Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta.

Abstract

BACKGROUND:

Postischemic administration of volatile anesthetics activates reperfusion injury salvage kinases and decreases myocardial damage. However, the mechanisms underlying anesthetic postconditioning are unclear.

METHODS:

Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane (1.5 minimum alveolar concentration) administered at the onset of reperfusion. In some experiments, atractyloside (10 microm), a mitochondrial permeability transition pore (mPTP) opener, and LY294002 (15 microm), a phosphatidylinositol 3-kinase inhibitor, were coadministered with isoflurane. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt and its downstream target glycogen synthase kinase 3beta after 15 min of reperfusion. Myocardial tissue content of nicotinamide adenine dinucleotide served as a marker for mPTP opening. Accumulation of MitoTracker Red 580 (Molecular Probes, Invitrogen, Basel, Switzerland) was used to visualize mitochondrial function.

RESULTS:

Anesthetic postconditioning significantly improved functional recovery and decreased infarct size (36 +/- 1% in unprotected hearts vs. 3 +/- 2% in anesthetic postconditioning; P < 0.05). Isoflurane-mediated protection was abolished by atractyloside and LY294002. LY294002 inhibited isoflurane-induced phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3beta and opened mPTP as determined by nicotinamide adenine dinucleotide measurements. Atractyloside, a direct opener of the mPTP, did not inhibit phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3beta by isoflurane but reversed isoflurane-mediated cytoprotection. Microscopy showed accumulation of the mitochondrial tracker in isoflurane-protected functional mitochondria but no staining in mitochondria of unprotected hearts.

CONCLUSIONS:

Anesthetic postconditioning by isoflurane effectively protects against reperfusion damage by preventing opening of the mPTP through inhibition of glycogen synthase kinase 3beta.

• Authors: Jianhua Feng, Eliana Lucchinetti, Preeti Ahuja, Thomas Pasch, Jean-Claude Perriard, Michael Zaugg
• Journal: Anesthesiology (Anesthesiology) Vol. 103 Issue 5 Pg. 987-95 (Nov 2005) ISSN: 0003-3022 [Print] United States
• PMID: 16249673 (Publication Type: Journal Article)

Chemical References

• Anesthetics, Inhalation
• Chromones
• Coloring Agents
• Enzyme Inhibitors
• Morpholines
• Organic Chemicals
• red dye CMXRos
• NAD
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Isoflurane
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Anesthetics, Inhalation (antagonists & inhibitors, pharmacology)
• Animals
• Blotting, Western
• Chromones (pharmacology)
• Coloring Agents
• Conditioning, Psychological (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Hemodynamics (drug effects)
• In Vitro Techniques
• Isoflurane (antagonists & inhibitors, pharmacology)
• Male
• Mitochondria, Heart (drug effects, metabolism)
• Morpholines (pharmacology)
• Myocardial Infarction (enzymology, pathology, prevention & control)
• Myocardium (metabolism)
• NAD (metabolism)
• Organic Chemicals
• Permeability (drug effects)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)