title: Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability.
abstract: BACKGROUND
  A mechanism for myocardial dysfunction after ischemia and reperfusion is Na(+)/H(+) exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na(+)/H(+) exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na(+)/H(+) exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na(+)/H(+) exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability.
  
  
  METHODS
  A coronary snare and sonomicrometry crystals were placed in pigs (n = 21, 32 kg). Coronary occlusion was instituted for 120 minutes followed by reperfusion for 180 minutes. At 105 minutes of ischemia, pigs were randomized to ischemia and reperfusion only (saline solution, n = 11) or Na(+)/H(+) exchanger inhibition (HOE-642, 3 mg/kg intravenously, n = 10). Myocardial injury was determined by tissue staining and measurement of plasma myocyte-specific enzymes. Myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (millimeters of mercury per centimeter) and by assessment of interregional shortening.
  
  
  RESULTS
  Infarct size was not different between groups (39% +/- 6%, P =.26). Moreover, at 180 minutes of reperfusion, plasma troponin-I and creatine kinase MB values had increased to identical levels in the ischemia and reperfusion-only and Na(+)/H(+) exchanger inhibition groups (300 +/- 35 and 50 +/- 6 ng/mL, respectively). At 90 minutes of ischemia, regional end-systolic pressure-dimension relation decreased from baseline (5.7 +/- 0.5 versus 2.7 +/- 0.3, P <.05) in the area at risk. By 30 minutes of reperfusion, regional end-systolic pressure-dimension relation decreased further in the ischemia and reperfusion-only group (1.6 +/- 0.2, P <.05), but improved with Na(+)/H(+) exchanger inhibition (4.4 +/- 0.7, P <.05).
  
  
  CONCLUSIONS
  Na(+)/H(+) exchanger inhibition instituted at reperfusion improved contractility independent of myocardial viability as assessed by absolute infarct size and myocyte-specific enzyme release. Thus, modulation of Na(+)/H(+) exchanger activity in the setting of prolonged ischemia and reperfusion may hold therapeutic potential.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina 29425, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Yarbrough
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: G Patricia
authors.initials: GP
authors.lastname: Escobar
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Mingoia
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sample
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hendrick
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Dowdy
authors.forename: Julie E
authors.initials: JE
authors.lastname: McLean
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006334:Heart Function Tests; D006439:Hemodynamics; D007262:Infusions, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology* / Q000601:surgery; D015425:Myocardial Reperfusion / Q000009:adverse effects / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011897:Random Allocation; D020127:Recovery of Function; D012016:Reference Values; D012680:Sensitivity and Specificity; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide