Top

Published in:

01-01-2022 | Electrocardiography

Comparative Therapeutic Potential of Cardioactive Glycosides in Doxorubicin Model of Heart Failure

Authors: Raquel da Silva Ferreira, Paula Bretas Ullmann Fernandes, Jéssica Pereira Oliveira da Cruz, Françoise Louanne Araújo Silva, Marthin Raboch Lempek, Gioavanni Naves Canta, Júlio César Cambraia Veado, Matheus Matioli Mantovani, Ana Flávia Machado Botelho, Marília Martins Melo

Published in: Cardiovascular Toxicology | Issue 1/2022

Abstract

In the present study, we investigated the cardioactive glycosides oleandrin and ouabain, and compared them to digoxin in a model of cardiotoxicity induced by doxorubicin. Adult rats were distributed into four experimental groups. Each group was challenged with a single intraperitoneal application of doxorubicin at a dose of 12 mg/kg. Then, they were treated with saline solution and the glycosides oleandrin, ouabain, and digoxin at a dose of 50 µg/kg, for 7 days. They underwent echocardiography, electrocardiography, hematologic, biochemical tests, and microscopic evaluation of the heart. All animals presented congestive heart failure, which was verified by a reduction in the ejection fraction. Oleandrin and digoxin were able to significantly reduce (p < 0.05) the eccentric remodeling caused by doxorubicin. Oleandrin and digoxin were significantly lower (p < 0.05) than the control group in maintaining systolic volume and left ventricular volume in diastole. Other parameters evaluated did not show significant statistical differences. All animals showed an increase in erythrocyte count, and an increase in the duration of the QRS complex on the ECG and myocardial necrosis at the histopathological analysis. It is concluded that the glycosides oleandrin, ouabain, and digoxin in the used dosage do not present therapeutic potential for the treatment of congestive heart failure caused by doxorubicin.

Mangini, F., Pires, P. P., Braga, F. G. M., & Bacal, F. (2013). Decompensated heart failure. Einstein, 11, 383–391.PubMedPubMedCentral

Savarese, G., & Lund, L. H. (2017). Global public health burden of heart failure. Cardiac Failure Review, 3, 7–11.PubMedPubMedCentral

Borlaug, A. B., & Paulus, W. J. (2010). Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment. European Heart Journal, 32, 670–679.PubMedPubMedCentral

Botelho, A. F. M., Pierezan, F., Soto-Blanco, B., et al. (2019). A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon, 158, 63–68.PubMed

Whayne Jr, T. F. (2018). Clinical use of digitalis: A state of art review. American Journal of Cardiovascular Drugs, 18, 427–440.

Formiga, F., & Ariza, A. (2018). Digoxin in reduced heart failure and sinus rhythm. When sould it be indicated in 2018? Revista Espanola de Geriatria y Gerontologia, 53, 119–120.PubMed

Pedroza, H. P., Ferreira, M. G., Carvalho, J. G., Melo, K. D. A., Keller, K. M., Melo, M. M., & Soto-Blanco, B. (2014). Concentrações de oleandrina nas folhas de Nerium oleander de diferentes cores de floração. Ciência Rural, 45, 864–866.

Kumar, A., Tamnoy, D., Mishra, A., et al. (2013). Oleandrin: A cardiac glycoside with potent cytotoxicity. Pharmacognosy Review, 7, 131–139.

Hamlyn, J., Blaustein, M. P., Bova, S., et al. (1991). Identification and characterization of an ouabain-like compound form human plasma. Proceedings of the National Academy of Sciences of the United States of America, 88, 6259–6263.PubMedPubMedCentral

10.

Hamlyn, J. M., & Manunta, P. (2015). Endogenous cardiotonic steroids in kidney failure: A review and a hypothesis. Advances in Kidney Chronic Disease, 22, 232–244.

11.

Manunta, P., Ferrandi, M., Bianchi, G., et al. (2009). Endogenous ouabain in cardiovascular function and disease. Journal of Hypertension, 27, 9–18.PubMed

12.

