Skip to main content
SpringerLink
Log in

Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity

Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3 mg/kg/day) orally for 5 days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150 mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (KATP) by coadministration of glibenclamide (GP) (5 mg/kg/day) 2 h before NIC (3 mg/kg/day) for 5 days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-l-arginine (l-NNA) (25 mg/kg/day) for 5 days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1 β), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or l-NNA could diminish the protective effect of NIC. This proves the important role of KATP and eNOS in mediating such protection.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Mahipal, P., & Pawar, R. S. (2017). Nephroprotective effect of Murraya koenigii on cyclophosphamide induced nephrotoxicity in rats. Asian Pacific Journal of Tropical Medicine,10, 808–812.

    Article  CAS  Google Scholar 

  2. Fouad, A. A., Qutub, H. O., & Al-Melhim, W. N. (2016). Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environmental Toxicology and Pharmacology,45, 158–162.

    Article  CAS  Google Scholar 

  3. Avci, H., Epikmen, E. T., Ipek, E., Tunca, R., Birincioglu, S. S., Aksit, H., et al. (2017). Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity. Experimental and Toxicologic Pathology,69, 317–327.

    Article  CAS  Google Scholar 

  4. El-Kashef, D. H. (2018). Role of venlafaxine in prevention of cyclophosphamide-induced lung toxicity and airway hyperactivity in rats. Environmental Toxicology and Pharmacology,58, 70–76.

    Article  CAS  Google Scholar 

  5. Mahmoud, A. M. (2014). Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARgamma and abrogation of oxidative stress and inflammation. Canadian Journal of Physiology and Pharmacology,92, 717–724.

    Article  CAS  Google Scholar 

  6. Nafees, S., Rashid, S., Ali, N., Hasan, S. K., & Sultana, S. (2015). Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: Role of NFkappaB/MAPK pathway. Chemico-Biological Interactions,231, 98–107.

    Article  CAS  Google Scholar 

  7. Refaie, M. M. M., El-Hussieny, M., & Zenhom, N. M. (2018). Protective role of nebivolol in cadmium-induced hepatotoxicity via downregulation of oxidative stress, apoptosis and inflammatory pathways. Environmental Toxicology and Pharmacology,58, 212–219.

    Article  CAS  Google Scholar 

  8. Potnuri, A. G., Allakonda, L., & Lahkar, M. (2018). Crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system. Biomedicine & Pharmacotherapy,101, 174–180.

    Article  CAS  Google Scholar 

  9. Omole, J. G., Ayoka, O. A., Alabi, Q. K., Adefisayo, M. A., Asafa, M. A., Olubunmi, B. O., et al. (2018). Protective effect of kolaviron on cyclophosphamide-induced cardiac toxicity in rats. Journal of Evidence-Based Integrative Medicine,23, 2156587218757649.

    Article  Google Scholar 

  10. Ravindran, S., Swaminathan, K., Ramesh, A., & Kurian, G. A. (2017). Nicorandil attenuates neuronal mitochondrial dysfunction and oxidative stress associated with murine model of vascular calcification. Acta Neurobiologiae Experimentalis (Wars),77, 57–67.

    Article  Google Scholar 

  11. Wu, H., Ye, M., Yang, J., Ding, J., Yang, J., Dong, W., et al. (2015). Nicorandil protects the heart from ischemia/reperfusion injury by attenuating endoplasmic reticulum response-induced apoptosis through PI3K/Akt signaling pathway. Cellular Physiology and Biochemistry,35, 2320–2332.

    Article  CAS  Google Scholar 

  12. Abdel-Raheem, I. T., Taye, A., & Abouzied, M. M. (2013). Cardioprotective effects of nicorandil, a mitochondrial potassium channel opener against doxorubicin-induced cardiotoxicity in rats. Basic & Clinical Pharmacology & Toxicology,113, 158–166.

    Article  CAS  Google Scholar 

  13. Zhai, X., Yang, X., Zou, P., Shao, Y., Yuan, S., Abd El-Aty, A. M., et al. (2018). Protective effect of chitosan oligosaccharides against cyclophosphamide-induced immunosuppression and irradiation injury in mice. Journal of Food Science,83, 535–542.

    Article  CAS  Google Scholar 

  14. Gunes, S., Sahinturk, V., Uslu, S., Ayhanci, A., Kacar, S., & Uyar, R. (2018). Protective effects of selenium on cyclophosphamide-induced oxidative stress and kidney injury. Biological Trace Element Research,185, 116–123.

