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The Role of Nitric Oxide Synthase and Heme Oxygenase in the Protective Effect of Hypothermia in Ischemia-Reperfusion Injury

¹ Departments of Orthopaedic Surgery (R.W., N.S., D.S., R.P., and C.C.) and Surgery (F.H. and E.C.), Scott and White Memorial Hospital, 2401 South 31st Street, Temple, TX 76508. E-mail address for N. Souder: nsouder{at}swmail.sw.org

Investigation performed at Scott and White Memorial Hospital and Texas A&M Health Sciences Center, Temple, Texas

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Foundation for Orthopaedic Trauma and the Orthopaedic Trauma Association. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Methods: Sprague-Dawley rats were randomized into nine groups. Postcapillary venules of the extensor digitorum longus muscle were visualized with use of intravital microscopy. Following an intravenous bolus of fluorescein isothiocyanate-labeled albumin, the intravascular and extravascular space was examined for leak. Rats in the sham group underwent a one-hour mock ischemic period without the application of a femoral artery tourniquet, followed by one hour of mock reperfusion. The treatment groups (n = 5 in each group) had the tourniquet applied for one hour, followed by one hour of reperfusion at 10°C (cold) alone, at 10°C with nitric oxide synthase inhibitor, at 10°C with heme oxygenase inhibitor, at 10°C with a combination of inhibitors, at 34°C (warm) alone, at 34°C with a heme oxygenase inducer, at 34°C with a nitric oxide synthase inducer, or at 34°C with a combination of inducers.

Results: Rats in the sham group did not show a significant increase in microvascular permeability. Rats in the warm ischemia/reperfusion group displayed significant increases in microvascular permeability, as did the rats that received inhibitors of heme oxygenase and nitric oxide synthase at 10°C. No significant increase in microvascular permeability was observed in the animals in the cold ischemia/reperfusion group or in animals that received inducers of heme oxygenase and nitric oxide synthase at 34°C.

Conclusions: Local hypothermia protects skeletal muscle from increased microvascular permeability following ischemia-reperfusion injury. This protective effect is also seen with the induction of the nitric oxide synthase and heme oxygenase systems at physiologic temperature. We also have shown that the protective effects of hypothermia are blocked by giving heme oxygenase and nitric oxide synthase inhibitors while keeping the muscle hypothermic. These findings demonstrate that heme oxygenase and nitric oxide synthase play a combined role in ischemia-reperfusion injury, suggesting possible pathways for clinical intervention to modulate injury seen following trauma, tourniquet use, vascular surgery, and microvascular surgery.

Clinical Relevance: The present study provides evidence for the use of local hypothermia following ischemia-reperfusion-related tissue injury and provides biochemical insight for future pharmacologic intervention.

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