BACKGROUND: Ischemia-reperfusion
injury plays an important role in limb salvage following limb
ischemia. The purpose of the present study was to evaluate the effect of local
hypothermia and chemical modulators on microvascular permeability following ischemia-reperfusion
injury in
skeletal muscle. 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 degrees C (
cold) alone, at 10 degrees C with
nitric oxide synthase inhibitor, at 10 degrees C with
heme oxygenase inhibitor, at 10 degrees C with a combination of inhibitors, at 34 degrees C (warm) alone, at 34 degrees C with a
heme oxygenase inducer, at 34 degrees C with a
nitric oxide synthase inducer, or at 34 degrees 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 degrees 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 degrees 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.
