title: Cardioprotective Effect of Ranolazine in the Process of Ischemia-reperfusion in Adult Rat Cardiomyocytes.
abstract: OBJECTIVE
  Ranolazine is used as a complementary treatment for angina in symptomatic patients who are inadequately controlled with first-line antianginal therapies. Ranolazine inhibits sodium voltage-dependent channels, suggesting their possible involvement in the reperfusion process by preventing the sodium and calcium overload that occurs during ischemia. In this study, we characterized the effect of ranolazine on calcium homeostasis in isolated adult cardiac myocytes from rats subjected to a simulated ischemia and reperfusion protocol.
  
  
  METHODS
  The effects of ranolazine on changes in intracellular calcium concentration were evaluated at different times using field electrostimulation. The study of intracellular calcium was performed using microfluorimetry with the fluorescent indicator, Fura-2, and by confocal microscopy with the indicator, Fluo-3.
  
  
  RESULTS
  We found that cardiomyocytes subjected to ischemia-reperfusion showed an increase in the diastolic calcium concentration and a decrease in the amplitude of intracellular calcium transients. The application of ranolazine during ischemia significantly improved intracellular calcium handling, preventing intracellular calcium overload, decreasing the diastolic calcium concentration, increasing the sarcoplasmic reticulum calcium load, and preserving the amplitude of the intracellular calcium transient, which was reflected by successful recovery in the process of excitation-contraction coupling during reperfusion. However, these effects of ranolazine did not occur when it was applied during reperfusion or when applied in both ischemia and reperfusion.
  
  
  CONCLUSIONS
  Ranolazine shows beneficial effects in cardiomyocytes exposed to ischemia/reperfusion but only when applied during ischemia. This effect is achieved through its improvement of calcium handling during ischemia.
authors.affiliation: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Calderón-Sánchez
authors.affiliation: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Inserm, Labex Lermit, Université Paris Sud, Chatenay-Malabry, France.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Domínguez-Rodríguez
authors.affiliation: Unidad de Imagen Cardiovascular, Área del Corazón, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: José
authors.initials: J
authors.lastname: López-Haldón
authors.affiliation: UGC del Corazón, Instituto de Biomedicina de Málaga (IBIMA), Hospital Clínico Universitario Virgen de la Victoria, Universidad de Málaga, RIC (Red de Investigación Cardiovascular), Málaga, Spain.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Jiménez-Navarro
authors.affiliation: Inserm, Labex Lermit, Université Paris Sud, Chatenay-Malabry, France.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gómez
authors.affiliation: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Tarik
authors.initials: T
authors.lastname: Smani
authors.affiliation: Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Unidad de Imagen Cardiovascular, Área del Corazón, Hospital Universitario Virgen del Rocío, Seville, Spain. Electronic address: antorfernan@us.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ordóñez
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000069458:Ranolazine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D026941:Sodium Channel Blockers; D000069458:Ranolazine; D002118:Calcium
keywords: Ca(2+); Cardioprotección; Cardioprotection; Ischemia-reperfusion; Isquemia-reperfusión; Ranolazina; Ranolazine