, Volume 35, Issue 6, pp 2089–2097 | Cite as

Effects of taxifolin on the activity of angiotensin-converting enzyme and reactive oxygen and nitrogen species in the aorta of aging rats and rats treated with the nitric oxide synthase inhibitor and dexamethasone

  • Tamara V. Arutyunyan
  • Antonina F. Korystova
  • Ludmila N. Kublik
  • Maria Kh. Levitman
  • Vera V. Shaposhnikova
  • Yuri N. KorystovEmail author


The action of taxifolin on the angiotensin-converting enzyme (ACE) and the formation of reactive oxygen and nitrogen species (ROS/RNS) in the aorta of aging rats and rats treated with nitric oxide synthase inhibitor (N ω-nitro-l-arginine methyl ester (L-NAME)) or dexamethasone have been studied. The ACE activity in aorta sections was determined by measuring the hydrolysis of hippuryl-l-histidyl-l-leucine, and the ROS/RNS production was measured by oxidation of dichlorodihydrofluorescein. It was shown that taxifolin at a dose of 30–100 μg/kg/day decreases the ACE activity in the aorta of aging rats and of rats treated with L-NAME or dexamethasone to the level of the ACE activity in young control rats. Taxifolin (100 μg/kg/day) was found to also reduce the amount of ROS/RNS in the aorta that increased as a result of L-NAME intake. L-NAME treatment increases the contribution of 5-lipoxygenase and NADPH oxidase to ROS/RNS production in the aorta, while taxifolin (100 μg/kg/day) decreases the contribution of these enzymes to the normal level.


