The authors have shown that exogenous nitric oxide (NO) protects innervated skeletal muscle against reperfusion injury. This study further evaluated the effects of exogenous NO donor on denervated skeletal muscle. Forty-eight denervated rat cremaster muscles underwent 3 hr of ischemia, followed by 90 min of reperfusion, and received systemic infusion of 100 nmol/min s-nitroso-n-acetylcysteine (SNAC) or an equal amount of phosphate-buffered saline (PBS). Results showed that the average diameter in 10 to 20 microm arterioles was between 107 percent and 123 percent of baseline in the SNAC group, and between 55 percent and 84 percent in the PBS group during 90 min of reperfusion. These values in 21 to 40 microm and 41 to 70 microm arteries were between 100 percent and 110 percent in the SNAC group, and between 70 percent and 90 percent in the PBS group from 20 to 90 min of reperfusion. Compared to the PBS group, the SNAC group had a statistically significantly greater vessel diameter in both 10 to 20 microm (p<0.001) and 21 to 40 microm arterioles (p<0.01) during 90 min of reperfusion, and in 41 to 70 microm arteries (p<0.02) from 20 to 90 min of reperfusion. The overall blood flow of the muscle in the SNAC group increased from 37 percent of baseline at 10 min to 108 percent at 40 min of reperfusion, and remained above baseline thereafter. In contrast, this value in the PBS group was only between 27 percent and 68 percent of baseline during 90 min of reperfusion. The blood flow was statistically significantly (p<0.03) greater in the SNAC group than in the PBS group from 40 to 90 min of reperfusion. Among the conclusions were: (1) NO donor SNAC improves the microcirculation of denervated skeletal muscle during early reperfusion; and (2) this protection against reperfusion injury is independent of innervation in skeletal muscle.