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Ischemia-induced reactive hyperemia (RH) is mediated by various factors including release of nitric oxide (NO). The contribution of NO to RH equals the extent of L-NMMA-dependent reduction of forearm blood flow (FBF). Because the optimal duration and location of ischemia that provokes maximum NO activation is unknown, we analyzed which duration and location stimulates most NO release, aiming at developing a noninvasive tool to measure endothelial integrity by NO synthase activity in humans.FBF was measured by strain gauge plethysmography after ischemia applied at the upper arm and wrist during intra-arterial infusion of L-NMMA or saline. To obtain similar FBF before RH, clamping with sodium nitroprissude was performed. Twenty-eight healthy male volunteers were randomly assigned to two groups (N = 15) undergoing ischemia of 1 and 5min or 2 and 5min (N = 13) at both locations.Peak FBF was not affected by L-NMMA infusion. The change of FBF during L-NMMA expressed as area under the curve (AUC) of the first minute was significantly reduced after 1 (−0.70 ± 1.63ml, P < 0.001) and 2min (1.67 ± 2.65ml, P < 0.01) of ischemia applied at wrist level compared to 5min (7.49 ± 7.92ml). Ischemia applied to the upper arm showed no significant differences of FBF after L-NMMA or saline infusion, irrespective of the duration of ischemia.Our data indicate that only immediately after ischemia the vasodilatatory response is most NO-dependent. RH as a test of NO activity in the forearm microcirculation should be applied at the wrist and last 1min.