title: Transient metabolic alkalosis during early reperfusion abolishes helium preconditioning against myocardial infarction: restoration of cardioprotection by cyclosporin A in rabbits.
abstract: BACKGROUND
  Intracellular acidosis during early reperfusion after coronary artery occlusion was recently linked to cardioprotection resulting from myocardial ischemic postconditioning. We tested the hypotheses that transient alkalosis during early reperfusion abolishes helium preconditioning and that the mitochondrial permeability transition pore inhibitor cyclosporin A (CsA) restores the cardioprotective effects of helium during alkalosis in vivo.
  
  
  METHODS
  Rabbits (n = 36) instrumented for hemodynamics measurement were subjected to a 30-min left anterior descending coronary artery occlusion and 3-h reperfusion. The rabbits received 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before left anterior descending coronary artery occlusion in the absence or presence of transient alkalosis (pH = 7.5) produced by administration of IV sodium bicarbonate (10 mEq) 2 min before reperfusion. Other rabbits preconditioned with helium received CsA (5 mg/kg) in the presence of alkalosis or CsA alone.
  
  
  RESULTS
  Helium reduced myocardial infarct size (25% +/- 4% of left ventricular area at risk; P < 0.05) compared with control (44% +/- 6%). Alkalosis during early reperfusion did not alter infarct size alone (46% +/- 2%), but this intervention abolished helium-induced cardioprotection (45% +/- 3%). CsA restored reductions in infarct size produced by helium preconditioning in the presence of alkalosis (28% +/- 6%; P < 0.05 versus control) but did not affect myocardial necrosis alone (43% +/- 6%).
  
  
  CONCLUSIONS
  The results demonstrate that transient alkalosis during early reperfusion abolishes helium preconditioning in rabbits. CsA restored helium-induced cardioprotection during alkalosis, suggesting that helium preconditioning inhibits mitochondrial permeability transition pore formation by maintaining intracellular acidosis during early reperfusion.
authors.affiliation: Department of Anesthesiology, The Medical Collegeof Wisconsin, Milwaukee, Wisconsin, USA. pspagel@mcw.edu
authors.forename: Paul S
authors.initials: PS
authors.lastname: Pagel
authors.forename: John G
authors.initials: JG
authors.lastname: Krolikowski
mesh_terms: D000138:Acidosis / Q000503:physiopathology; D000280:Administration, Inhalation; D000471:Alkalosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006371:Helium / Q000008:administration & dosage*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D011817:Rabbits; D017693:Sodium Bicarbonate
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D006371:Helium; D016572:Cyclosporine; D017693:Sodium Bicarbonate