Skip to main content
SpringerLink
Log in

Genes targets identification of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one in an in vivo model of arrhythmia

  • Published:
Russian Journal of Bioorganic Chemistry Aims and scope Submit manuscript

Abstract

The molecular mechanisms of action of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one (P11), a compound possessing strong antiarrhythmic, nootropic, anti-inflammatory and analgesic activity, have been studied. Cardiac rhythm disturbances were modeled by administering the arrhythmogenic compound aconitin in a dose of 50 μg/kg to the animals from the control group. P-11 in a dose of 0.3 mg/kg was injected intravenously in the experimental group of animals 2 min before aconitin administration. P-11 target genes were identified using the Atlas™ Rat cDNA Expression macroarray (#7738-1, BD Biosciences, United States). Reproducible changes in the expression levels of 16 genes in the heart of rats treated with P-11 concommitantly to arrhythmia modeling in vivo were detected. The genes regulated by the substance coded for proteins of the extracellular matrix are (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp3), intracellular signaling proteins (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12), proteins involved in glycolysis (phosphofructokinase 1, Pfk1), intercellular interactions (junction plakoglobin, Jup), and hemostasis (tissue plasminogen activator, Plat), membranebound pumps and transporters (solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and others (c-fos proto-oncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa1). Therefore, the data concerning the selective effect of P-11 on genes coding for proteins involved in arrhythmogenesis allow for considering this compound as a promising medication for pathogenetically oriented therapy of arrhythmias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

WHO:

World Health Organisation

ECG:

electrocardiogram

ED50-50%:

efficient dose

References

  1. Informative Bulletin No. 317, WHO, 2009.

  2. Vaughan Williams, E.M., J. Clin. Pharmacol., 1984, vol. 24, pp. 129–147.

    PubMed  CAS  Google Scholar 

  3. Kaverina, N.V., Berdyaev, S.Yu., Kishchuk, E.P., and Paskhina, O.E., Vedom. Farmakol. Komit., 1998, no. 2, pp. 11–19.

  4. Ross, H.M., Kocovic, D.Z., and Kowey, P.R., Am. J. Geriatr. Cardiol., 2005, vol. 14, no. (2), pp. 62–67.

    Article  PubMed  Google Scholar 

  5. Garpinchenko, V.A., Yatsynich, E.A., Petrov, D.V., Karachurina, L.T., and Khisamutdinova, R.Yu., Baschenko, N.Zh., Dokichev, V.A., Tomilov, Yu.V., Khim.-Farm. Zh., 2005, vol. 39, pp. 9–11.

    Google Scholar 

  6. Petrov, D.V., Gorpinchenko, V.A., Shafikova, E.A., Zarudii, F.S., Baschenko, N.Zh., Khisamutdinova, R.Yu., Makara, N.S., Vakhitov, V.A., Vakhitova, Yu.V., Chzhan Veimu, Alimbekov, R.I., Dokichev, V.A., Tomilov, Yu.V., and Nefedov, O.M., RF Patent No. 2281938, Byull. Izobret., 2006, no. 23.

  7. Marri, R., in Biokhimiya cheloveka (Human Biochemistry), Moscow: Mir, 1993.

    Google Scholar 

  8. Russell, D.C., Lawrie, J.S., Riemersma, R.A., and Oliver, M.F., Acta Med. Scand. Suppl., 1981, vol. 651, pp. 71–81.

    PubMed  CAS  Google Scholar 

  9. Saffitz, J.E., Ann. N. Y. Acad. Sci., 2005, vol. 1047, pp. 336–344.

    Article  PubMed  CAS  Google Scholar 

  10. Remme, C.A. and Bezzina, C.R., Cell Cycle, 2010, vol. 9, pp. 1246–1252.

    Article  PubMed  CAS  Google Scholar 

  11. Bierkamp, C., Mclaughlin, K.J., Schwarz, H., Huber, O., and Kemler, R., Dev. Biol., 1996, vol. 180, pp. 780–785.

    Article  PubMed  CAS  Google Scholar 

  12. Kaplan, S.R., Gard, J.J., Protonotarios, N., Tsatsopoulou, A., Spiliopoulou, C., Anastasakis, A., Squarcioni, C.P., McKenna, W.J., Thiene, G., Basso, C., Brousse, N., Fontaine, G., and Saffitz, J.E., Heart Rhythm, 2004, vol. 1, pp. 3–11.

