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Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism.

AbstractBACKGROUND:
The role of endothelial nitric oxide synthase (eNOS) in isoflurane postconditioning (IsoPC)-elicited cardioprotection is poorly understood. The authors addressed this issue using eNOS mice.
METHODS:
In vivo or Langendorff-perfused mouse hearts underwent 30 min of ischemia followed by 2 h of reperfusion in the presence and absence of postconditioning produced with isoflurane 5 min before and 3 min after reperfusion. Ca+-induced mitochondrial permeability transition (MPT) pore opening was assessed in isolated mitochondria. Echocardiography was used to evaluate ventricular function.
RESULTS:
Postconditioning with 0.5, 1.0, and 1.5 minimum alveolar concentrations of isoflurane decreased infarct size from 56 +/- 10% (n = 10) in control to 48 +/- 10%, 41 +/- 8% (n = 8, P < 0.05), and 38 +/- 10% (n = 8, P < 0.05), respectively, and improved cardiac function in wild-type mice. Improvement in cardiac function by IsoPC was blocked by N-nitro-L-arginine methyl ester (a nonselective nitric oxide synthase inhibitor) administered either before ischemia or at the onset of reperfusion. Mitochondria isolated from postconditioned hearts required significantly higher in vitro Ca+ loading than did controls (78 +/- 29 microm vs. 40 +/- 25 microm CaCl2 per milligram of protein, n = 10, P < 0.05) to open the MPT pore. Hearts from eNOS mice displayed no marked differences in infarct size, cardiac function, and sensitivity of MPT pore to Ca+, compared with wild-type hearts. However, IsoPC failed to alter infarct size, cardiac function, or the amount of Ca+ necessary to open the MPT pore in mitochondria isolated from the eNOS hearts compared with control hearts.
CONCLUSIONS:
IsoPC protects mouse hearts from reperfusion injury by preventing MPT pore opening in an eNOS-dependent manner. Nitric oxide functions as both a trigger and a mediator of cardioprotection produced by IsoPC.
AuthorsZhi-Dong Ge, Danijel Pravdic, Martin Bienengraeber, Phillip F Pratt Jr, John A Auchampach, Garrett J Gross, Judy R Kersten, David C Warltier
JournalAnesthesiology (Anesthesiology) Vol. 112 Issue 1 Pg. 73-85 (Jan 2010) ISSN: 1528-1175 [Electronic] United States
PMID19996950 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anesthetics, Inhalation
  • Cardiotonic Agents
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Nitric Oxide
  • Isoflurane
  • Nitric Oxide Synthase Type III
Topics
  • Anesthetics, Inhalation (pharmacology)
  • Animals
  • Cardiotonic Agents
  • Echocardiography
  • Heart Rate (drug effects)
  • In Vitro Techniques
  • Isoflurane (pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart (drug effects)
  • Mitochondrial Membrane Transport Proteins (drug effects)
  • Mitochondrial Permeability Transition Pore
  • Myocardial Reperfusion Injury (prevention & control)
  • Nitric Oxide (physiology)
  • Nitric Oxide Synthase Type III (genetics, physiology)
  • Permeability (drug effects)

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