title: Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo.
abstract: BACKGROUND
  Sevoflurane post-conditioning (SpostC) protects young hearts against ischemia-reperfusion injury. It is unknown whether the infarct-limiting effect is also maintained in aged cohorts and whether there are age-associated differences in the underlying mechanisms.
  
  
  METHODS
  Young or old rats were randomly subjected to 30-min myocardial ischemia, followed by 120-min reperfusion in vivo, with or without SpostC in the presence or absence of phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor. Western blotting was used to determine the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). Myocardial nicotinamide adenine dinucleotide (NAD(+) ) level was measured to indicate mitochondrial permeability transition pore (mPTP) opening.
  
  
  RESULTS
  SpostC significantly decreased infarct size in young (35 ± 4% vs. 56 ± 3%, P < 0.05) but not old rats (45 ± 3% vs. 47 ± 4%, P > 0.05) compared with each control group. SpostC substantially augmented phosphorylation of Akt (0.74 ± 0.03 arbitrary units vs. 0.27 ± 0.03 arbitrary units, P < 0.05) or ERK1/2 (0.85 ± 0.04 arbitrary units vs. 0.29 ± 0.04 arbitrary units, P < 0.05) compared with control group, which was abolished by PI3K or MEK1/2 inhibitor in young rats, respectively, but failed to activate Akt and ERK1/2 in old rats. NAD(+) level (nmol/g tissue) was higher in SpostC group in young (118.57 ± 9.27 vs. 46.78 ± 4.54, P < 0.05) but not old rats (58.50 ± 7.16 vs. 61.15 ± 5.50, P > 0.05) compared with each control group. PI3K or MEK1/2 inhibitor abrogated the infarct-sparing effect and inhibition of loss of NAD(+) induced by SpostC in young rats, respectively.
  
  
  CONCLUSIONS
  SpostC-mediated cardioprotection in young rats is not effective in senescent rats, which may at least be the consequence of failure to activate Akt and ERK1/2, and resultant failure to inhibit mPTP opening.
authors.affiliation: Department of Anesthesiology, Fuwai Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Fang
authors.forename: Y
authors.initials: Y
authors.lastname: Yao
authors.forename: L
authors.initials: L
authors.lastname: Li
mesh_terms: D000375:Aging / Q000502:physiology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation; D057775:Ischemic Postconditioning / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008738:Methyl Ethers / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D009243:NAD; D000077149:Sevoflurane; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases