Isoflurane Postconditioning Protects against Reperfusion Injury by Preventing Mitochondrial Permeability Transition by an Endothelial Nitric Oxide Synthase-dependent Mechanism

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. In vivo or Langendorff-perfused mouse hearts underwent 30 min of ischemia followed by 2 h of reperfusion in th...

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Published in:	Anesthesiology (Philadelphia) 2010, Vol.112 (1), p.73-85
Main Authors:	GE, Zhi-Dong, PRAVDIC, Danijel, BIENENGRAEBER, Martin, PRATT, Phillip F, AUCHAMPACH, John A, GROSS, Garrett J, KERSTEN, Judy R, WARLTIER, David C
Format:	Article
Language:	eng
Subjects:	Anesthesia Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Anesthetics, Inhalation - pharmacology Animals Biological and medical sciences Cardiotonic Agents Echocardiography Heart Rate - drug effects In Vitro Techniques Isoflurane - pharmacology Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mitochondria, Heart - drug effects Mitochondrial Membrane Transport Proteins - drug effects Myocardial Reperfusion Injury - prevention & control Nitric Oxide - physiology Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - physiology Permeability - drug effects
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Summary:	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. 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. 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. 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.
ISSN:	0003-3022 1528-1175