Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity
| Autor: | Sayed Shehata, Asmaa M.A. Bayoumi, Wedad M. Abdelraheem, Maram El-Hussieny, Marwa M.M. Refaie |
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| Rok vydání: | 2019 |
| Předmět: |
Cardiotoxicity
biology ATP-sensitive potassium channel Chemistry 030204 cardiovascular system & hematology Pharmacology Toxicology biology.organism_classification Potassium channel Glibenclamide Superoxide dismutase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Enos 030220 oncology & carcinogenesis Lactate dehydrogenase medicine biology.protein Cardiology and Cardiovascular Medicine Nicorandil Molecular Biology medicine.drug |
| Zdroj: | Cardiovascular Toxicology. 20:71-81 |
| ISSN: | 1559-0259 1530-7905 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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