    Article  PubMed  Google Scholar 

  13. Herren, T., Gerber, P.A., and Duru, F., Clin. Res. Cardiol., 2009, vol. 98, pp. 141–158.

    Article  PubMed  Google Scholar 

  14. Houslay, M.D., Schafer, P., and Zhang, K.Y., Drug Discov. Today, 2005, vol. 10, pp. 1503–1519.

    Article  PubMed  CAS  Google Scholar 

  15. Xiang, Y., Naro, F., Zoudilova, M., Jin, S.L., Conti, M., and Kobilka, B., Proc. Natl. Acad. Sci. USA, 2005, vol. 102, pp. 909–914.

    Article  PubMed  CAS  Google Scholar 

  16. Osadchii, O.E., Cardiovasc. Drugs Ther., 2007, vol. 21, pp. 171–194.

    Article  PubMed  CAS  Google Scholar 

  17. Leevers, S.J., Vanhaesebroeck, B., and Waterfield, M.D., Curr. Opin. Cell Biol., 1999, vol. 11, pp. 219–225.

    Article  PubMed  CAS  Google Scholar 

  18. Cantley, L.C., Science, 2002, vol. 296, pp. 1655–1657.

    Article  PubMed  CAS  Google Scholar 

  19. Fruman, D.A., Meyers, R.E., and Cantley, L.C., Annu. Rev. Biochem., 1998, vol. 67, pp. 481–507.

    Article  PubMed  CAS  Google Scholar 

  20. Luo, J., McMullen, J.R., Sobkiw, C.L., Zhang, L., Dorfman, A.L., Sherwood, M.C., Logsdon, M.N., Horner, J.W., DePinho, R.A., Izumo, S., and Cantley, L.C., Mol. Cell Biol., 2005, vol. 25, pp. 9491–9502.

    Article  PubMed  CAS  Google Scholar 

  21. Caporali, A. and Emanueli, C., Physiol. Rev., 2009, vol. 89, pp. 279–308.

    Article  PubMed  CAS  Google Scholar 

  22. Emanueli, C., Salis, M.B., Pinna, A., Graiani, G., Manni, L., and Madeddu, P., Circulation, 2002, vol. 106, pp. 2257–2262.

    Article  PubMed  CAS  Google Scholar 

  23. Kawaguchi-Manabe, H., Ieda, M., Kimura, K., Manabe, T., Miyatake, S., Kanazawa, H., Kawakami, T., Ogawa, S., Suematsu, M., and Fukuda, K., Life Sci., 2007, vol. 81, pp. 385–392.

    Article  PubMed  CAS  Google Scholar 

  24. Bonen, A., Eur. J. Appl. Physiol., 2001, vol. 86, pp. 6–11.

    Article  PubMed  CAS  Google Scholar 

  25. Vandenberg, J.I., Metcalfe, J.C., and Grace, A.A., Circ. Res., 1993, vol. 72, pp. 993–1003.

    PubMed  CAS  Google Scholar 

  26. Bonen, A., Tonouchi, M., Miskovic, D., Heddle, C., Heikkila, J.J., and Halestrap, A.P., Am. J. Physiol. Endocrinol. Metab., 2000, vol. 279, pp. 1131–1138.

    Google Scholar 

  27. Boldyrev, A.A., Soros. Obrazovat. Zh., 1998, no. 4, pp. 2–9.

  28. Helms, J.B., Arnett, K.L., Gatto, C., and Milanick, M.A., Blood Cells Mol. Dis., 2004, vol. 32, pp. 394–400.

    Article  PubMed  CAS  Google Scholar 

  29. Kostin, S., Klein, G., Szalay, Z., Hein, S., Bauer, E.P., and Schaper, J., Cardiovasc. Res., 2002, vol. 54, pp. 361–379.

