Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 387, Issue 9, pp 823–835 | Cite as

Oral administration of quercetin is unable to protect against isoproterenol cardiotoxicity

  • Michal Říha
  • Marie Vopršalová
  • Veronika Pilařová
  • Vladimír Semecký
  • Magdalena Holečková
  • Jaroslava Vávrová
  • Vladimir Palicka
  • Tomáš Filipský
  • Radomír Hrdina
  • Lucie Nováková
  • Přemysl Mladěnka
Original Article

Abstract

Catecholamines are endogenous amines that participate in the maintenance of cardiovascular system homeostasis. However, excessive release or exogenous administration of catecholamines is cardiotoxic. The synthetic catecholamine, isoprenaline (isoproterenol, ISO), with non-selective β-agonistic activity has been used as a viable model of acute myocardial toxicity for many years. Since the pathophysiology of ISO–cardiotoxicity is complex, the aim of this study was to elucidate the effect of oral quercetin pretreatment on myocardial ISO toxicity. Wistar–Han rats were randomly divided into four groups: solvent or quercetin administered orally by gavage in a dose of 10 mg kg−1 daily for 7 days were followed by s.c. water for injection or ISO in a dose of 100 mg kg−1. Haemodynamic, ECG and biochemical parameters were measured; effects on blood vessels and myocardial histology were assessed, and accompanying pharmacokinetic analysis was performed. Quercetin was unable to protect the cardiovascular system against acute ISO cardiotoxicity (stroke volume decrease, cardiac troponin T release, QRS-T junction elevation and histological impairment). The sole positive effect of quercetin on catecholamine-induced cardiotoxicity was the normalization of increased left ventricular end-diastolic pressure caused by ISO. Quercetin did not reverse the increased responsiveness of rat aorta to vasoconstriction in ISO-treated animals, but it decreased the same parameter in the control animals. Accompanying pharmacokinetic analysis showed absorption of quercetin and its metabolite 3-hydroxyphenylacetic acid formed by bacterial microflora. In conclusion, a daily oral dose of 10 mg kg−1 of quercetin for 7 days did not ameliorate acute ISO–cardiovascular toxicity in rats despite minor positive cardiovascular effects.

