title: Preservation of mitochondrial function may contribute to cardioprotective effects of Na+/Ca2+ exchanger inhibitors in ischaemic/reperfused rat hearts.
abstract: OBJECTIVE
  Na+/Ca2+ exchanger (NCX) inhibitors are known to attenuate myocardial reperfusion injury. However, the exact mechanisms for the cardioprotection remain unclear. The present study was undertaken to examine the mechanism underlying the cardioprotection by NCX inhibitors against ischaemia/reperfusion injury.
  
  
  METHODS
  Isolated rat hearts were subjected to 35-min ischaemia/60-min reperfusion or 20-min ischaemia/60-min reperfusion. NCX inhibitors (3-30 microM KB-R7943 (KBR) or 0.3-1 microM SEA0400 (SEA)) were given for 5 min prior to ischaemia (pre-ischaemic treatment) or for 10 min after the onset of reperfusion (post-ischaemic treatment).
  
  
  RESULTS
  With 35-min ischaemia/60-min reperfusion, pre- or post-ischaemic treatment with KBR or SEA neither enhanced post-ischaemic contractile recovery nor attenuated ischaemia- or reperfusion-induced Na+ accumulation and damage to mitochondrial respiratory function. With the milder model (20-min ischaemia/reperfusion), pre- or post-ischaemic treatment with 10 microM KBR or 1 microM SEA significantly enhanced the post-ischaemic contractile recovery, associated with reductions in reperfusion-induced Ca2+ accumulation, damage to mitochondrial function, and decrease in myocardial high-energy phosphates. Furthermore, Na+ influx to mitochondria in vitro was enhanced by increased concentrations of NaCl. KBR (10 microM) and 1 microM SEA partially decreased the Na+ influx.
  
  
  CONCLUSIONS
  The NCX inhibitors exerted cardioprotective effects during relatively mild ischaemia. The mechanism may be attributable to prevention of mitochondrial damage, possibly mediated by attenuation of Na+ overload in cardiac mitochondria during ischaemia and/or Ca2+ overload via the reverse mode of NCX during reperfusion.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Motegi
authors.forename: K
authors.initials: K
authors.lastname: Tanonaka
authors.forename: Y
authors.initials: Y
authors.lastname: Takenaga
authors.forename: N
authors.initials: N
authors.lastname: Takagi
authors.forename: S
authors.initials: S
authors.lastname: Takeo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009249:NADP / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010647:Phenyl Ethers / Q000494:pharmacology; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013779:Tetrodotoxin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000814:Aniline Compounds; D002316:Cardiotonic Agents; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D010725:Phosphocreatine; D013779:Tetrodotoxin; D009249:NADP; D000255:Adenosine Triphosphate; D012964:Sodium; D003402:Creatine Kinase; D013890:Thiourea; D002122:Calcium Chloride; D002118:Calcium