    Article  PubMed  CAS  Google Scholar 

  30. Nattel, S. and Maguy, A., Le Bouter S., Yeh Y.H., Physiol. Rev., 2007, vol. 87, pp. 425–456.

    Article  PubMed  CAS  Google Scholar 

  31. Espira, L. and Czubryt, M.P., Can. J. Physiol. Pharmacol., 2009, vol. 87, pp. 996–1008.

    Article  PubMed  CAS  Google Scholar 

  32. Spinale, F.G., Physiol. Rev., 2007, vol. 87, pp. 1285–1342.

    Article  PubMed  CAS  Google Scholar 

  33. Vanhoutte, D., Schellings, M., Pinto, Y., and Heymans, S., Cardiovasc. Res., 2006, vol. 69, pp. 604–613.

    Article  PubMed  CAS  Google Scholar 

  34. Fedak, P.W.M., Smookler, D.S., Kassiri, Z., Ohno, N., Leco, K.J., et al., Circulation, 2004, vol. 110, pp. 2401–2409.

    Article  PubMed  CAS  Google Scholar 

  35. English, J.L., Kassiri, Z., Koskivirta, I., Atkinson, S.J., Di Grappa, M., et al., J. Biol. Chem., 2006, vol. 281, pp. 10337–10346.

    Article  PubMed  CAS  Google Scholar 

  36. Creemers, E.E., Cleutjens J.P., Smits J.F., Daemen M.J., Circ. Res., 2001, vol. 89, pp. 201–210.

    Article  PubMed  CAS  Google Scholar 

  37. Filmus, J. and Selleck, S.B., J. Clin. Invest., 2001, vol. 108, pp. 497–501.

    PubMed  CAS  Google Scholar 

  38. Asundi, V.K., Keister, B.F., Stahl, R.C., and Carey, D.J., Exp. Cell Res., 1997, vol. 230, pp. 145–153.

    Article  PubMed  CAS  Google Scholar 

  39. Kirn-Safran, C., Farach-Carson, M.C., and Carson, D.D., Cell Mol. Life Sci., 2009, vol. 66, pp. 3421–3434.

    Article  PubMed  CAS  Google Scholar 

  40. Song, H.H., Shi, W., and Filmus, J., J. Biol. Chem., 1997, vol. 272, pp. 7574–7577.

    Article  PubMed  CAS  Google Scholar 

  41. Filmus, J., Capurro, M., and Rast, J., Genome Biol., 2008, vol. 9, p. 224.

  42. Sanguinetti, M.C. and Bennett, P.B., Circ. Res., 2003, vol. 93, pp. 491–499.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biochemistry and Genetics of the Ufa Research Center of the Russian Academy of Sciences, prosp. Oktyabrya 71, Ufa, 450054, Russia

    Yu. V. Vakhitova, E. I. Antipina & R. S. Yamidanov

  2. Institute of Organic Chemistry of the Ufa Research Center of the Russian Academy of Sciences, Ufa, Russia

    R. Yu. Khisamutdinova, F. S. Zarudii, N. Zh. Baschenko & V. A. Dokichev

  3. Zelinsky institute of Organic Chemistry of the Russian Academy of Sciences, Moscow, Russia

    Yu. V. Tomilov & O. M. Nefedov

Authors
  1. Yu. V. Vakhitova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. I. Antipina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. S. Yamidanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Yu. Khisamutdinova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. S. Zarudii
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Zh. Baschenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. A. Dokichev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu. V. Tomilov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O. M. Nefedov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu. V. Vakhitova.

Additional information

Original Russian Text © Yu.V. Vakhitova, E.I. Antipina, R.S. Yamidanov, R.Yu. Khisamutdinova, F.S. Zarudii, N.Zh. Baschenko, V.A. Dokichev, Yu.V. Tomilov, O.M. Nefedov, 2011, published in Bioorganicheskaya Khimiya, 2011, Vol. 37, No. 6, pp. 821–829.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vakhitova, Y.V., Antipina, E.I., Yamidanov, R.S. et al. Genes targets identification of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one in an in vivo model of arrhythmia. Russ J Bioorg Chem 37, 744–751 (2011). https://doi.org/10.1134/S1068162011060148

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1068162011060148

Keywords

Search

Navigation