Advertisement

Anti-Ischemic Activity of Triamine ALM-802 under Conditions of Endothelial Dysfunction

  • V. V. Barchukov
  • I. B. Tsorin
  • A. M. Likhosherstov
  • M. B. Vititnova
  • G. V. Mokrov
  • T. A. Gudasheva
  • S. A. KryzhanovskiiEmail author
Article
  • 3 Downloads

Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 μg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.

Key Words

α,ω-diarylmethyl derivatives of bis-(ω-aminoalkyl)amines ALM-802 endocardial ischemia endothelial dysfunction p-FOX inhibitors 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Korokin MV, Pokrovskii MV, Kochkarov VI, Gudyrev OS, Pokrovskaia TG, Korokina LV, Polyanskaya OS. Research of endothelio-and cardioprotective effects of enalapril, lozartan and amlodipin at modelling hyperhomocystein induced endothelial dysfunction. Ross. Med.-Biol. Vestn. 2014;(1):60-65. Russian.Google Scholar
  2. 2.
    Bhandari B, Subramanian L. Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorders. Recent. Pat. Cardiovasc. Drug Discov. 2007;2(1):35-39.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD. Targeting fatty acid and carbohydrate oxidation — a novel therapeutic intervention in the ischemic and failing heart. Biochim. Biophys. Acta. 2011;1813(7):1333-1350.CrossRefGoogle Scholar
  5. 5.
    Kolwicz SC Jr, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ. Res. 2013;113(5):603-616.CrossRefGoogle Scholar
  6. 6.
    Lam A, Lopaschuk GD. Anti-anginal effects of partial fatty acid oxidation inhibitors. Curr. Opin. Pharmacol. 2007;7(2):179-185.CrossRefGoogle Scholar
  7. 7.
    Mamamtavrishvili N, Sanikidze T, Pavliashvili N, Kvirkvelia A, Narsia E. Some aspects of metabolic remodeling of myocard during chronic heart failure. Georgian Med. News. 2008;(154):33-36.Google Scholar
  8. 8.
    Myrmel Т, Korvald С. New aspects of myocardial oxygen consumption. Invited review. Scand. Cardiovasc. J. 2000; 34(3): 233-241.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    Singer HA, Peach MJ. Calcium- and endothelial-mediated vascular smooth muscle relaxation in rabbit aorta. Hypertension. 1982;4(3, Pt 2):19-25.CrossRefGoogle Scholar
  11. 11.
    Tousoulis D, Bakogiannis C, Briasoulis A, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Kampoli AM, Charakida M, Toutouzas K, Stefanadis C. Targeting myocardial metabolism for the treatment of stable angina. Curr. Pharm. Des. 2013;19(9):1587-1592.Google Scholar
  12. 12.
    Tuunanen H, Knuuti J. Metabolic remodelling in human heart failure. Cardiovasc. Res. 2011;90(2):251-257.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    Yamamoto S, Matsui K, Sasabe M, Ohashi N. 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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • V. V. Barchukov
    • 1
  • I. B. Tsorin
    • 1
  • A. M. Likhosherstov
    • 1
  • M. B. Vititnova
    • 1
  • G. V. Mokrov
    • 1
  • T. A. Gudasheva
    • 1
  • S. A. Kryzhanovskii
    • 1
    Email author
  1. 1.V. V. Zakusov Research Institute of PharmacologyMoscowRussia

Personalised recommendations