It has been shown that substance P causes endothelium-dependent vasodilation in the human coronary and forearm vessels. However, the precise mechanism whereby substance P dilates the coronary and peripheral vasculatures is unknown in humans. The aim of this study was to examine whether the vasodilator effect of substance P is mediated by nitric oxide in the human coronary and forearm vessels. Eight patients with normal coronary angiograms were studied for the measurements of coronary blood flow (intracoronary Doppler guide wire and quantitative coronary arteriography) and forearm blood flow (strain-gauge plethysmograph). Intracoronary acetylcholine (10 micrograms/min for 2 min) and substance P (30 and 90 ng/min for 2 min) increased coronary blood flow from the baseline value. Intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) at 200 mumol significantly attenuated the magnitudes of increase in coronary blood flow induced by both acetylcholine (p < 0.01) and substance P (p < 0.01). Acetylcholine (4, 8, and 16 micrograms/min for 2 min) and substance P (0.8, 1.6, and 3.2 ng/min for 2 min) also increased forearm blood flow in a dose-dependent manner. Intraarterial L-NMMA (8 mumol/min for 5 min) decreased the magnitudes of increase in forearm blood flow induced by acetylcholine (p < 0.01). L-NMMA at the same dosage decreased the increase in forearm blood flow induced by substance P, but the magnitude of the inhibitory effect of L-NMMA on blood-flow responses to substance P was significantly smaller in the forearm than in coronary vessels. It is suggested that endothelium-derived nitric oxide contributes to substance P-induced vasodilation, and that the contribution of nitric oxide to substance P-induced vasodilation is smaller in the forearm than in coronary circulation.