Cavalcante-Silva, L. H. A., Lima, E. A., Carvalho, D. C. M., et al. (2017). Much more than a cardiotonic steroid: Modulation of inflammation by ouabain. Frontiers in Physiology, 8, 1–8.

13.

Henriksen, P. A. (2018). Anthracycline cardiotoxicity: An update on mechanism, monitoring and prevention. Heart, 104, 971–977.PubMed

14.

Botelho, A. F. M., Miranda, A. L. S., Freitas, T. G., et al. (2020). Comparative cardiotoxicity of low doses of digoxin, ouabain, and oleandrin. Cardiovascular Toxicology, 20, 539–547.PubMed

15.

Botelho, A. F. M., Joviano-Santos, J. V., Santos-Miranda, A., et al. (2019). Noninvasive ECG recording and QT interval correction assessment in anesthetized rats and mice. Pesquisa Veterinária Brasileira, 39, 409–415.

16.

Teixeira, M. A., Chaguri, L. C. A. G., & Carissimi, A. S. (2000). Hematological and biochemical profiles of rats (Rattus novergicus) kept under microenvironmental ventilation system. Brazilian Journal of Veterinary Research and Animal Science, 37, 341–347.

17.

Pontes, J. C. D. V., Gomes, J. F., Jr., Silva, G. V. R., et al. (2010). Estudo anatomopatológico da miocardiopatia induzida pela doxorrubicina em ratos. Acta Cirúrgica Brasileira, 25, 137–143.PubMed

18.

Oliveira, M. S., Melo, M. B., Carvalho, J. L., et al. (2013). Doxorubicin cardiotoxicity and cardiac function improvement after stem cell therapy diagnosed by strain echocardiography. Journal of Cancer Science & Theraphy, 5, 52–57.

19.

O’connell, J. L., Romano, M. M. D., Pulici, E. C. C., et al. (2017). Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes. Experimental and Toxicologic Pathology, 69, 213–219.PubMed

20.

Polegato, B. F., Minicucci, M. F., Azevedo, P. S., et al. (2015). Acute doxorubicin-induced cardiotoxicity is associated with matrix metalloproteinase-2 alterations in rats. Cellular Physiology and Biochemistry, 35, 1924–1933.PubMed

21.

Kim, E., Lim, K., Kim, K., et al. (2009). Doxorubicin-induced platelet cytotoxicity: A new contributory factor for doxorubicin-mediated thrombocytopenia. Journal of Thrombosis and Haemostasis, 7, 1172–1183.PubMed

22.

Rau, S. E., Barber, L. G., & Burgess, K. E. (2010). Eficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs. Journal of Veterinary Internal Medicine, 24, 1452–1457.PubMed

23.

Campbell, J. T., & Macdonald, P. S. (2003). Digoxin in heart failure and cardiac arrhythmias. The Medical Journal of Australia, 179, 98–102.PubMed

24.

Langford, S. D., & Boor, P. J. (1996). Oleander toxicity: An examination of human and animal toxic exposures. Toxicology, 109, 1–13.PubMed

25.

Wallick, D. W., Valencic, F., Fratianne, R. B., et al. (1984). Effects of ouabain and vagal stimulation on heart rate in dog. Cardiovascular Research, 18, 75–79.PubMed

26.

Murkofsky, R. L., Dangas, G., Diamond, J. A., et al. (1998). A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction [see comment]. Journal of The American College of Cardiology, 32(2), 476–482.PubMed

27.

Stemmer, P., & Tai, A. (1998). Sodium-pump activity and its inhibition by extracellular calcium in cardiac myocytes of guinea pigs. Biochimica et Biophysica Acta, 940, 188–196.

28.

Alexandre, J., Moslehi, J. J., & Bersell, K. R. (2018). Anticancer drug-induced cardiac rythm disorders: Current knowledge and basic underlying mechanisms. Pharmacology & Therapeutics, 189, 89–103.

29.

Chatterjee, K., Zhang, J., Honbo, N., et al. (2010). Doxorubicin cardiomyopathy. Cardiology, 115, 155–162.PubMed

30.

