Potential Cardioprotective potential of Stevioside and Verapamil in Cyclophosphamide-Induced Cardiotoxicity in Rats

Abstract

Introduction: Stevioside (STV), obtained from Stevia rebaudiana leaves, is a calcium channel blocker and inhibits CYP3A4, the primary enzyme responsible for VPML metabolism, thereby STV may elevate VPML plasma concentrations and potentiate its cardioprotective action when co-administered against oxidative cardiac injury. Cyclophosphamide (CYP), a key alkylating agent in cancer chemotherapy for lymphomas and leukaemias, induces acute cardiotoxicity via metabolites (phosphoramide mustard, acrolein) that trigger oxidative stress, endothelial damage, myocardial haemorrhage, necrosis, and ECG alterations, limiting its therapeutic use. Aim & Objectives: This study aimed to investigate STV's enhancement of VPML's cardioprotective effects against CYP-induced cardiotoxicity in rats, with objectives to evaluate serum biomarker normalization (LDH, CK-MB, CK-NAC, AST, ALT, ALP), ECG restoration (heart rate, PR, QRS, QT, RR intervals), and combinatorial synergy. Methods: Wistar rats of either sex (n=6/group) received CYP (200 mg/kg, i.p.) on day 1. Treatments VPML (9 mg/kg, p.o.), STV (50 mg/kg, p.o.), and STV+VPML were given orally for 10 days post-CYP. Cardiac damage was assessed biochemically and electrocardiographically on day 11. Results: CYP markedly elevated biomarkers (e.g., LDH: 676.22 ± 4.10 IU/L vs normal 296.90 ± 4.56 IU/L; CK-MB: 223.62 ± 5.73 IU/L; p<0.001) and disrupted ECG (reduced heart rate, prolonged PR/QRS/QT/RR). VPML and STV attenuated these (p<0.05), but STV+VPML excelled (LDH: 321.43 ± 5.07 IU/L; CK-MB: 101.05 ± 2.62 IU/L; p<0.001 vs. CYP/VPML; ECG normalized). ​Summary & Conclusion: In conclusion, STV with VPML robustly counteracts CYP cardiotoxicity, suggesting clinical potential for safer chemotherapy via antioxidant-calcium blockade combination.