Keywords

Cardiotoxicity Catecholamine Isoproterenol Quercetin 

References

  1. Afanas'ev IB, Dorozhko AI, Brodskii AV, Kostyuk VA, Potapovitch AI (1989) Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol 38:1763–1769PubMedCrossRefGoogle Scholar
  2. Ajay M, Gilani AU, Mustafa MR (2003) Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta. Life Sci 74:603–612PubMedCrossRefGoogle Scholar
  3. Beinfield WH, Lehr D (1968) QRS-T variations in the rat electrocardiogram. Am J Physiol 214:197–204PubMedGoogle Scholar
  4. Bieger J, Cermak R, Blank R, de Boer VC, Hollman PC, Kamphues J, Wolffram S (2008) Tissue distribution of quercetin in pigs after long-term dietary supplementation. J Nutr 138:1417–1420PubMedGoogle Scholar
  5. Blasig IE, Zipper J, Muschick P, Modersohn D, Lowe H (1985) Absolute and relative myocardial ischemia by isoproterenol overdosage. Biomed Biochim Acta 44:1641–1649PubMedGoogle Scholar
  6. Cermak R, Landgraf S, Wolffram S (2003) The bioavailability of quercetin in pigs depends on the glycoside moiety and on dietary factors. J Nutr 133:2802–2807PubMedGoogle Scholar
  7. Chagoya de Sanchez V, Hernandez-Munoz R, Lopez-Barrera F, Yanez L, Vidrio S, Suarez J, Cota-Garza MD, Aranda-Fraustro A, Cruz D (1997) Sequential changes of energy metabolism and mitochondrial function in myocardial infarction induced by isoproterenol in rats: a long-term and integrative study. Can J Physiol Pharmacol 75:1300–1311PubMedGoogle Scholar
  8. Cialdella-Kam L, Nieman DC, Sha W, Meaney MP, Knab AM, Shanely RA (2013) Dose-response to 3 months of quercetin-containing supplements on metabolite and quercetin conjugate profile in adults. Br J Nutr 109(11):1923–1933PubMedCrossRefGoogle Scholar
  9. Clements P, Brady S, York M, Berridge B, Mikaelian I, Nicklaus R, Gandhi M, Roman I, Stamp C, Davies D, McGill P, Williams T, Pettit S, Walker D, Turton J (2010) Time course characterization of serum cardiac troponins, heart fatty acid-binding protein, and morphologic findings with isoproterenol-induced myocardial injury in the rat. Toxicol Pathol 38:703–714PubMedCrossRefGoogle Scholar
  10. Costa VM, Carvalho F, Bastos ML, Carvalho RA, Carvalho M, Remiao F (2011) Contribution of catecholamine reactive intermediates and oxidative stress to the pathologic features of heart diseases. Curr Med Chem 18:2272–2314PubMedCrossRefGoogle Scholar
  11. Dhalla NS, Adameova A, Kaur M (2010) Role of catecholamine oxidation in sudden cardiac death. Fundam Clin Pharmacol 24:539–546PubMedCrossRefGoogle Scholar
  12. Diaz-Munoz M, Alvarez-Perez MA, Yanez L, Vidrio S, Martinez L, Rosas G, Yanez M, Ramirez S, de Sanchez VC (2006) Correlation between oxidative stress and alteration of intracellular calcium handling in isoproterenol-induced myocardial infarction. Mol Cell Biochem 289:125–136PubMedCrossRefGoogle Scholar
  13. Doss RC, Perkins JP, Harden TK (1981) Recovery of beta-adrenergic receptors following long term exposure of astrocytoma cells to catecholamine. Role of protein synthesis. J Biol Chem 256:12281–12286PubMedGoogle Scholar
  14. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T (2007) Quercetin reduces blood pressure in hypertensive subjects. J Nutr 137:2405–2411PubMedGoogle Scholar
  15. Egert S, Wolffram S, Bosy-Westphal A, Boesch-Saadatmandi C, Wagner AE, Frank J, Rimbach G, Mueller MJ (2008) Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr 138:1615–1621PubMedGoogle Scholar
  16. Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, Plachta-Danielzik S, Wagner AE, Frank J, Schrezenmeir J, Rimbach G, Wolffram S, Muller MJ (2009) Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 102:1065–1074PubMedCrossRefGoogle Scholar
  17. Ellison GM, Torella D, Karakikes I, Purushothaman S, Curcio A, Gasparri C, Indolfi C, Cable NT, Goldspink DF, Nadal-Ginard B (2007) Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem 282:11397–11409PubMedCentralPubMedCrossRefGoogle Scholar
