Skip to main content

Advertisement

SpringerLink
Log in

Bisoprolol and linagliptin ameliorated electrical and mechanical isometric myocardial contractions in doxorubicin-induced cardiomyopathy in rats

  • Article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Doxorubicin is an anthracycline chemotherapeutic agent that causes cardiomyopathy as a side effect. Here, we aimed to investigate the effects of linagliptin and bisoprolol on the management of doxorubicin-induced cardiomyopathy in rats.

Methods

Wistar rats were divided into six groups (n = 8). Group I received saline for 4 weeks; group II received 1 mg/kg bisoprolol for 8 weeks; group III received 3 mg/kg linagliptin for 8 weeks; group IV received 1.25 mg/kg doxorubicin for 4 weeks for the induction of cardiomyopathy; group V received 1.25 mg/kg doxorubicin for 4 weeks plus 1 mg/kg bisoprolol for 8 weeks; and group VI received 1.25 mg/kg doxorubicin for 4 weeks plus 3 mg/kg linagliptin for 8 weeks. Electrocardiography and isometric mechanography were conducted to measure ventricular contractile responses. Myocardial tissue and serum samples were analyzed for oxidative and cardiotoxic markers by ELISA.

Results

Electrocardiography revealed that QRS, QT and Tp intervals were longer in group IV than group I. Doxorubicin caused a significant decrease in ventricular contraction, which was significantly prevented by bisoprolol. Doxorubicin resulted in myocardial fiber disorganization and disruption, but bisoprolol or linagliptin improved this myocardial damage. Glutathione peroxidase was significantly decreased in groups IV and V. Bisoprolol or linagliptin treatment attenuated the significant doxorubicin-mediated increase in malondialdehyde. Doxorubicin and linagliptin provided significant elevations in CK-MB activity and troponin-I levels.

Conclusions

Doxorubicin resulted in pronounced oxidative stress. The beneficial effects of bisoprolol and linagliptin on myocardial functional, histopathological and biochemical changes could be related to the attenuation of oxidative load.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115:155–62.

    Article  CAS  Google Scholar 

  2. Takemura G, Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis. 2007;49:330–52.

    Article  CAS  Google Scholar 

  3. Odom AL, Hatwig CA, Stanley JS, Benson AM. Biochemical determinants of adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol. 1992;43:831–6.

    Article  CAS  Google Scholar 

  4. Monti E, Prosperi E, Supino R, Bottiroli G. Free radical-dependent DNA lesions are involved in the delayed cardiotoxicity induced by adriamycin in the rat. Anticancer Res. 1995;15:193–7.

    CAS  PubMed  Google Scholar 

  5. Dulhunty AF, Casarotto MG, Beard NA. The ryanodine receptor: a pivotal Ca2+ regulatory protein and potential therapeutic drug target. Curr Drug Targets. 2011;12:709–23.

    Article  CAS  Google Scholar 

  6. Cecen E, Dost T, Culhaci N, Karul A, Ergur B, Birincioglu M. Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac J Cancer Prev. 2011;12:2697–704.

    CAS  PubMed  Google Scholar 

  7. Yarmohmmadi F, Rahimi N, Faghir-Ghanesefat H, Javadian N, Abdollahi A, Pasalar P, et al. Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat. Eur J Pharmacol. 2017;796:39–44.

    Article  CAS  Google Scholar 

  8. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005;111:1601–10.

    Article  CAS  Google Scholar 

  9. Bien S, Riad A, Ritter CA, Gratz M, Olshausen F, Westermann D, et al. The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res. 2007;67:10428–35.

    Article  CAS  Google Scholar 

  10. Aykan DA, Kesim M, Ayan B, Kurt A. Anti-inflammatory and antinociceptive activities of glucagon-like peptides: evaluation of their actions on serotonergic, nitrergic, and opioidergic systems. Psychopharmacology. 2019. https://doi.org/10.1007/s00213-018-5154-7.

    Article  PubMed  Google Scholar 

  11. Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol. 2015;14:129.

    Article  Google Scholar 

  12. Wang X, Ding Z, Yang F, Dai Y, Chen P, Theus S, et al. Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together. Clin Sci. 2016;130:1353–62.

    Article  CAS  Google Scholar 

  13. Du Y, Zhang J, Xi Y, Wu G, Han K, Huang X, et al. β1-Adrenergic blocker bisoprolol reverses down-regulated ion channels in sinoatrial node of heart failure rats. J Physiol Biochem. 2016;72:293–302.

    Article  CAS  Google Scholar 

  14. Abdelrady AM, Zaitone SA, Farag NE, Fawzy MS, Moustafa YM. Cardiotoxic effect of levofloxacin and ciprofloxacin in rats with/without acute myocardial infarction: impact on cardiac rhythm and cardiac expression of Kv4.3, Kv1.2 and Nav1.5 channels. Biomed Pharmacother. 2017;92:196–206.

    Article  CAS  Google Scholar 

  15. Coşkun B, Cömelekoğlu U, Polat A, Kaymaz FF. Evaluation of the toxic effects of cypermethrin inhalation on the frog heart. Ecotoxicol Environ Saf. 2004;57:220–5.

    Article  Google Scholar 

  16. Shaker RA, Abboud SH, Assad HC, Hadi N. Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Pharmacol Toxicol. 2018;19:3.

    Article  Google Scholar 

  17. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70:158–69.

    CAS  PubMed  Google Scholar 

  18. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.

