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

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 (K_ATP) 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 K_ATP and eNOS in mediating such protection.

Keywords: Cardiotoxicity; Cyclophosphamide; Endothelial nitric oxide synthase; Glibenclamide; Nicorandil; Potassium channel.