Ranolazine attenuates diabetic cardiomyopathy in rats by suppressing AGE-RAGE axis and oxidative stress

OBJECTIVE: Diabetes mellitus is a significant global health issue. Chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) and oxidative stress, both of which contribute to diabetic complications, including cardiovascular diseases. This study explores the effects of ranolazine, an antianginal agent with known metabolic benefits, on AGEs, their receptor (RAGE), and oxidative stress in type 2 diabetic rats. RESULTS: Ranolazine treatment did not significantly reduce serum glucose levels in diabetic rats but significantly decreased malondialdehyde (MDA) levels and increased glutathione peroxidase (GPx) activity. Serum levels of pentosidine and carboxymethyl-lysine (CML) were also significantly lowered in ranolazine-treated diabetic rats. Furthermore, ranolazine downregulated RAGE expression in cardiac tissue, suggesting a reduction in AGE-mediated damage. In vitro assays showed that ranolazine did not directly inhibit albumin glycation, implying that its effects on AGEs and RAGE are likely mediated through improved metabolic and antioxidative mechanisms rather than direct interference with glycation. These findings highlight ranolazine’s potential to mitigate AGE-related damage and oxidative stress in diabetic cardiomyopathy, independent of glucose-lowering effects.