Mathew, T., Williams, L., Navaratnam, G., et al. (2017). Diagnosis and assessment of dilated cardiomyopathy: A guideline protocol from the British Society of Echocardiography. Echo Research and Practice, 4, 1–13.

31.

Smith, P. A., Aldridge, B. M., & Kittleson, M. D. (2003). Oleander toxicosis in a donkey. Journal of Veterinary Internal Medicine, 17, 111–114.PubMed

32.

Neves, C. H., Tibana, R. A., Prestes, J., et al. (2017). Digoxin induces cardiac hypertrophy without negative effects on cardiac function and physical performance in trained normotensive rats. International Journal of Sports Medicine, 38, 263–269.PubMed

33.

Simonini, M., Pozzoli, S., Bignami, E., et al. (2015). Endogenous ouabain: An old cardiotonic steroid as a new biomarker of heart failure and a predictor of mortality after cardiac surgery. Biomed Research International. https://doi.org/10.1155/2015/714793CrossRefPubMedPubMedCentral

34.

Silva, C. E. V., & Camacho, A. A. (2005). Alterações ecocardiográficas em cães sob tratamento prolongado com doxorrubicina. Arquivo Brasileiro de Medicina Veterinária e Zootecnia, 57, 300–306.

35.

Markiewicz, W., Robinson, E., Peled, B., et al. (1980). Early detection of doxorubicin cardiotoxicity by M-mode echocardiography. Cancer Chemotherapy and Pharmacology, 5, 119–125.PubMed

36.

Deavers, S., Rosborough, J. P., & McCrady, J. D. (1979). The effects of oleandrin on cardiac contractility in the normal dog. Archives Internacionales de Pharmacodynamie et de Therapie, 239, 283–289.

37.

Van Boxtel, C. J., Koopmans, R., Oosterhuis, B., et al. (1985). Red blood cell electrolytes for monitoring digoxin therapy in adults. Therapeutic Drug Monitoring, 7, 191–196.PubMed

38.

Sleijfer, S., Rizzo, E., Litiére, S., et al. (2018). Predictors for doxorubicin- induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database. Acta Oncologica, 57, 1117–1126.PubMed

39.

Abdou, R. H., Basha, W. A., & Khalil, W. F. (2019). Subacute toxicity of Nerium oleander ethanolic extract in mice. Toxicological Research, 35, 233–239.PubMedPubMedCentral

40.

Roevens, P., & Courcelles, D. C. (1990). Ouabain increases the calcium concentration in intracellular stores involved in stimulus-response coupling in human platelets. Circulation Research, 67, 1494–1502.PubMed

41.

Young, R. C., Nachman, R. L., & Horowitz, H. I. (1966). Thrombocytopenia due to digoxin. The American Journal of Medicine, 41, 605–614.PubMed

42.

Medenica, R., Hatam, K., Hatam, V., et al. (1972). Digitoxin-induced thrombocytopenia. International Archives of Allergy and Applied Immunology, 43, 1–8.PubMed

43.

Henry, C. J., Brewer, W. G., & Stutler, S. A. (1993). Early onset leukopenia and severe thrombocytopenia following doxorubicin chemotheraphy for tonsillar squamous cell carcinoma in a dog. The Cornell Veterinarian, 82, 163–168.

44.

De Vasconcelos, D. I., Leite, J. A., Carneiro, L. T., et al. (2011). Anti-inflammatory and antinociceptive activity of ouabain in mice. Mediators of Inflammation. https://doi.org/10.1155/2011/912925CrossRefPubMedPubMedCentral

45.

Esposito, A. L. (1985). Digoxin disrupts the inflammatory response in experimental pneumococcal pneumonia. The Journal of Infectious Diseases, 152, 14–23.PubMed

46.

Dey, P. (2020). The pharmaco-toxicological conundrum of oleander: Potential role of gut microbiome. Biomedicine & Pharmacotherapy, 129, 1–13.

47.

Tolaney, S. M., Najita, J., Winer, E. P., et al. (2008). Lymphopenia associated with adjuvant anthracycline/taxane regimens. Clinical Breast Cancer, 8, 352–356.PubMed

48.

