Pycnogenol, an extract of bark from the French maritime pine, Pinus pinaster Ait., consists of a concentrate of water-soluble polyphenols. Pycnogenol contains the bioflavonoids catechin and taxifolin as well as phenolcarbonic acids. Antioxidants, such as bioflavonoids, enhance endothelial nitric oxide (NO) synthase expression and subsequent NO release from endothelial cells. The purpose of this study was to determine Pycnogenol's effects on endothelium-dependent vasodilation in humans. This was a double-blind, randomized, placebo and active drug study. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, in healthy young men before and after 2 weeks of daily oral administration of Pycnogenol (180 mg/day) (n=8) or placebo (n=8). FBF was measured by using strain-gauge plethysmography. Neither the placebo nor Pycnogenol altered forearm or systemic hemodynamics. Pycnogenol, but not placebo, augmented FBF response to ACh, from 13.1 +/- 7.0 to 18.5 +/- 4.0 mL/min per 100 mL tissue (p<0.05). SNP-stimulated vasodilation was similar before and after 2 weeks of treatment in the control and Pycnogenol groups. The administration of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished Pycnogenol-induced augmentation of the FBF response to ACh. These findings suggest that Pycnogenol augments endothelium-dependent vasodilation by increasing in NO production. Pycnogenol would be useful for treating various diseases whose pathogeneses involve endothelial dysfunction.