    Article  CAS  Google Scholar 

  15. Saito, M., Ohmasa, F., Tsounapi, P., Inoue, S., Dimitriadis, F., Kinoshita, Y., et al. (2012). Nicorandil ameliorates hypertension-related bladder dysfunction in the rat. Neurourology and Urodynamics,31, 695–701.

    Article  CAS  Google Scholar 

  16. Ahmed, L. A., El-Maraghy, S. A., & Rizk, S. M. (2015). Role of the KATP channel in the protective effect of nicorandil on cyclophosphamide-induced lung and testicular toxicity in rats. Scientific Reports,5, 14043.

    Article  CAS  Google Scholar 

  17. Ibrahim, M. A., Geddawy, A., & Abdel-Wahab, S. (2018). Sitagliptin prevents isoproterenol-induced myocardial infarction in rats by modulating nitric oxide synthase enzymes. European Journal of Pharmacology,829, 63–69.

    Article  CAS  Google Scholar 

  18. Mihara, M., & Uchiyama, M. (1983). Properties of thiobarbituric acid-reactive materials obtained from lipid peroxide and tissue homogenate. Chemical and Pharmaceutical Bulletin (Tokyo),31, 605–611.

    Article  CAS  Google Scholar 

  19. Nishikimi, M., Appaji, N., & Yagi, K. (1972). The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochemical and Biophysical Research Communications,46, 849–854.

    Article  CAS  Google Scholar 

  20. El-Agamy, D. S., Abo-Haded, H. M., & Elkablawy, M. A. (2016). Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Experimental Biology and Medicine (Maywood),241, 1577–1587.

    Article  CAS  Google Scholar 

  21. VanGuilder, H. D., Vrana, K. E., & Freeman, W. M. (2008). Twenty-five years of quantitative PCR for gene expression analysis. BioTechniques,44, 619–626.

    Article  CAS  Google Scholar 

  22. Ewees, M. G., Messiha, B. A. S., Abdel-Bakky, M. S., Bayoumi, A. M. A., & Abo-Saif, A. A. (2018). Tempol, a superoxide dismutase mimetic agent, reduces cisplatin-induced nephrotoxicity in rats. Drug and Chemical Toxicology,1, 8. https://doi.org/10.1080/01480545.2018.1485688.

    Article  CAS  Google Scholar 

  23. Gonzalez-Moles, M. A., Bascones-Ilundain, C., Gil Montoya, J. A., Ruiz-Avila, I., Delgado-Rodriguez, M., & Bascones-Martinez, A. (2006). Cell cycle regulating mechanisms in oral lichen planus: Molecular bases in epithelium predisposed to malignant transformation. Archives of Oral Biology,51, 1093–1103.

    Article  CAS  Google Scholar 

  24. Sherif, I. O. (2018). The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway. International Immunopharmacology,61, 29–36.

    Article  CAS  Google Scholar 

  25. Mansour, D. F., Saleh, D. O., & Mostafa, R. E. (2017). Genistein ameliorates cyclophosphamide—induced hepatotoxicity by modulation of oxidative stress and inflammatory mediators. Open Access Macedonian Journal of Medical Sciences,5, 836–843.

    Article  Google Scholar 

  26. Elshater, A. A., Haridy, M. A. M., Salman, M. M. A., Fayyad, A. S., & Hammad, S. (2018). Fullerene C60 nanoparticles ameliorated cyclophosphamide-induced acute hepatotoxicity in rats. Biomedicine & Pharmacotherapy,97, 53–59.

    Article  CAS  Google Scholar 

  27. Bertinchant, J. P., Polge, A., Juan, J. M., Oliva-Lauraire, M. C., Giuliani, I., Marty-Double, C., et al. (2003). Evaluation of cardiac troponin I and T levels as markers of myocardial damage in doxorubicin-induced cardiomyopathy rats, and their relationship with echocardiographic and histological findings. Clinica Chimica Acta,329, 39–51.

    Article  CAS  Google Scholar 

  28. Asiri, Y. A. (2010). Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxidative Medicine and Cellular Longevity,3, 308–316.

    Article  Google Scholar 

  29. Nagi, M. N., Al-Shabanah, O. A., Hafez, M. M., & Sayed-Ahmed, M. M. (2011). Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. Journal of Biochemical and Molecular Toxicology,25, 135–142.

    Article  CAS  Google Scholar 

  30. Asiri, Y. A. (2010). Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxidative Medicine and Cellular Longevity,3(5), 308–316.