Vecchi, A., Mantovani, A., Taglibue, A., et al. (1976). A characterization of the immunosuppressive activity of Adriamycin and daunomycin on humoral antibody production and tumor allograft rejection. Cancer Research, 36, 1222–1227.PubMed

49.

Marchand, D. J., & Renton, K. W. (1984). Depression of cytochrome P-450-dependent drug biotransformation by adriamicyn. The Journal of Pharmacology and Experimental Therapeutics, 229, 299–304.

50.

Graf, J., & Peterlik, M. (1976). Ouabain mediated sodium uptake and bile formation by isolated perfused rat liver. American Journal of Physiology, 230, 876–885.PubMed

51.

Ceci, L., Girolami, F., & Cappuchio, M. T. (2020). Outbreak of oleander (Nerium oleander) poisoning in dairy cattle: Clinical and food safety implication. Toxins, 471, 1–11.

52.

Adamcova, M., Skarkova, V., Seifertova, J., et al. (2019). Cardiac troponins are among targets of doxorubicin-induced cardiotoxicity in hiPCS-CMs. International Journal of Molecular Sciences, 20, 1–13.

53.

Polena, S., Shikara, M., Naik, S., et al. (2005). Troponin I as a marker of doxorubicin induced cardiotoxicity. Proceeding of the Western Pharmacology Society, 48, 142–144.

54.

Shivakumar, P., Rani, M. U., Reddy, A. G., et al. (2012). A Study on the toxic effects of doxorubicin on the histology of certain organs. Toxicology International, 19(3), 241–244.PubMedPubMedCentral

55.

Bourdois, P. S., Dancla, J. L., Faccini, J. M., et al. (1982). The sub-acute toxicology of digoxin in dogs; clinical chemistry and histopathology of heart and kidneys. Archives of Toxicology, 51, 273–283.

56.

Botelho, A. F. M., Santos-Miranda, A., Joca, H. C., et al. (2017). Hydroalcoholic extract from Nerium oleandar L. (Apocynaceae) elicits arrhythmogenic activity. Journal of Ethnopharmacology, 206, 170–177.PubMed

57.

Wu, J., Li, D., Du, L., et al. (2015). Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase α in mouse. Cell & Bioscience, 64, 1–15.

Title: Comparative Therapeutic Potential of Cardioactive Glycosides in Doxorubicin Model of Heart Failure
Authors: Raquel da Silva Ferreira
Paula Bretas Ullmann Fernandes
Jéssica Pereira Oliveira da Cruz
Françoise Louanne Araújo Silva
Marthin Raboch Lempek
Gioavanni Naves Canta
Júlio César Cambraia Veado
Matheus Matioli Mantovani
Ana Flávia Machado Botelho
Marília Martins Melo
Publication date: 01-01-2022
Publisher: Springer US
Keywords: Electrocardiography
Digoxin
Heart Failure
Electrocardiography
Published in: Cardiovascular Toxicology / Issue 1/2022
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-021-09702-w

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Comparative Therapeutic Potential of Cardioactive Glycosides in Doxorubicin Model of Heart Failure

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2022

Effects of FW2 Nanoparticles Toxicity in a New In Vitro Pulmonary Vascular Cells Model Mimicking Endothelial Dysfunction

In Vivo and In Vitro Cardioprotective Effect of Gossypin Against Isoproterenol-Induced Myocardial Infarction Injury

Oxidative Stress Indices Changes in the Hearts of Rat Pups in Response to Maternal Buprenorphine Treatment during Gestation and Lactation

AAV9-Mediated Cardiac CNTF Overexpression Exacerbated Adverse Cardiac Remodeling in Streptozotocin-Induced Type 1 Diabetic Models

Refractory Shock from Amlodipine Overdose Overcomed with Hyperinsulinemia

Correction to: AAV9-Mediated Cardiac CNTF Overexpression Exacerbated Adverse Cardiac Remodeling in Streptozotocin-Induced Type 1 Diabetic Models

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page