title: The cardioprotective effect of brief acidic reperfusion after ischemia in perfused rat hearts is not mimicked by inhibition of the Na(+)/H(+) exchanger NHE1.
abstract: BACKGROUND
  Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na(+)/H(+) exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC.
  
  
  RESULTS
  We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA.
  
  
  CONCLUSIONS
  In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.
authors.affiliation: Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ann-Dorit
authors.initials: AD
authors.lastname: Andersen
authors.forename: Bo Hjorth
authors.initials: BH
authors.lastname: Bentzen
authors.forename: Henrik
authors.initials: H
authors.lastname: Salling
authors.forename: Henrik
authors.initials: H
authors.lastname: Klingberg
authors.forename: Morten
authors.initials: M
authors.lastname: Kanneworff
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Stine F
authors.initials: SF
authors.lastname: Pedersen
mesh_terms: D000143:Acids / Q000378:metabolism; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006863:Hydrogen-Ion Concentration; D057775:Ischemic Postconditioning; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000378:metabolism / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000143:Acids; D018696:Neuroprotective Agents; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; C039614:ethylisopropylamiloride