  18. Erlund I, Kosonen T, Alfthan G, Maenpaa J, Perttunen K, Kenraali J, Parantainen J, Aro A (2000) Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 56:545–553PubMedCrossRefGoogle Scholar
  19. Feng W, Li W (2010) The study of ISO induced heart failure rat model. Exp Mol Pathol 88:299–304PubMedCrossRefGoogle Scholar
  20. Filipsky T, Zatloukalova L, Mladenka P, Hrdina R (2012) Acute initial haemodynamic changes in a rat isoprenaline model of cardiotoxicity. Hum Exp Toxicol 31:830–843PubMedCrossRefGoogle Scholar
  21. Galindo P, Gonzalez-Manzano S, Zarzuelo MJ, Gomez-Guzman M, Quintela AM, Gonzalez-Paramas A, Santos-Buelga C, Perez-Vizcaino F, Duarte J, Jimenez R (2012) Different cardiovascular protective effects of quercetin administered orally or intraperitoneally in spontaneously hypertensive rats. Food Funct 3:643–650PubMedCrossRefGoogle Scholar
  22. Graefe EU, Derendorf H, Veit M (1999) Pharmacokinetics and bioavailability of the flavonol quercetin in humans. Int J Clin Pharmacol Ther 37:219–233PubMedGoogle Scholar
  23. Hendriks T, Assmann RF (1990) Spectrophotometric correction for bile pigments in the thiobarbituric acid test for malondialdehyde-like substances in plasma. Med Lab Sci 47:10–16PubMedGoogle Scholar
  24. Hertel C, Perkins JP (1984) Receptor-specific mechanisms of desensitization of beta-adrenergic receptor function. Mol Cell Endocrinol 37:245–256PubMedCrossRefGoogle Scholar
  25. Jalili T, Carlstrom J, Kim S, Freeman D, Jin H, Wu TC, Litwin SE, David Symons J (2006) Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction. J Cardiovasc Pharmacol 47:531–541PubMedCrossRefGoogle Scholar
  26. Joseph X, Whitehurst VE, Bloom S, Balazs T (1981) Enhancement of cardiotoxic effects of beta-adrenergic bronchodilators by aminophylline in experimental animals. Fundam Appl Toxicol 1:443–447PubMedCrossRefGoogle Scholar
  27. Karthick M, Prince SM (2006) Preventive effect of rutin, a bioflavonoid, on lipid peroxides and antioxidants in isoproterenol-induced myocardial infarction in rats. J Pharm Pharmacol 58:701–707PubMedCrossRefGoogle Scholar
  28. Kubota Y, Umegaki K, Tanaka N, Mizuno H, Nakamura K, Kunitomo M, Shinozuka K (2002) Safety of dietary supplements: chronotropic and inotropic effects on isolated rat atria. Biol Pharm Bull 25:197–200PubMedGoogle Scholar
  29. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD (2008a) Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr 88:1018–1025PubMedGoogle Scholar
  30. Loke WM, Proudfoot JM, McKinley AJ, Needs PW, Kroon PA, Hodgson JM, Croft KD (2008b) Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation. J Agric Food Chem 56:3609–3615PubMedCrossRefGoogle Scholar
  31. Manach C, Morand C, Texier O, Favier ML, Agullo G, Demigne C, Regerat F, Remesy C (1995) Quercetin metabolites in plasma of rats fed diets containing rutin or quercetin. J Nutr 125:1911–1922PubMedGoogle Scholar
  32. Mladenka P, Hrdina R, Bobrovova Z, Semecky V, Vavrova J, Holeckova M, Palicka V, Mazurova Y, Nachtigal P (2009a) Cardiac biomarkers in a model of acute catecholamine cardiotoxicity. Hum Exp Toxicol 28:631–640PubMedCrossRefGoogle Scholar
  33. Mladenka P, Zatloukalova L, Simunek T, Bobrovova Z, Semecky V, Nachtigal P, Haskova P, Mackova E, Vavrova J, Holeckova M, Palicka V, Hrdina R (2009b) Direct administration of rutin does not protect against catecholamine cardiotoxicity. Toxicology 255:25–32PubMedCrossRefGoogle Scholar
  34. Neri M, Cerretani D, Fiaschi AI, Laghi PF, Lazzerini PE, Maffione AB, Micheli L, Bruni G, Nencini C, Giorgi G, D'Errico S, Fiore C, Pomara C, Riezzo I, Turillazzi E, Fineschi V (2007) Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine administration in rats. J Cell Mol Med 11:156–170PubMedGoogle Scholar
