrossrefPubMedGoogle Scholar
  • 29 Han SZ, Karaki H, Ouchi Y, Akishita M, Orimo H. 17 beta-Estradiol inhibits Ca2+ influx and Ca2+ release induced by thromboxane A2 in porcine coronary artery. Circulation 1995; 91: 2619-2626
    CrossrefPubMedGoogle Scholar
  • 30 Setchell KD, Brown NM, Desai P, Zimmer-Nechemias L, Wolfe BE, Brashear WT, Kirschner AS, Cassidy A, Heubi JE. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 2001; 131: 1362S-1375S
    CrossrefPubMedGoogle Scholar
  • 31 Setchell KD, Brown NM, Desai PB, Zimmer-Nechimias L, Wolfe B, Jakate AS, Creutzinger V, Heubi JE. Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes. J Nutr 2003; 133: 1027-1035
    CrossrefPubMedGoogle Scholar
  • 32 Wu Z, Song L, Feng S, Liu Y, He G, Yioe Y, Liu SQ, Huang D. Germination dramatically increases isoflavonoid content and diversity in chickpea (Cicer arietinum L.) seeds. J Agric Food Chem 2012; 60: 8606-8615
    CrossrefPubMedGoogle Scholar
  • 33 Hloucalova P, Skladanka J, Horky P, Klejdus B, Pelikan J, Knotova D. Determination of phytoestrogen content in fresh-cut legume forage. Animals (Basel) 2016; 6: 43
    CrossrefPubMedGoogle Scholar
  • 34 Chukwumah Y, Walker L, Vogler B, Verghese M. Changes in the phytochemical composition and profile of raw, boiled, and roasted peanuts. J Agric Food Chem 2007; 55: 9266-9273
    CrossrefPubMedGoogle Scholar
  • 35 Kuhnle GG, DellʼAquila C, Aspinall SM, Runswick SA, Mulligan AA, Bingham SA. Phytoestrogen content of beverages, nuts, seeds, and oils. J Agric Food Chem 2008; 56: 7311-7315
    CrossrefPubMedGoogle Scholar