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.

Keywords:

• Endothelial nitric oxide synthase
• hepatotoxicity
• methotrexate
• nicorandil
• p-glycoprotein

Author contributions

Dr. WYA, SS, MMMR, and NNW contributed to selecting the point of research, data analysis, drafting, revising the article, giving final approval of the version to be published, and agreeing to be accountable for all aspects of the work. Dr. ME performed and wrote the part on histopathology, immunohistochemistry and revised the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.