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Publication Detail
Mitochondria as targets for nitric oxide-induced protection during simulated ischemia and reoxygenation in isolated neonatal cardiomyocytes
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Rakhit RD, Mojet MH, Marber MS, Duchen MR
  • Publication date:
    2001
  • Pagination:
    2617, 2623
  • Journal:
    Circulation
  • Volume:
    103
  • Issue:
    21
  • Print ISSN:
    0009-7322
  • Keywords:
    calcium, cardiomyocyte, control, culture, Fluorescence, ischemia, mechanisms, membrane, Methods, mitochondria, nitric oxide, preconditioning, rat, respiration
  • Addresses:
    Departments of Cardiology, Kings College London, St Thomas' Hospital , University College London, UK
Abstract
BACKGROUND: As shown previously, exposure to NO donors initiates protective mechanisms in cardiomyocytes that persist after removal of the donor, a form of pharmacological preconditioning. Because NO also affects mitochondrial respiration, we studied the effect of NO on mitochondrial Ca(2+) uptake. METHODS AND RESULTS: Neonatal rat ventricular myocytes in primary culture were exposed to 1 hour of simulated ischemia and 1 hour of reoxygenation (sI/R). Pretreatment with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) (1 mmol/L for 90 minutes), followed by washing and incubation for 10 to 30 minutes, reduced sI/R-induced cell death to 25.4% compared with control (propidium iodide exclusion assay, P<0.001). Short (10-second) exposures to SNAP reversibly suppressed mitochondrial respiration without a detectable change in mitochondrial potential. In contrast, treatment with SNAP for 90 minutes caused a modest but sustained mitochondrial depolarization, as judged by JC-1 fluorescence. SNAP pretreatment limited cellular Ca(2+) overload during ischemia (fura-2 ratio rose to 226+/-40% versus 516+/-170% of baseline, n=5, P<0.05) and prevented loss of cell membrane integrity during reoxygenation. SNAP pretreatment also significantly reduced the ability of mitochondria to accumulate Ca(2+) in the face of a similar cytosolic Ca(2+) load (peak rhod-2 fluorescence 133+/-4% versus 166+/-7% of baseline at similar fluo-3 levels, P=0.0004, n=52 and 25, respectively). CONCLUSIONS: Pretreatment with an NO donor induces a modest, sustained mitochondrial depolarization and protects cardiomyocytes from sI/R injury. The demonstrated reduction in mitochondrial Ca(2+) uptake possibly reduces cytosolic Ca(2+) overload, providing a likely mechanism for NO-induced protection
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