Metilin Improves Cardiac Function in Rabbits With Chronic Heart Failure

Aim. To study effects of intravenous infusion of a cardioprotective drug metilin, developed at the “National Medical Research Center of Cardiology” on indices of cardiac function in rabbits in vivo after prolonged administration of doxorubicin. Materials and Methods. Animals of the experimental group were intravenously injected with doxorubicin (2 mg/kg once a week) for 8 weeks, animals of the control group received the same volume of saline. Myocardial damage was characterized by an increase in concentration of malondialdehyde (MDA), troponin (TnI) and MB-fraction of creatine kinase (CK-MB) in venous blood and by disturbances in the left ventricle (LV) structure at morphological examination. Metilin effects on cardiac function were assessed by echocardiography and LV catheterization by the Millar catheter tip pressure transducer. Results. Doxorubicin administration led to a decrease of the body mass of animals, an increase of the plasma concentration of cardiac markers CK-MB and TnI, lipid peroxidation (LPO) product MDA in venous blood, and pronounced disturbances in the structure of LV fibers and microvessels. At the same time, a significant decrease of myocardial contractility indices was observed. Manifestations of this decrease were increase of the end-diastolic and end-systolic dimensions (EDD and ESD, respectively), and decreases in the shortening fraction and ejection fraction (SF and EF, respectively) com pared to baseline values. These changes indicated development of chronic heart failure (CHF) in animals of the experimental group. Against this background, intravenous infusion of metilin significantly increased SF and EF, but did not affect the heart rate. Beneficial effects of metilin on the indices of cardiac contractility and relaxation were maintained after the infusion was stopped. Noteworthy, metilin exerted greater influence on cardiac function of rabbits with CHF compared to control animals that did not receive doxorubicin. Conclusion. The obtained results indicate the potential of metilin to reduce LV dysfunction during chemotherapy with doxorubicin.

метилин, хроническая сердечная недостаточность, доксорубицин, функция сердца, кролики, metilin, CHF, doxorubicin, cardiac function, rabbits

1. Carvalho C., Santos R. X., Cardoso S. et al. Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem 2009;16:3267-3285. DOI: 10.2174/092986709788803312

2. Minotti G., Menna P., Salvatorelli E. et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56:185-229. DOI: 10.1124/pr. 56.2.6.

3. Myers C. E., McGuire W. P., Liss R. H. et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977;197:165-167. DOI: 10.1126/science. 877547

4. Tokarska-Schlattner M., Wallimann T., Schlattner U. Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin. C. R. Biol 2006;329:657-668. DOI:10.1016/j.crvi. 2005.08.007

5. Wang G. X., Wang Y. X., Zhou X. B. et al. Effects of doxorubicinol on excitation-contraction coupling in guinea pig ventricular myocytes. EurJ Pharmacol 2001;423:99-107. doi.org/10.1016/S0014-2999 (01) 01096-2

6. Капелько В. И., Вилиамс К., Морган Дж. П. Концентрация Са2+ в миоплазме кардиомиоцитов и сократительная функция сердца на ранней стадии адриамициновой кардиомиопатии. Кардиология 1996;12:57-61.

7. Bertinchant J. P., Polge A., Juan J. M. et al. Evaluation of cardiac troponin I. and T. levels as markers of myocardial damage in doxorubicin-induced cardiomyopathy rats, and their relationship with echocardiographic and histological findings. Clin Chim Acta 2003;329:39-51. doi.org/10.1016/S0009-8981 (03) 00013-5

8. Koutinos G., Stathopoulos G. P., Dontas I. et al. The effect of doxorubicin and its analogue mitoxantrone on cardiac muscle and on serum lipids: an experimental study. Anticancer Res 2002;22:815-820. PMID: 12014656

9. Wakabayashi I., Groschner K. Vascular actions of anthracycline antibiotics. Curr Med Chem 2003;10:427-436. DOI: 10.2174/0929867033368259

10. Vaidyanathan S., Boroujerdi M. Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin. Cancer Chemother Pharmacol 2000;46:93-100. DOI: 10.1007/s002800000122

11. Ocal B., Oguz D., Karademir S. et al. Myocardial performance index combining systolic and diastolic myocardial performance in doxorubicin-treated patients and its correlation to conventional echo/Doppler indices. Pediatr Cardiol 2002;23:522-527. PMID: 12211201

12. Swain S., Whaley F. S., Ewer M. S. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97:2869-2879. DOI: 10.1002/cncr. 11407

13. Ichikawa Y., Ghanefar M., Bayeva M. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation J. Clin Invest 2014;124:617-630. DOI: 10.1172/JCI72931

14. Salouege I., Ben A. R., Ben S. D. et al. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J. Cancer Res Ther 2014;10:274-278. DOI: 10.4103/0973-1482.136557

15. Greenlee H., Shaw J., Lau Y-K. et al. Effect of coenzyme Q10 on doxorubicin cytotoxicity in breast cancer cell cultures. Integr Cancer Ther 2012;11: DOI: 10.1177/1534735412439749.

16. Dong Q., Chen L., Lu Q. et al. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression. Br J. Pharmacol 2014;171:4440-4454. DOI: 10.1111/bph. 12795

17. Писаренко О. И., Шульженко В. С., Студнева И. М. и соавт. Сигнальные пути структурного аналога апелина-12, участвующие в механизмах защиты сердца от ишемического/реперфузионного повреждения. Пептиды 2015;73:67-76). DOI: 10.1016/j. peptides. 2015.09.001

18. Писаренко О. И., Шульженко В. С., Студнева И. М. и др. Структурные аналоги апелина: ингибирование генерации активных форм кислоро да в митохондриях и кардиометаболическая защита при миокардиальном ишемическом/реперфузионном повреждении. Британский журнал фармакологии 2015;172:2933-2945). DOI: 10.1111/bph. 13038

19. Лакомкин В. Л., Абрамов А. А., Лукошкова Е. В. и др. Действие апелина-12 и его аналога на гемодинамику и сократительную функцию сердца крыс с изопротереноловым поражением миокарда. Кардиология 2015;55:54-62). DOI: https://dx.doi.org / 10.18565 / cardio. 2015.6.54-62

20. Писаренко О. И., Ланкин В. З., Коновалова Г. Г. и соавт. Апелин-12 и его структурный аналог увеличивают антиоксидантную защиту миокарда при экспериментальной ишемии и реперфузии. Молекулярная и клеточная биохимия 2014;391:241-250.) DOI 10.1007/s11010-014-2008-4

21. Пелогейкина Ю. А., Шульженко В. С., Студнева И. М. и др. Терапевтический потенциал структурных аналогов пептида апелина-12 при интраоперационной защите миокарда. Кардиологический вестник 2015; Х:16-26.

22. Szokodi I., Tavi P., Földes G. et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 2002;91:434-440. doi.org/10.1161/01. RES. 0000033522.37861.69

23. Wang C., Liu N., Luan R. et al. Apelin protects sarcoplasmic reticulum function and cardiac performance by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Cardiovasc Res 2013;100:114-124. DOI:10.1093/cvr/cvt160