Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo

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. Conclusion: 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.