Aging Angiotensin-converting enzyme Aorta Dexamethasone L-NAME Taxifolin ROS/RNS 


  1. Ackermann A, Fernandez-Alfonso MS, Sanchez-de-Rojas R, Ortega T, Paul M, Gonzales C (1998) Modulation of angiotensin-converting enzyme by nitric oxide. Br J Pharmacol 124:291–298PubMedCrossRefGoogle Scholar
  2. Actis-Gorettaa L, Ottaviania JI, Keenb CL, Fragaa CG (2003) Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett 555:597–600CrossRefGoogle Scholar
  3. Actis-Gorettaa L, Ottaviania JI, Fragaa CG (2006) Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. J Agricult Food Chem 54:229–234CrossRefGoogle Scholar
  4. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F (2007) Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293:H1351–H1358PubMedCrossRefGoogle Scholar
  5. Braga FC, Serra CP, Viana Junior NS, Oliveira AB, Cortes SF, Lombardi JA (2007) Angiotensin-converting enzyme inhibition by Brazilian plants. Fitoterapia 78:353–358PubMedCrossRefGoogle Scholar
  6. Choi H, Leto TL, Hunyady L, Catt KJ, Bae YS, Rhee SG (2008) Mechanism of angiotensin II-induced superoxide production in cells reconstituted with angiotensin type 1 receptor and the components of NADPH oxidase. J Biol Chem 283:255–267PubMedCrossRefGoogle Scholar
  7. Deschamps JD, Kenyon VA, Holman TR (2006) Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases. Bioorg Med Chem 14:4295–4301PubMedCrossRefGoogle Scholar
  8. Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A, Tamargo J (2001) Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol 133:117–124PubMedCrossRefGoogle Scholar
  9. Dzau VJ (2001) Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 37:1047–1052PubMedCrossRefGoogle Scholar
  10. Emel’yanov MO, Korystova AF, Kublik LN, Levitman MK, Shaposhnikova VV, Korystov YN (2012) Low doses of ethanol decrease the activity of the angiotensin-converting enzyme in the aorta of aging rats and rats treated with a nitric oxide synthase inhibitor and dexamethasone. Clin Sci 122:75–81PubMedCrossRefGoogle Scholar
  11. Galisteo M, Garcia-Saura MF, Jimenez R, Villar IC, Zarzuelo A, Vargas F, Duarte J (2004) Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt-hypertensive rats. Mol Cell Biochem 259:91–99PubMedCrossRefGoogle Scholar
  12. Grassi D, Desideri G, Ferri C (2010) Flavonoids: antioxidants against atherosclerosis. Nutrients 2:889–902PubMedCrossRefGoogle Scholar
  13. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW (1994) Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74:1141–1148PubMedCrossRefGoogle Scholar
  14. Hamberg M (1976) On the formation of thromboxane B2 and 12L-hydroxy-5, 8,10,14-eicosatetraenoic acid (12 ho-20:4) in tissues from the guinea pig. Biochim Biophys Acta 431:651–654PubMedCrossRefGoogle Scholar
  15. Hansen K, Adsersen A, Smitt UW, Nyman U, Christensen SB, Schwartner C, Wagner H (1996) Angiotensin converting enzyme (ACE) inhibitory flavonoids from Erythroxylum laurifolium. Phytomedicine 2:313–317PubMedCrossRefGoogle Scholar
  16. Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M (1997) Reduced progression of atherosclerosis in apolipoprotein E-deficient mice after consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol 17:2744–2752PubMedCrossRefGoogle Scholar
  17. Heeneman S, Sluimer JC, Daemen M (2007) Angiotensin-converting enzyme and vascular remodeling. Circ Res 101:441–454PubMedCrossRefGoogle Scholar
  18. Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D (1993) Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 342:1007–1111PubMedCrossRefGoogle Scholar
  19. Hishikawa K, Nakaki T, Fujita T (2005) Oral flavonoid supplementation attenuates atherosclerosis development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:442–446PubMedCrossRefGoogle Scholar
  20. Kameda K, Takaku T, Okuda H, Rimura Y (1987) Inhibitory effects of various flavonoids isolated from leaves of persimmon on angiotensin-converting enzyme activity. J Nat Prod 50:680–683PubMedCrossRefGoogle Scholar
  21. Kato H, Hou J, Chobanian AV, Brecher P (1996) Effects of angiotensin II infusion and inhibition of nitric oxide synthase on the rat aorta. Hypertension 28:153–158PubMedCrossRefGoogle Scholar
  22. Katoh M, Egashira K, Kataoka C, Usui M, Koyanagi M, Kitamoto S, Ohmachi Y, Takeshita A, Narita H (2001) Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats. Am J Physiol Heart Circ Physiol 280:H2306–H2312PubMedGoogle Scholar
  23. Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–34PubMedGoogle Scholar
  24. Kitts DD, Yuan YV, Godin DV (1998) Plasma and lipoprotein lipid composition and hepatic antioxidant status in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Can J Physiol Pharmacol 76:202–209PubMedCrossRefGoogle Scholar
  25. Korystov YN, Emel’yanov MO, Korystova AF, Levitman MK, Shaposhnikova VV (2009) Determination of reactive oxygen and nitrogen species in rat aorta using the dichlorofluorescein assay. Free Radic Res 43:149–155PubMedCrossRefGoogle Scholar
