COMPARISON OF INOTROPIC AND ANTIARRHYTHMIC ACTIVITY OF FLAVONOIDS — QUERCETIN, RUTIN AND (+)-CATECHIN

Aim. Studying of inotropic and antiarrhythmic action of flavonoids — quercetin, rutin and (+)-catechin on functional activity of rodent myocardium.

Material and methods. Mechanical parameters of papillary muscle in isometric regimen were registered via the sensor F30, in simulation with the impulses 5-10 ms duration and amplitude, higher than threshold for ~20%. For defining of flavonoids action mechanism we used the inhibitory method of the being studied compounds with ion-transporting system and receptors of cardiomyocytes sarcolemma. To study antiarrhythmic action of flavonoids we used the method of experimental acotinin-induced arrhythmia.

Results. It is found that quercetin and rutin have biphasic inotropic effect on contractility of rodent papillary muscle, and rutin leads to significantly lower positive inotropic effect than quercetin. In diapason of higher concentrations quercetin (100-200 mcM) and
rutin (200-300) lead just to negative inotropic effect. In such conditions the value of ЕС50 for quercetin and rutin was 229 mcM or pD2 (–log EC50)=3,64 and 245,4 mcM or pD2 (–log EC50)=3,61 resp. It was found that (+)-catechin shows only negative inotropic
effect (ЕС50=45,7 mcM and pD2 (–log EC50)=4,34). In incubation of the muscle with (±)-propranolol (10 mcM), blocker of Ἰ-adrenoreceptor, there is a decrease of positive inotropic effect of quercetin and rutin. In experiments we found that in presence of
Са2+L-channel antagonist — nifedipine (ЕС50), querctin (229 mcM), rutin (245,4 mcM) and (+)-catechin (45,7 mcM) additionally decreased the amplitude of myocardium contractile response by 41,3±5,4%, 43,6±6,5% and 37,2±4,8%, resp, relatively to nifedipine effect. Revealed, that the studied flavonoids, in 20-25 min after addition to the incubation medium, suppress the rate of arrhythmia, caused by aconitin (1 mcM). Also the most effective was quercetin, and in concentration 100 mcM it decreases the rate of
tachycardia, caused by aconitine from от 264±14 bpm to 32±12 bpm.

Conclusion. Analyzing the data obtained, it is possible to presume that positive inotropic effect of quercetin and rutin might be related to their activtion of ⊘-andrenoreceptors, which causes the increase of [cAMP]in and, hence leads to increase of intracellular [Ca2+]in in cardiomyocytes. Negative action of the studied flavonoids might be relevant to their interaction with Са2+-channels of cardiomyocytes sarcolemma. Also the action of the flavonoids might be related to the production of functional activity modulation of Na+ and Са2+-channels in cardiomyocytes.

1. Malik A. Catechins and Proanthocyanidins from Zizizphus jujuba and Alhagi sparsifolia. Avtoreferat of Thesis c.ch.n., Tashkent, 1998: 3-18. Russian (Малик А. Катехины и проантоцианидины Zizizphus jujuba и Alhagi sparsifolia. Автореферат дисс. ... к. х.н. Ташкент, 1998: 3-18).

2. Olchowika E, Sciepuka A, Mavlyanov S, et al. Antioxidant capacities of polyphenols from Sumac (Rhus typhina L.) leaves in protection of erythrocytes against oxidative damage. Biomedicine & Preventive Nutrition 2012; 2(2): 99-105a.

3. Olchowik E, Lotkowski K, Mavlyanov S, et al. Stabilization of erythrocyte against xidative and hypotonic stress by some tannins isolated from sumac (Rhus typhina L.) leaves and grape seeds (Vitis vinifera L.). Cellular & Molecular Biology Letters 2012; 17: 333-348b.

4. Olchowik-Grabarek E, Swiecicka I, et al. Role of structural changes induced in biological membranes by hydrolysable tannins from Sumac leaves (Rhus typhina L.) in their antihemolytic and antibacterial effects. J Membrane Biol 2014: 533-40.

5. Borisov МP, Kataev AA, Mavlyanov SM,et al. Action of hydrolized tannin on native and artificial biological membranes. J Biological membranes 2014; 31(4): 278-87. Russian (Борисова М. П., Катаев А. А., Мавлянов С. М., и др. Действие гидролизуемого танина на нативные и искусственные биологические мембраны. Биологические мембраны 2014; 31(4): 27887).

6. Larson AJ, Symons JD, Jalili T. Therapeutic potential of Quercetin to decrease blood pressure: Review of efficacy and mechanisms. Adv Nutr 2012; 3: 39-46.

7. Kleemann R, Verschuren L, Morrison M, et al. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis 2011; 218: 44-52.

8. Gross M. Flavonoids and cardiovascular disease. Pharm Biology 2004; 42: 21-35.

9. Tarakhovskiy YS, et al. Phlovonoids: biochemistry, biophysics, medicine. Pushino. Sуnchrobook, 2013. Russian (Тараховский Ю. С. и др. Флавоноиды: биохимия, биофизика, медицина. Пущино: Sуnchrobook, 2013).

10. Wright SN. Comparison of aconitine-modified human heart (hH1) and rat skeletal (micro 1) muscle Na+ channels: an important role for external Na+ ions. J Physiol 2002; 538: 759-71.

11. Schьssler M, Hцlzl J, Fricke U. Myocardial effects of flavonoids from Crataegus species. Arzneim Forschung Drug Res 1995; 45:842-5.

12. Alloatti G, Marcantoni A, Levi R, et al. Phosphoinositide 3-kinase c controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level. FEBS Letters 2005; 579: 133-40.

13. Hirano T, Oka K, Akiba M. Effects of synthetic and naturally occurring flavonoids on Na+/K+-ATPase: aspects of the structure-activity relationship and action mechanism. Life Sci 1989; 45(12): 1111-7.

14. Umarova FT, Khushbactova ZA, Batirov EH, et al. Inhibition of Na+/K+-ATPase by flavonoids and their inotropic effect. Investigation of the structure-activity relationship. Membr Cell Biol 1998; 12: 27-40.

15. Tang JS, Hou YL, Gao H, et al. Polyphenols from Parabarium huaitingii and their positive inotropic and anti-myocardial infarction effects in rats. Phytomedicine 2011; 18(7): 544-50.

16. Wen-Feng C, Guo-Fen Q, Yan-Jie L, et al. Flavonoids from Chinese Viscum coloratum: antiarrhythmic efficacy and ionic mechanisms. Phytother Res 2006; 20: 1100-12.

17. Kurcok A. Ischaemia- and reperfusion-induced cardiac injury: effects of two flavonoid containing plant extracts possessing radical scavenging properties. Naunyn-Schmiebergнs Arch Pharmacol 1992; 345: R81.

18. Wu JX, Yu GR, Wang BY, et al. Effects of Viscum coloratum flavonoids on fast response action potentials of hearts. Zhong guo Yao Li Xue Bao 1994; 15: 169-72.

19. Wallace CH, Baczkу I, Jones L, et al. Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. Br J Pharmacol 2006; 149(6): 657-65