title: Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo.
abstract: OBJECTIVE
  The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca(2+) overload is a main inductor of mPTP opening, we examined the effect of Ru(360), a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model.
  
  
  METHODS
  Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru(360) treatment.
  
  
  RESULTS
  Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru(360) (15-50 nmol kg(-1)), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru(360)-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter.
  
  
  CONCLUSIONS
  We showed that Ru(360) treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru(360) administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru(360) could be used in reperfusion therapy to prevent the occurrence of arrhythmia.
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México DF, México.
authors.forename: G de J
authors.initials: Gde J
authors.lastname: García-Rivas
authors.forename: K
authors.initials: K
authors.lastname: Carvajal
authors.forename: F
authors.initials: F
authors.lastname: Correa
authors.forename: C
authors.initials: C
authors.lastname: Zazueta
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017975:Ruthenium Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012430:Ruthenium Red / Q000494:pharmacology; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000517:prevention & control
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C112020:Ru 360; D017975:Ruthenium Compounds; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D016572:Cyclosporine; D000154:Aconitate Hydratase; D002118:Calcium