AUTHOR=Wahid Muqeet , Saqib Fatima , Abbas Ghulam , Shah Shahid , Alshammari Abdulrahman , Albekairi Thamer H. , Ali Anam , Khurm Muhammad , Mubarak Mohammad S. 

TITLE=Cardioprotective and hypotensive mechanistic insights of hydroethanolic extract of Cucumis melo L. kernels in isoprenaline-induced cardiotoxicity based on metabolomics and in silico electrophysiological models

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1277594

DOI=10.3389/fphar.2023.1277594

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Cardiovascular diseases (CVD) continue to threaten health worldwide, and account for a significant portion of deaths and illnesses. In both developing and industrialized nations, they challenge their health systems. There are several traditional uses of <italic>Cucurbitaceae</italic> seeds in Pakistan, India, Iran, and China, including treating cardiovascular, neurological, and urogenital diseases.</p><p><bold>Methods:</bold> In the present work, integrated techniques of metabolomics profiling and computational cardiomyocyte stimulation were used to investigate possible mechanisms of <italic>C. melo</italic> in isoprenaline (ISO)-induced myocardial infarction. <italic>In vitro</italic>, vasoconstrictions, paired atria, and <italic>in vivo</italic> invasive blood pressure measurement models were performed to explore the mechanism of action of <italic>C. melo</italic> hydroethanolic seed extract (Cm-EtOH).</p><p><bold>Results:</bold> Results showed that Cm-EtOH demonstrates NO-based endothelium-derived relaxing factor (EDRF) vasorelaxant response, negative chronotropic and inotropic response in the atrium, and hypotensive effects in normotensive rats. Results also revealed that Cm-EtOH decreases cardiomyocyte hypertrophy and reverts the altered gene expressions, biochemical, and metabolites in ISO-induced myocardial infarction (MI) rats. The extract additionally reversed ISO-induced MI-induced oxidative stress, energy consumption, and amino acid metabolism. Moreover, <italic>C. melo</italic> seeds increased EDRF function, energy production, and antioxidant capacity to treat myocardial and vascular disorders. In computational cardiomyocyte simulation, gallic acid reduced action potential duration, upstroke velocity (dV/dt<sub>max</sub>), and effective refractory period.</p><p><bold>Conclusion:</bold> This study highlights the therapeutic potential of <italic>C. melo</italic> seeds to treat cardiovascular diseases and provides mechanistic insight into its antihypertensive and cardioprotective activities.</p>