Exploring the role of ATP-sensitive potassium channel, eNOS, and P-glycoprotein in mediating the hepatoprotective activity of nicorandil in methotrexate-induced liver injury in rats.

Abstract

Background: Methotrexate (MTX) is a commonly used chemotherapeutic agent; however, its clinical use is challenged by various types of injuries, including hepatotoxic side effects. Therefore, finding new protective drugs against MTX-induced toxicities is a critical need. Moreover, the different mechanisms mediating such effects are still not clear. The current study aimed to evaluate the possible ameliorative action of nicorandil (NIC) in MTX-induced hepatotoxicity and examine the roles of the ATP-sensitive potassium channel (K_ATP), endothelial nitric oxide synthase (eNOS), and P-glycoprotein (P-gp).

Materials and methods: Thirty-six male Wistar albino rats were used. NIC (3 mg/kg/day) was given orally for 2 weeks, and hepatotoxicity was induced by a single intraperitoneal injection of MTX (20 mg/kg) on the 11th day of the experiment. We confirmed the role of K_ATP by co-administering glimepiride (GP) (10 mg/kg/day) 30 min before NIC. The measured serum biomarkers were [alanine transaminase (ALT) and aspartate transaminase (AST)], total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NOx), tumor necrosis factor-alpha (TNFα), superoxide dismutase (SOD), and P-gp. Histopathology, eNOS, and caspase-3 immunoexpression were evaluated.

Results: The MTX group displayed hepatotoxicity in the form of elevations of ALT, AST, MDA, NOx, and caspase-3 immunoexpression. Furthermore, the histopathological examination showed marked liver injury. TAC, SOD, P-gp, and eNOS immunoexpression showed significant inhibition. In the protective group, all parameters improved (P value < 0.05).

Conclusion: NIC has an ameliorative action against MTX-induced hepatotoxicity, most probably via its antioxidant, anti-inflammatory, and anti-apoptotic functions together with the modulation of the K_ATP channel, eNOS, and P-glycoprotein.