  26. Korystova AF, Emel’yanov MO, Kublik LN, Levitman MK, Shaposhnikova VV, Kim YA, Korystov YN (2012) Distribution of the activity of the angiotensin-converting enzyme in the rat aorta and changes in the activity with aging and by the action of L-NAME. Age 34:821–830PubMedCrossRefGoogle Scholar
  27. Koshihara Y, Neichi T, Murota S, Lao A, Fujimoto Y, Tatsuno T (1984) Caffeic acid is a selective inhibitor for leukotriene biosynthesis. Biochim Biophys Acta 792:92–97PubMedCrossRefGoogle Scholar
  28. Koyanagi M, Egashira K, Kubo-Inoue M, Usui M, Kitamoto S, Tomita H, Shimokawa H, Takeshita A (2000) Role of transforming growth factor-1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis. Hypertension 35:86–90PubMedCrossRefGoogle Scholar
  29. Lacaille-Dubois MA, Franck U, Wagner H (2001) Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants. Phytomedicine 8:47–52PubMedCrossRefGoogle Scholar
  30. Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG (2002) Role of p47phox in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40:511–515PubMedCrossRefGoogle Scholar
  31. Linz W, Wohlfarta P, Scholkensa BA, Malinskib T, Wiemer G (1999) Interactions among ACE, kinins and NO. Cardiovasc Res 43:549–561PubMedCrossRefGoogle Scholar
  32. Liu D, Homan LL, Dillon JS (2004) Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 3′,5′-monophosphate-dependent mechanism. Endocrinology 145:5532–5539PubMedCrossRefGoogle Scholar
  33. Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A, Menichini F (2007) Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae). Phytother Res 21:32–36PubMedCrossRefGoogle Scholar
  34. Luchtefeld M, Drexler H, Schieffer B (2003) 5-Lipoxygenase is involved in the angiotensin II-induced NAD(P)H oxidase activation. Biochem Biophys Res Commun 308:668–672PubMedCrossRefGoogle Scholar
  35. Maron DJ (2004) Flavonoids for reduction of atherosclerotic risk. Curr Atheroscler Rep 6:73–78PubMedCrossRefGoogle Scholar
  36. Mehrabian M, Allayee H (2003) 5-Lipoxygenase and atherosclerosis. Cur Opin Lipidol 14:447–457CrossRefGoogle Scholar
  37. Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–C97PubMedCrossRefGoogle Scholar
  38. Meunier M-T, Villié F, Jonadet M, Bastide J, Bastide P (1987) Inhibition of angiotensin I converting enzyme by flavanolic compounds: in vitro and in vivo studies. Planta Med 53:12–15PubMedCrossRefGoogle Scholar
  39. Miyamoto A, Murata S, Nishio A (2002) Role of ACE and NEP in bradykinin-induced relaxation and contraction response of isolated porcine basilar artery. Naunyn-Schmiedeberg’s Arch Pharmacol 365:365–370CrossRefGoogle Scholar
  40. Morrow JD, Roberts LJ (1996) The isoprostanes. Current knowledge and directions for future research. Biochem Pharmacol 51:1–9PubMedCrossRefGoogle Scholar
  41. Munzel T, Keaney JF (2001) Are ACE inhibitors a “magic bullet” against oxidative stress? Circulation 104:1571–1574PubMedCrossRefGoogle Scholar
  42. Nandave M, Ojha SK, Arya DS (2005) Protective role of flavonoids in cardiovascular diseases. Nat Prod Radiance 4:166–176Google Scholar
  43. Nashel DJ (1986) Is atherosclerosis a complication of long-term corticosteroid treatment. Am J Med 80:925–929PubMedCrossRefGoogle Scholar
  44. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916–1923PubMedCrossRefGoogle Scholar
  45. Reed J (2002) Cranberry flavonoids, atherosclerosis and cardiovascular health. Crit Rev Food Sci Nutr 42:301–316PubMedCrossRefGoogle Scholar
  46. Sampson L, Rimm E, Hollman PC, de Vries JH, Katan MB (2002) Flavonol and flavone intakes in US health professionals. J Am Diet Assoc 102:1414–1420PubMedCrossRefGoogle Scholar
  47. Saruta T (1996) Mechanism of glucocorticoid-induced hypertension. Hypertens Res 19:1–8PubMedCrossRefGoogle Scholar
  48. Serhan CN (1997) Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell–cell interactions or a therapeutic opportunity. Prostaglandins 53:107–137PubMedGoogle Scholar
  49. Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts ACG, Leufkens HGM, Walker BR (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study. Heart 90:859–865PubMedCrossRefGoogle Scholar
  50. Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A (1997) Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 99:278–287PubMedCrossRefGoogle Scholar
  51. Xu Y-Y, Yang C, Li S-N (2006) Effects of genistein on angiotensin-converting enzyme in rats. Life Sci 24:828–837CrossRefGoogle Scholar

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Tamara V. Arutyunyan
    • 1
  • Antonina F. Korystova
    • 1
  • Ludmila N. Kublik
    • 1
  • Maria Kh. Levitman
    • 1
  • Vera V. Shaposhnikova
    • 1
  • Yuri N. Korystov
    • 1
    Email author
  1. 1.Institute of Theoretical and Experimental BiophysicsRussian Academy of SciencesPushchinoRussia

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