Cardioprotective Effect of Polymyxin‐B and Dantrolene Combination on Isoproterenol‐Induced Hypertrophic Cardiomyopathy in Rats, via Attenuation of Calmodulin‐Dependent Protein Kinase II

Abstract

Hypertrophic cardiomyopathy is a major cause of mortality worldwide. In this study, we hypothesized that the combination of Dantrolene and Polymyxin-B will provide cardioprotective action against isoproterenolinduced hypertrophic cardiomyopathy via attenuation of Calmodulin-dependent protein kinase II (CaMKII). Hypertrophic cardiomyopathy was induced in rats by subcutaneous administration of isoproterenol (5 mg/kg) for 14 days. Simultaneously, animals were treated with Polymyxin-B per se, Dantrolene per se, and Dantrolene and Polymyxin-B combination for 14 days. Hemodynamic parameters, biochemical parameters, and histological analysis were performed. Administration of isoproterenol for 14 days resulted in severe myocardial damage, characterized by cardiac hypertrophy and increase serum CK-MB, CK-Nac, LDH, AST, and ALT levels. It also caused alteration in electrocardiogram and blood pressure. A significant increase in CaMKII was observed in heart homogenate. Treatment with the Polymyxin-B and Dantrolene combination significantly ameliorated cardiac hypertrophy, biochemical parameters, ECG parameters, and heart histopathology. Further, significant attenuation in CaMKII levels was observed. The effect of the combination was more than per se treatment. Results of the current study showed that the combination of Polymyxin-B and Dantrolene prevented the development of isoproterenol-induced hypertrophic cardiomyopathy in rats via attenuation of the CaMKII.

The lncRNA ADAMTS9-AS1/miR-185-5p/KAT7 ceRNA network inhibits cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy

“…In spite of the improved understanding of causal mutation, the genetics that defines HOCM is limited due to (a) insufficient evidences of disease association and (b) involvement with other diseases and therefore warrants further investigation (Teekakirikul et al 2019). On a separate note, isoproterenol (ISO) is a nonselective beta-adrenergic agonist and is commonly used to induce various cardiac disorders, including HOCM, fibrosis, myocardial infarction (MI), and heart failure (Chang et al 2018;Liu et al 2018;Feng et al 2019;Shaikh and Bhatt 2022). Therefore, this study employed the ISO cell model to explore the molecular landscape of HOCM and further provide novel targets for HOCM diagnosis and treatment.…”