    CAS  PubMed  Google Scholar 

  19. Raj S, Franco VI, Lipshultz SE. Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med. 2014;16:1–14.

    Article  Google Scholar 

  20. Kalivendi SV, Kotamraju S, Zhao H, Joseph J, Kalyanaraman B. Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase. Effect of antiapoptotic antioxidants and calcium. J Biol Chem. 2001;276:47266–76.

    Article  CAS  Google Scholar 

  21. Kotamraju S, Konorev EA, Joseph J, Kalyanaraman B. Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. J Biol Chem. 2000;275:33585–92.

    Article  CAS  Google Scholar 

  22. Ichihara S, Yamada Y, Ichihara G, Kanazawa H, Hashimoto K, Kato Y, et al. Attenuation of oxidative stress and cardiac dysfunction by bisoprolol in an animal model of dilated cardiomyopathy. Biochem Biophys Res Commun. 2006;350:105–13.

    Article  CAS  Google Scholar 

  23. Nishio M, Sakata Y, Mano T, Ohtani T, Takeda Y, Miwa T, et al. Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats. Eur J Heart Fail. 2008;10:446–53.

    Article  CAS  Google Scholar 

  24. Chaykovska L, von Websky K, Rahnenführer J, Alter M, Heiden S, Fuchs H, et al. Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy. PLoS ONE. 2011;6:e27861.

    Article  CAS  Google Scholar 

  25. Dietrich N, Kolibabka M, Busch S, Bugert P, Kaiser U, Lin J, et al. The DPP4 inhibitor linagliptin protects from experimental diabetic retinopathy. PLoS ONE. 2016;11:e0167853.

    Article  Google Scholar 

  26. Morandi P, Ruffini PA, Benvenuto GM, Raimondi R, Fosser V. Serum cardiac troponin I levels and ECG/echo monitoring in breast cancer patients undergoing high-dose (7 g/m2) cyclophosphamide. Bone Marrow Transplant. 2001;28:277–82.

    Article  CAS  Google Scholar 

  27. Aries P, Paradis P, Lefevre C, Schwartz RJ, Nemer M. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci USA. 2004;101:6975–80.

    Article  CAS  Google Scholar 

  28. Levick SP, Soto-Pantoja DR, Bi J, Hundley WG, Widiapradja A, Manteufel EJ, et al. Doxorubicin-induced myocardial fibrosis involves the neurokinin-1 receptor and direct effects on cardiac fibroblasts. Heart Lung Circ. 2019;28:1598–605.

    Article  Google Scholar 

  29. Rahimi Balaei M, Momeny M, Babaeikelishomi R, Mehr SE, Tavangar SM, Dehpour AR. The modulatory effect of lithium on doxorubicin-induced cardiotoxicity in rat. Eur J Pharmacol. 2010;641:193–8.

    Article  CAS  Google Scholar 

  30. Cole MP, Chaiswing L, Oberley TD, Edelmann SE, Piascik MT, Lin S, et al. The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity. Cardiovasc Res. 2006;69:186–97.

    Article  CAS  Google Scholar 

Download references

Funding

Kahramanmaraş Sütçü Imam University Scientific Research Projects, Kahramanmaraş, Turkey, has given grant support to this research (2017/7-198M).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Kahramanmaras Sütçü Imam University, Avsar Kampusu, Onikisubat, Kahramanmaras, Turkey

    Duygun Altıntaş Aykan, Nadire Eser, Akif Hakan Kurt & Yusuf Ergün

  2. Department of Biophysics, Faculty of Medicine, Kahramanmaras Sütçü Imam University, Kahramanmaras, Turkey

    Selma Yaman

  3. Department of Histology and Embryology, Faculty of Medicine, Kahramanmaras Sütçü Imam University, Kahramanmaras, Turkey

    Tuba Özcan Metin

  4. Department of Biochemistry, Faculty of Medicine, Kahramanmaras Sütçü Imam University, Kahramanmaras, Turkey

    Muhammed Seyithanoğlu

  5. Department of Cardiology, Faculty of Medicine, Kahramanmaras Sütçü Imam University, Kahramanmaras, Turkey

    Ahmet Çağrı Aykan

Authors
  1. Duygun Altıntaş Aykan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Selma Yaman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadire Eser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tuba Özcan Metin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muhammed Seyithanoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmet Çağrı Aykan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akif Hakan Kurt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yusuf Ergün
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DAA: conceptualization; DAA, SY, NE, TOM, MS, AHK: data curation; DAA, AÇA: formal analysis; DAA: funding acquisition; DAA, SY, NE, MS, TOM: investigation; DAA: methodology; DAA: project administration; DAA, SY, NE, TOM, MS, AHK, YE, AÇA: resources; DAA: software; DAA, YE, AHK, AÇA: supervision; DAA: validation; DAA: visualization; DAA: writing—original draft; DAA, YE, AÇA: writing—review and editing.

Corresponding author

Correspondence to Duygun Altıntaş Aykan.

Ethics declarations

Conflict of interest

There is no conflict of interest to be declared.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aykan, D.A., Yaman, S., Eser, N. et al. Bisoprolol and linagliptin ameliorated electrical and mechanical isometric myocardial contractions in doxorubicin-induced cardiomyopathy in rats. Pharmacol. Rep 72, 867–876 (2020). https://doi.org/10.1007/s43440-019-00034-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43440-019-00034-9

Keywords

Search

Navigation