    Article  Google Scholar 

  31. Kupsco, A., & Schlenk, D. (2015). Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity. International Review of Cell and Molecular Biology,317, 1–66.

    Article  CAS  Google Scholar 

  32. Lixin, X., Lijun, Y., & Songping, H. (2019). Ganoderic acid A against cyclophosphamide-induced hepatic toxicity in mice. Journal of Biochemical and Molecular Toxicology,33, e22271.

    Article  Google Scholar 

  33. Has, A. L., Alotaibi, M. F., Bin-Jumah, M., Elgebaly, H., & Mahmoud, A. M. (2019). Olea europaea leaf extract up-regulates Nrf2/ARE/HO-1 signaling and attenuates cyclophosphamide-induced oxidative stress, inflammation and apoptosis in rat kidney. Biomedicine & Pharmacotherapy,111, 676–685.

    Article  Google Scholar 

  34. Tang, J., Zhen, H., Wang, N., Yan, Q., Jing, H., & Jiang, Z. (2019). Curdlan oligosaccharides having higher immunostimulatory activity than curdlan in mice treated with cyclophosphamide. Carbohydrate Polymers,207, 131–142.

    Article  CAS  Google Scholar 

  35. Dantas, A., Batista-Júnior, F., Macedo, L., Mendes, M., Azevedo, I., & Medeiros, A. (2010). Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats. Acta Cirúrgica Brasileira,25(1), 43–46.

    Article  Google Scholar 

  36. Singh, N., & Kumar, R. (2003). Effect of nicorandil and amlodipine on bio-chemical parameters during isoproterenol induced myocardial necrosis in rats. Indian Journal of Clinical Biochemistry,18, 99–102.

    Article  CAS  Google Scholar 

  37. Tajima, M., Ishizuka, N., Saitoh, K., & Sakagami, H. (2008). Nicorandil enhances the effect of endothelial nitric oxide under hypoxia-reoxygenation: Role of the KATP channel. European Journal of Pharmacology,579, 86–92.

    Article  CAS  Google Scholar 

  38. Horinaka, S., Kobayashi, N., Higashi, T., Hara, K., Hara, S., & Matsuoka, H. (2001). Nicorandil enhances cardiac endothelial nitric oxide synthase expression via activation of adenosine triphosphate-sensitive K channel in rat. Journal of Cardiovascular Pharmacology,38, 200–210.

    Article  CAS  Google Scholar 

  39. Lee, T. M., Lin, S. Z., & Chang, N. C. (2018). Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho-kinase signalling in infarcted rats. Journal of Cellular and Molecular Medicine,22, 1056–1069.

    Article  CAS  Google Scholar 

  40. Ahmed, L. A., & El-Maraghy, S. A. (2013). Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: possible mechanism of cardioprotection. Biochemical Pharmacology,86, 1301–1310.

    Article  CAS  Google Scholar 

  41. Afzal, M. Z., Reiter, M., Gastonguay, C., McGivern, J. V., Guan, X., Ge, Z. D., et al. (2016). Nicorandil, a nitric oxide donor and ATP-sensitive potassium channel opener, protects against dystrophin-deficient cardiomyopathy. Journal of Cardiovascular Pharmacology and Therapeutics,21, 549–562.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Sara Mohamed Naguib Abdel Hafez, Department of Histology and Cell Biology, Faculty of Medicine, Minia University, for carrying out the morphometrical study and interpretation of its data.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Marwa M. M. Refaie

  2. Department of Cardiology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Sayed Shehata

  3. Department of Pathology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Maram El-Hussieny

  4. Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt

    Wedad M. Abdelraheem

  5. Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt

    Asmaa M. A. Bayoumi

Authors
  1. Marwa M. M. Refaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sayed Shehata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maram El-Hussieny
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wedad M. Abdelraheem
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asmaa M. A. Bayoumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MMR and SS selected the point, performed the experimental part, wrote the manuscript, and sent it for publication. ME performed and wrote the histopathology and revised the manuscript. WMA performed and wrote the rt-PCR part. AMAB performed and wrote the part of western blotting and revised the manuscript.

Corresponding author

Correspondence to Marwa M. M. Refaie.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

Additional information

Handling Editor: Mitzi C. Glover.

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

Refaie, M.M.M., Shehata, S., El-Hussieny, M. et al. Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity. Cardiovasc Toxicol 20, 71–81 (2020). https://doi.org/10.1007/s12012-019-09535-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-019-09535-8

Keywords

Search

Navigation