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J Appl Physiol 94: 1473-1478, 2003. First published December 27, 2002; doi:10.1152/japplphysiol.00789.2002
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Vol. 94, Issue 4, 1473-1478, April 2003

Reperfusion injury is reduced in skeletal muscle by inhibition of inducible nitric oxide synthase

Li Zhang1, Colin G. Looney1, Wen-Ning Qi1, Long-En Chen1, Anthony V. Seaber1, Jonathan S. Stamler2, and James R. Urbaniak1

1 Orthopaedic Microsurgery Laboratory, Department of Surgery, and 2 Howard Hughes Medical Institute, Pulmonary and Cardiovascular Divisions, Department of Medicine, and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

This study evaluated the effects of the selective inducible nitric oxide synthase (iNOS) inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W) on the microcirculation in reperfused skeletal muscle. The cremaster muscles from 32 rats underwent 5 h of ischemia followed by 90 min of reperfusion. Rats received either 3 mg/kg 1400W or PBS subcutaneously before reperfusion. We found that blood flow in reperfused muscles was <45% of baseline in controls but sharply recovered to near baseline levels in 1400W-treated animals. There was a significant (P < 0.01 to P < 0.001) difference between the two groups at each time point throughout the 90 min of reperfusion. Vessel diameters remained <80% of baseline in controls during reperfusion, but recovered to the baseline level in the 1400W group by 20 min, and reached a maximum of 121 ± 14% (mean ± SD) of baseline in 10- to 20-µm arterioles, 121 ± 6% in 21- to 40-µm arterioles, and 115 ± 8% in 41- to 70-µm arteries (P < 0.01 to P < 0.001). The muscle weight ratio between ischemia-reperfused (left) and non-ischemia-reperfused (right) cremaster muscles was 193 ± 42% of normal in controls and 124 ± 12% in the 1400W group (P < 0.001). Histology showed that neutrophil extravasation and edema were markedly reduced in 1400W-treated muscles compared with controls. We conclude that ischemia-reperfusion leads to increased generation of NO from iNOS in skeletal muscle and that the selective iNOS inhibitor 1400W reduces the negative effects of ischemia-reperfusion on vessel diameter and muscle blood flow. Thus 1400W may have therapeutic potential in treatment of ischemia-reperfusion injury.

ischemia; microcirculation; selective inhibitor; rat


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