A comparative study of the anti-ischemic activity of trimetazidine and the compound ALM-802 under conditions of endothelial dysfunction

Resume. Methods. Acute subendocardial myocardial ischemia in anesthetized rats (urethane 1300 mg/kg, i.p.) was caused by isoproterenol (20 |jg/kg/ min, i.v.). Endothelial dysfunction was induced, causing hyperhomocysteinemia in rats (methionine 3 g/kg intragastrically 1 time per day for 7 days). The aim. To study on the subendocardial ischemia model in rats the peculiarities of the anti-ischemic action of p-FOX inhibitor trimetazidine and trihydrochloride N¹-(2,3,4-trimethoxybenzyl)-N²-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine constructed on the basis of its structure (compound ALM-802) under conditions of endothelial dysfunction. Results. It was shown that in rats with an intact vascular bed and the reference drug trimetazidine (30 mg/kg, i.v.) and the compound ALM-802 (2 mg/kg, i.v.) demonstrated pronounced anti-ischemic activity, while in animals with endothelial dysfunction only the compound ALM-802 was effective. Conclusion. Endothelial dysfunction prevents the implementation of the trimetazidine anti-ischemic action, but does not affect on the compound ALM-802 effect. When studying the anti-ischemic properties of new pharmacological substances, it is advisable to carry out a certain part of the experiments in model experiments that reproduce endothelial dysfunction.

α, ω-диарилметильные производные бис-(ω-аминоалкил)аминов, АЛМ-802, триметазидин, субэндокардиальная ишемия, эндотелиальная дисфункция, р-FOX ингибиторы, α, ω-diarylmethyl derivatives of bis-(ω-aminoalkyl) amines, ALM-802, trimetazidine, subendocardial ischemia, endothelial dysfunction, p-FOX inhibitors

1. Чичканов Г.Г., Цорин И.Б. Методические рекомендации по изучению противоишемического (антиангинального) действия лекарственных средств. В кн.: Руководство по проведению доклинических исследований лекарственных средств. Под ред. Миронова А.Н. Часть первая – М.: Гриф и К. 2013 – С. 417–433 [Chichkanov GG, Tsorin IB. Metodicheskie rekomendatsii po izucheniyu protivoishemicheskogo (antianginal'nogo) deistviya lekarstvennykh sredstv. V kn.; Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Pod redaktsiei. Mironova A.N. Chast' pervaya Moscow: Grif i K. 2013 (In Russ).]

2. McKechnie R, Mosca L. Physical activity and coronary heart disease: prevention and effect on risk factors. Cardiol Res. 2003;11:21–25. DOI: 10.1097/01.CRD.0000044662.35377.51

3. Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol. 1998;32(Suppl.3):S2-S13.

4. Dinimeler S, Hermann C, Zeiher AM. Apoptosis of endothelial cells. Contribution to the pathophysiology of atherosclerosis. Eur Cytokine Netw. 1998;9:697–698.

5. Hamilton CA, Berg G, Mcintyre M, et al. Effects of nitric oxide and super oxide on relaxation in human artery and vein. Atherosclerosis. 1997;133:77–86.

6. Корж А.Н. Значение эндотелиальной дисфункции в развитии заболеваний сердечно-сосудистой системы // Международный медицинский журнал. – 2003. – № 3. – С. 10–14 [Korzh A.N. Znachenie endotelial'noi disfunktsii v razvitii zabolevanii serdechno-sosudistoi sistemy. Mezhdunarodnyi meditsinskii zhurnal. 2003;3:10–14 (In Russ).].

7. Myrmel Т, Korvald С. New aspects of myocardial oxygen consumption. Invited review. Scand Cardiovasc J. 2000;34(3):233–241.

8. Tousoulis D, Bakogiannis C, Briasoulis A, et al. Targeting myocardial metabolism for the treatment of stable angina. Curr Pharm. Des. 2013;19(9):1587–1592.

9. van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ. Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res. 2004;61(2):218–226.

10. Fukushima A, Milner K, Gupta A, Lopaschuk GD. Myocardial energy substrate metabolism in heart failure: From pathways to therapeutic targets. Curr Pharm Des. 2015;21(25):3654–3664.

11. van Bilsen M, van Nieuwenhoven FA, van der Vusse GJ. Metabolic remodelling of the failing heart: beneficial or detrimental? Cardiovasc Res. 2009;81(3):420–428. DOI: 10.1093/cvr/cvn282

12. Mamamtavrishvili N, Sanikidze T, Pavliashvili N, et al. Some aspects of metabolic remodeling of myocard during chronic heart failure. Georgian Med News. 2008;154:33–36.

13. Tuunanen H, Knuuti J. Metabolic remodelling in human heart failure. Cardiovasc Res. 2011;90(2):251–257. DOI: 10.1093/cvr/cvr052

14. Kolwicz SCJr, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res. 2013;113(5):603–616. DOI: 10.1161/CIRCRESAHA.113.302095

15. Rupp H, Zarain-Herzberg A, Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Herz. 2002;27(7):621–636. DOI: 10.1007/s00059-002-2428-x

16. Jaswal JS, Keung W, Wang W, et al. Targeting fatty acid and carbohydrate oxidation — a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta. 2011;1813(7);1333–1350. DOI: 10.1016/j.bbamcr.2011.01.015

17. Fukushima A, Milner K, Gupta A, Lopaschuk GD. Myocardial energy substrate metabolism in heart failure: From pathways to therapeutic targets. Curr Pharm Des. 2015;21(25):3654–3664.

18. Lam A, Lopaschuk GD. Anti-anginal effects of partial fatty acid oxidation inhibitors. Curr Opin Pharmacol. 2007;7(2):179–185. DOI: 10.1016/j.coph.2006.10.008

19. Bhandari B, Subramanian L. Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorder. Recent Pat Cardiovasc Drug Discov. 2007;2(1):35–39.

20. Крыжановский С.А., Лихошерстов А.М., Цорин И.Б., и др. Скрининг кардиотропной активности в ряду α,αω-диарилметильных производных бис-(αω-аминоалкил)аминов // Фармакокинетика и Фармакодинамика. – 2016. – № 2. – С. 10–13. [Kryzhanovskii SA, Likhosherstov AM, Tsorin IB, et al. Screening of the compounds having cardiotropic activity among the α, αω-diarilmetil derivatives of bis-(ω-aminoalkyl)amines. Farmakokinetika i Farmakodinamika. 2016;2:10–13 (In Russ).].

21. Yamamoto S, Matsui K, Sasabe M, Ohashi NJ. Effect of an orally active Na+/H+ exchange inhibitor, SMP-300, on experimental angina and myocardial infarction models in rats. Cardiovasc Pharmacol. 2002; 39(2):234–241.

22. Корокин М.В., Покровский М.В., Кочкаров В.И., идр. Исследование эндотелио- и кардиопротективных эффектов эналаприла, лозартана и амлодипина при моделировании гипергомоцистеин индуцированной эндотелиальной дисфункции // Росcийский медико-биологический вестник имени академика И.П. Павлова. –2014. – № 1. – С. 60–65. [Korokin M.V., Pokrovskii MV, Kochkarov VI, Gudyrev OS, et al. Research of endothelio- and cardioprotective effects of enalapril, lozartan and amlodipin at modelling hyperhomocystein induced endothelial dysfunction. Rosciiskii medikobiologicheskii vestnik imeni akademika I.P. Pavlova. 2014;1:60–65 (In Russ).]