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Reperfusion injury in skeletal muscle is reduced in inducible nitric oxide synthase knockout mice

¹Orthopaedic Microsurgery Laboratories, Department of Surgery, and ²Pulmonary Divisions, Departments of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Submitted 7 April 2004 ; accepted in final form 26 May 2004

Inducible nitric oxide synthase (iNOS) participates in many pathological events, and selective inhibition of iNOS has been shown to reduce ischemia-reperfusion (I/R) injury in different tissues. To further confirm its role in this injury process, I/R injury was observed in denervated cremaster muscles of iNOS-deficient (iNOS–/–) and wild-type mice. After 3-h ischemia and 90-min reperfusion, blood flow in reperfused muscle was 80 ± 8.5% (mean ± SE) of baseline at 10-min reperfusion and completely returned to the preischemia baseline after 20 min in iNOS–/– mice. In contrast, blood flow was 32 ± 7.4% at 10 min and increased to 60 ± 20% of the baseline level at 90 min in wild-type mice (P < 0.001 vs. iNOS–/– mice at all time points). The increased muscle blood flow in iNOS–/– mice was associated with significantly less vasospasm in all three sizes of arterial vessel size categories. The weight ratio to the contralateral muscle not subjected to I/R was greater in wild-type mice (173 ± 11%) than in iNOS–/– mice (117 ± 3%; P < 0.01). Inflammation and neutrophil extravasation were also more severe in wild-type mice. Western blot analysis demonstrated an absence of iNOS protein band in iNOS–/– mice and upregulation of iNOS protein expression in wild-type mice. Our results confirm the importance of iNOS in I/R injury. Upregulated iNOS exacerbates I/R injury and appears to be a therapeutic target in protection of tissues against this type of injury.

vessel diameter; blood flow; mRNA; protein