OBJECTIVES: Vascular endothelial growth factor (VEGF) and nitric oxide (NO) produce vasodilation, induce angiogenesis, and improve survival of surgical flaps. We used the rat epigastric skin flap to study the effect of a single intra-arterial dose of VEGF or L-arginine, a substrate for NO production, on flap regional necrosis and pedicle dependence of flap perfusion. METHODS: In 30 Sprague-Dawley rats an 8 x 8 cm2 skin flap, consisting of four vertical zones marked A through D (right to left), based on the proximal right inferior epigastric vessels was raised. Subsequently, 1 ml of either saline (control, n =10), 5 microg VEGF (VEGF, n = 10), or 50 mg of L-arginine (L-arginine, n = 10) was injected into the arterial pedicle by cannulating the right saphenous artery, and the flap was resutured in place. After 8 days, the animals were perfused systemically with 15 microm coloured fluorescent microspheres before (blue) and after (yellow-green) ligation of the right inferior epigastric vascular pedicle. After sacrifice, the area of flap necrosis was measured in each zone by templates and weight-to-surface ratio, and the flap zones were harvested and processed for determination of fluorescence and blood flow. RESULTS: Administration of VEGF or L-arginine resulted in decreased total and regional (zone D) flap necrosis (ANOVA <0.001). The total and regional flap shrinkage was greater in the experimental groups (ANOVA <0.02). While VEGF and L-arginine decreased the percentage of necrosis in the zone most distal to the pedicle (ANOVA <0.01) only L-arginine diminished percentage of total flap necrosis (p = 0.04). In the VEGF group, total and regional flap perfusion did not change after pedicle ligation, but perfusion decreased significantly in zones B through D in the L-arginine treated rats. CONCLUSION: Single intra-pedicle administration of VEGF or L-arginine decreased necrosis of the epigastric skin flap at 8 days postoperatively, but flap shrinkage also increased in the zone with the greatest degree of necrosis. Perfusion data suggest that beneficial effects of VEGF and L-arginine on flap survival may be based on different mechanisms.