phkineticaФармакокинетика и ФармакодинамикаPharmacokinetics and Pharmacodynamics2587-78362686-8830ООО «Издательство ОКИ»10.24411/2587-7836-2019-10042phkinetica-89Research ArticleДОКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ ФАРМАКОДИНАМИКИPRECLINICAL PHARMACODYNAMICS STUDIESСравнительное изучение антиишемической активности триметазидина и соединения АЛМ-802 в условиях эндотелиальной дисфункцииA comparative study of the anti-ischemic activity of trimetazidine and the compound ALM-802 under conditions of endothelial dysfunctionБарчуковВладимир ВалерьевичBarchukovV. V.noemail@neicon.ruЦоринИосиф БорисовичTsorinI. B.noemail@neicon.ruЛихошерстовАркадий МихайловичLikhosherstovA. M.noemail@neicon.ruВититноваМарина БорисовнаVititnovaM. B.noemail@neicon.ruМокровГригорий ВладимировичMokrovG. V.noemail@neicon.ruКрыжановскийСергей АлександровичKryzhanovskiiS. A.SAK-538@yandex.ruФГБНУ «НИИ фармакологии имени В.В. Закусова»РоссияFSBI «Zacusov Institute of Pharmacology»Russian Federation201906022019022327Copyright © Барчуков В.В., Цорин И.Б., Лихошерстов А.М., Вититнова М.Б., Мокров Г.В., Крыжановский С.А., 20192019Барчуков В.В., Цорин И.Б., Лихошерстов А.М., Вититнова М.Б., Мокров Г.В., Крыжановский С.А.Barchukov V.V., Tsorin I.B., Likhosherstov A.M., Vititnova M.B., Mokrov G.V., Kryzhanovskii S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacokinetica.ru/jour/article/view/89

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.

αω-диарилметильные производные бис-(ω-аминоалкил)аминовАЛМ-802триметазидинсубэндокардиальная ишемияэндотелиальная дисфункцияр-FOX ингибиторыαω-diarylmethyl derivatives of bis-(ω-aminoalkyl) aminesALM-802trimetazidinesubendocardial ischemiaendothelial dysfunctionp-FOX inhibitorsИсследование выполнено в рамках Государственного задания № 0521-2019-0005ReferencesЧичканов 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).]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).]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.0000044662.35377.51McKechnie 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.0000044662.35377.51Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol. 1998;32(Suppl.3):S2-S13.Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol. 1998;32(Suppl.3):S2-S13.Dinimeler S, Hermann C, Zeiher AM. Apoptosis of endothelial cells. Contribution to the pathophysiology of atherosclerosis. Eur Cytokine Netw. 1998;9:697–698.Dinimeler S, Hermann C, Zeiher AM. Apoptosis of endothelial cells. Contribution to the pathophysiology of atherosclerosis. Eur Cytokine Netw. 1998;9:697–698.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.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.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).].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).].Myrmel Т, Korvald С. New aspects of myocardial oxygen consumption. Invited review. Scand Cardiovasc J. 2000;34(3):233–241.Myrmel Т, Korvald С. New aspects of myocardial oxygen consumption. Invited review. Scand Cardiovasc J. 2000;34(3):233–241.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.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.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.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.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.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.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/cvn282van 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/cvn282Mamamtavrishvili 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.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.Tuunanen H, Knuuti J. Metabolic remodelling in human heart failure. Cardiovasc Res. 2011;90(2):251–257. DOI: 10.1093/cvr/cvr052Tuunanen H, Knuuti J. Metabolic remodelling in human heart failure. Cardiovasc Res. 2011;90(2):251–257. DOI: 10.1093/cvr/cvr052Kolwicz 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.113.302095Kolwicz 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.113.302095Rupp 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-xRupp 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-xJaswal 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.2011.01.015Jaswal 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.2011.01.015Fukushima 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.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.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.2006.10.008Lam 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.2006.10.008Bhandari 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.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.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).].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).].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.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.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).]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).]

The authors declare that there are no conflicts of interest present.