title: Myocardial reperfusion injury: reactive oxygen species vs. NHE-1 reactivation.
abstract: OBJECTIVE
  Flow restoration to ischemic myocardium reduces infarct size (IS), but it also promotes reperfusion injury. A burst of reactive oxygen species (ROS) and/or NHE-1 reactivation were proposed to explain this injury. Our study was aimed to shed light on this unresolved issue.
  
  
  METHODS
  Regional infarction (40 min-ischemia/2 hs-reperfusion) was induced in isolated and perfused rat hearts. Maximal doses of N-(2-mercaptopropionyl)-glycine (MPG 2mmol/L, ROS scavenger), cariporide (10μmol/L, NHE-1 inhibitor), or sildenafil (1μmol/L, phosphodiesterase5A inhibitor) were applied at reperfusion onset. Their effects on IS, myocardial concentration of thiobarbituric acid reactive substances (TBARS), ERK1/2, p90(RSK), and NHE-1 phosphorylation were analyzed.
  
  
  RESULTS
  All treatments decreased IS ∼ 50% vs. control. No further protection was obtained by combining cariporide or MPG with sildenafil. Myocardial TBARS increased after infarction and were decreased by MPG or cariporide, but unaffected by sildenafil. In line with the fact that ROS induce MAPK-mediated NHE-1 activation, myocardial infarction increased ERK1/2, p90(RSK), and NHE-1 phosphorylation. MPG and cariporide cancelled these effects. Sildenafil did not reduce the phosphorylated ERK1/2-p90(RSK) levels but blunted NHE-1 phosphorylation suggesting a direct dephosphorylating action.
  
  
  CONCLUSIONS
  1) Reperfusion injury would result from ROS-triggered MAPK-mediated NHE-1 phosphorylation (and reactivation) during reperfusion; 2) sildenafil protects the myocardium by favouring NHE-1 dephosphorylation and bypassing ROS generation.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina.
authors.forename: Carolina D
authors.initials: CD
authors.lastname: Garciarena
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Fantinelli
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Caldiz
authors.forename: Gladys
authors.initials: G
authors.lastname: Chiappe de Cingolani
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Néstor G
authors.initials: NG
authors.lastname: Pérez
authors.forename: Horacio E
authors.initials: HE
authors.lastname: Cingolani
authors.forename: Susana M
authors.initials: SM
authors.lastname: Mosca
mesh_terms: D000818:Animals; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D000068677:Sildenafil Citrate; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D006146:Guanidines; C110658:N-(2-mercaptoproprionyl)-glycine; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D013438:Sulfhydryl Compounds; D013450:Sulfones; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide; D000068677:Sildenafil Citrate; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005998:Glycine