BACKGROUND: Nitric oxide (NO), the endogenous vasodilator, is an important regulator of vascular tone. We investigated NO production following lower extremity ischemia. METHODS: Rabbits underwent 6 hours of bilateral leg ischemia followed by unrestricted reperfusion. Physiologic parameters were continuously measured and blood was assayed for NO2 and NO3. RESULTS: Acute ischemia of the lower extremities produced an immediate increase in mean arterial blood pressure while later reperfusion induced a significant decrease (P < 0.0005). There was a fall in femoral blood flow during reperfusion. NO2/NO3 concentrations decreased significantly to 89% of baseline values after ischemia and 77% after 1 hour of reperfusion (P < 0.005). A significantly higher mortality was found in association with decreased NO2/NO3 concentrations. CONCLUSIONS: Nitric oxide appears to be a regulator of regional blood flow during reperfusion following extremity ischemia. Decreased NO production may contribute to impaired regional blood flow and mortality.