Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes.

OBJECTIVE The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells. MATERIALS AND METHODS We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells. RESULTS Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX. CONCLUSIONS The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.

[1]  K. Huber,et al.  Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Leigheb,et al.  Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice , 2022, Metabolites.

[3]  E. Selçuk,et al.  Protective effect of dexpanthenol against methotrexate-induced liver oxidative toxicity in rats , 2022, Drug and chemical toxicology.

[4]  H. Mächler,et al.  Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes , 2021, Antioxidants.

[5]  C. Guruvayoorappan,et al.  Antioxidant-rich fraction of Amomum subulatum fruits mitigates experimental methotrexate-induced oxidative stress by regulating TNF-α, IL-1β, and IL-6 proinflammatory cytokines. , 2021, Journal of food biochemistry.

[6]  O. Ozmen,et al.  Apigenin alleviates methotrexate-induced liver and kidney injury in mice , 2021, Human & experimental toxicology.

[7]  M. Kalantar,et al.  Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity , 2020, Naunyn-Schmiedeberg's Archives of Pharmacology.

[8]  H. Li,et al.  Effects of ranolazine on cardiac function in rats with heart failure. , 2019, European review for medical and pharmacological sciences.

[9]  S. Majagi,et al.  Effect of anti-inflammatory activity of ranolazine in rat model of inflammation , 2018, The Indian journal of medical research.

[10]  C. Coppola,et al.  Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine , 2018, OncoTargets and therapy.

[11]  S. Vatner,et al.  Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck) , 2018, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  C. Coppola,et al.  Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production , 2018, Front. Physiol..

[13]  F. Crea,et al.  Microvascular ischemia in patients with successful percutaneous coronary intervention: effects of ranolazine and isosorbide-5-mononitrate. , 2017, European review for medical and pharmacological sciences.

[14]  M. Abdel-Daim,et al.  Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice , 2017, Oxidative medicine and cellular longevity.

[15]  A. C. Uguz,et al.  Vitamin C attenuates methotrexate-induced oxidative stress in kidney and liver of rats. , 2017, Physiology international.

[16]  D. El-Agamy,et al.  Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity , 2017, PloS one.

[17]  Terruzzi Ileana,et al.  Ranolazine promotes muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells , 2016, Endocrine.

[18]  E. Obrador,et al.  Effects of Ranolazine on Astrocytes and Neurons in Primary Culture , 2016, PloS one.

[19]  J. Makielski,et al.  Late sodium current: A mechanism for angina, heart failure, and arrhythmia. , 2016, Trends in cardiovascular medicine.

[20]  Chien‐Jung Chang,et al.  Selective and non-selective non-steroidal anti-inflammatory drugs differentially regulate pulmonary vein and atrial arrhythmogenesis. , 2015, International journal of cardiology.

[21]  C. Coppola,et al.  Ranolazine protects from doxorubicin‐induced oxidative stress and cardiac dysfunction , 2014, European journal of heart failure.

[22]  C. Fontes-Ribeiro,et al.  Role of Methamphetamine on Glioblastoma Cytotoxicity Induced by Doxorubicin and Methotrexate , 2014, Neurotoxicity Research.

[23]  P. Marchio,et al.  Anti-inflammatory and antioxidant effects of ranolazine on primary cultured astrocytes , 2014, Critical Care.

[24]  A. Sestito,et al.  The patient with chronic ischemic heart disease. Role of ranolazine in the management of stable angina. , 2012, European review for medical and pharmacological sciences.

[25]  O. Guralp,et al.  Protein oxidation markers in women with and without gestational diabetes mellitus: a possible relation with paraoxonase activity. , 2011, Diabetes research and clinical practice.

[26]  J. Siamwala,et al.  Chick Embryo Partial Ischemia Model: A New Approach to Study Ischemia Ex Vivo , 2010, PloS one.

[27]  Y. Gupta,et al.  Oxygen Glucose Deprivation Model of Cerebral Stroke in PC-12 Cells: Glucose as a Limiting Factor , 2009, Toxicology mechanisms and methods.

[28]  R. Kloner,et al.  Late sodium current inhibition as a new cardioprotective approach. , 2008, Journal of molecular and cellular cardiology.

[29]  G. Hasenfuss,et al.  Mechanism of action of the new anti-ischemia drug ranolazine , 2007, Clinical Research in Cardiology.

[30]  J. Sabrià,et al.  Contribution of caspase-mediated apoptosis to the cell death caused by oxygen–glucose deprivation in cortical cell cultures , 2005, Neurobiology of Disease.

[31]  K. Nugent,et al.  Acute Cardiac Toxicity Associated with High‐Dose Intravenous Methotrexate Therapy: Case Report and Review of the Literature , 2005, Pharmacotherapy.

[32]  R. Giffard,et al.  Geldanamycin treatment reduces delayed CA1 damage in mouse hippocampal organotypic cultures subjected to oxygen glucose deprivation , 2005, Neuroscience Letters.

[33]  B. Yeğen,et al.  Melatonin prevents methotrexate‐induced hepatorenal oxidative injury in rats , 2003, Journal of pineal research.

[34]  J. Aarbakke,et al.  LEUCOVORIN AND MAXIMUM TOLERATED DOSE TOXICITY OF METHOTREXATE IN RATS , 2000, Pediatric hematology and oncology.

[35]  Y. Abiko,et al.  Protective effects of ranolazine, a novel anti-ischemic drug, on the hydrogen peroxide-induced derangements in isolated, perfused rat heart: comparison with dichloroacetate. , 1998, Japanese journal of pharmacology.

[36]  J J Strain,et al.  The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. , 1996, Analytical biochemistry.

[37]  B. Blazar,et al.  Serum catalase as marker of graft-vs-host disease in allogeneic bone marrow transplant recipients: pilot study. , 1995, Clinical chemistry.

[38]  G. Lutty,et al.  Measurement and characterization of free radical generation in reoxygenated human endothelial cells. , 1994, The American journal of physiology.

[39]  S. Wolff,et al.  Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein. , 1992, Analytical biochemistry.

[40]  G. Weber,et al.  Malignant transformation‐linked imbalance: Decreased xanthine oxidase activity in hepatomas , 1975, FEBS letters.

[41]  M. Dadlez,et al.  Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern , 2021 .

[42]  I. Regla,et al.  Effects of ranolazine on vasomotor responses of rat aortic rings. , 2013, Archives of medical research.

[43]  M. Bhori,et al.  An in vitro study of the ameliorative role of α-tocopherol on methotrexate-induced oxidative stress in rat heart mitochondria , 2012, Journal of basic and clinical physiology and pharmacology.

[44]  M. Hu,et al.  Measurement of protein thiol groups and glutathione in plasma. , 1994, Methods in enzymology.

[45]  S. Aust,et al.  Microsomal lipid peroxidation. , 1978, Methods in enzymology.