  35. Olthof MR, Hollman PC, Buijsman MN, van Amelsvoort JM, Katan MB (2003) Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans. J Nutr 133:1806–1814PubMedGoogle Scholar
  36. Pick R, Jalil JE, Janicki JS, Weber KT (1989) The fibrillar nature and structure of isoproterenol-induced myocardial fibrosis in the rat. Am J Pathol 134:365–371PubMedCentralPubMedGoogle Scholar
  37. Prince PS (2011) A biochemical, electrocardiographic, electrophoretic, histopathological and in vitro study on the protective effects of (-)epicatechin in isoproterenol-induced myocardial infarcted rats. Eur J Pharmacol 671:95–101PubMedCrossRefGoogle Scholar
  38. Prince PS, Sathya B (2010) Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats. Eur J Pharmacol 635:142–148PubMedCrossRefGoogle Scholar
  39. Prochazkova D, Bousova I, Wilhelmova N (2011) Antioxidant and prooxidant properties of flavonoids. Fitoterapia 82:513–523PubMedCrossRefGoogle Scholar
  40. Raff GL, Glantz SA (1981) Volume loading slows left ventricular isovolumic relaxation rate. Evidence of load-dependent relaxation in the intact dog heart. Circ Res 48:813–824PubMedCrossRefGoogle Scholar
  41. Ramesh CV, Malarvannan P, Jayakumar R, Jayasundar S, Puvanakrishnan R (1998) Effect of a novel tetrapeptide derivative in a model of isoproterenol induced myocardial necrosis. Mol Cell Biochem 187:173–182PubMedCrossRefGoogle Scholar
  42. Rona G (1985) Catecholamine cardiotoxicity. J Mol Cell Cardiol 17:291–306PubMedCrossRefGoogle Scholar
  43. Rona G, Chappel CI, Balazs T, Gaudry R (1959) An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. AMA Arch Pathol 67:443–455PubMedGoogle Scholar
  44. Sawai Y, Kohsaka K, Nishiyama Y, Ando K (1987) Serum concentrations of rutoside metabolites after oral administration of a rutoside formulation to humans. Arzneimittelforschung 37:729–732PubMedGoogle Scholar
  45. Shanely RA, Knab AM, Nieman DC, Jin F, McAnulty SR, Landram MJ (2010) Quercetin supplementation does not alter antioxidant status in humans. Free Radic Res 44:224–231PubMedCrossRefGoogle Scholar
  46. Singal PK, Kapur N, Dhillon KS, Beamish RE, Dhalla NS (1982) Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 60:1390–1397PubMedGoogle Scholar
  47. Strobel NA, Fassett RG, Marsh SA, Coombes JS (2011) Oxidative stress biomarkers as predictors of cardiovascular disease. Int J Cardiol 147:191–201PubMedGoogle Scholar
  48. Weiss JL, Frederiksen JW, Weisfeldt ML (1976) Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest 58:751–760PubMedCentralPubMedCrossRefGoogle Scholar
  49. Wexler BC, McMurtry JP (1981) Allopurinol amelioration of the pathophysiology of acute myocardial infarction in rats. Atherosclerosis 39:71–87PubMedCrossRefGoogle Scholar
  50. Widimský P, Špaček R (2004) Infarkt myokardu. In: Aschermann M (ed) Kardiologie, vol 1. Galén, Praha [book in Czech]Google Scholar
  51. Zatloukalova L, Filipsky T, Mladenka P, Semecky V, Macakova K, Holeckova M, Vavrova J, Palicka V, Hrdina R (2012) Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity. Can J Physiol Pharmacol 90:473–484PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Michal Říha
    • 1
  • Marie Vopršalová
    • 1
  • Veronika Pilařová
    • 2
  • Vladimír Semecký
    • 3
  • Magdalena Holečková
    • 4
    • 5
  • Jaroslava Vávrová
    • 4
    • 5
  • Vladimir Palicka
    • 4
    • 5
  • Tomáš Filipský
    • 1
  • Radomír Hrdina
    • 1
  • Lucie Nováková
    • 2
  • Přemysl Mladěnka
    • 1
  1. 1.Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  2. 2.Department of Analytical Chemistry, Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  3. 3.Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  4. 4.Faculty of Medicine in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  5. 5.University Hospital Hradec KrálovéHradec KrálovéCzech Republic

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