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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1995    most recent 01312.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Shao, Z.-H. Articles by Vanden Hoek, T. L. Search for Related Content PubMed PubMed Citation Articles by Shao, Z.-H. Articles by Vanden Hoek, T. L.

Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling

¹The Emergency Resuscitation Center, Sections of Emergency Medicine and ²Pulmonary/Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois; ³Department of Emergency Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, China; ⁴Emergency Department, Tan Tock Seng Hospital, Singapore; and ⁵Emergency Department, Tri-Service General Hospital, National Defense Medical Center, Taiwan, China

Submitted 13 December 2005 ; accepted in final form 5 December 2006

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 ± 3.4% cell death. Hypothermia induction to 25°C was most protective (14.3 ± 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 ± 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 ± 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor N-nitro-L-arginine methyl ester (200 µM) reversed these changes and abrogated hypothermia protection. In addition, the PKC inhibitor myr-PKC v1-2 (5 µM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase C; nitric oxide synthase.

reperfusion injury; nitric oxide; apoptosis; protein kinase C; nitric oxide synthase

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