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Pycnogenol (P) is purported to exhibit effects that could be beneficial in terms of prevention of chronic age-related diseases such as atherosclerosis. The most studied of these effects is its antioxidant/free radical-scavenging activity. In this study, we investigated the possibility that this supplement might produce vascular effects by stimulation of nitric oxide (NO) production by vascular endothelial cells. In the in vitro experiments, P (1-10 μg/ml) relaxed epinephrine (E)-, norepinephrine (NE)-, and phenylephrine (PE)-contracted intact rat aortic ring preparations in a concentration-dependent manner. However, when the endothelial lining of the aortic ring was removed, P had no effect, indicating an endothelium-dependent relaxing (EDR) effect. This EDR response was caused by enhanced NO levels, because the NO synthase (NOS) inhibitor N-methyl-L-arginine (NMA) reversed (or prevented) the relaxation, and this response, in turn, was reversed by addition of L-arginine, the normal substrate for NOS. Pycnogenol-induced EDR persisted after exposure of intact rings to high levels of superoxide dismutase (SOD), suggesting that the mechanism of EDR did not involve scavenging of superoxide anion. In addition to causing relaxation, preincubation of aortic rings with P (1-10 μg/ml) inhibited subsequent E- and NE-induced contractions in a concentration-dependent manner. Fractionation of P by Sephadex LH-20 chromatography resulted in three fractions, one of which (fraction 3, oligomeric procyanidins) exhibited potent EDR activity. These results indicate that P, in addition to its antioxidant activity, stimulates constitutive endothelial NOS (eNOS) activity to increase NO levels, which could counteract the vasoconstrictor effects of E and NE. Furthermore, additional protective effects could result from the well-established properties of NO to decrease platelet aggregation and adhesion, as well as to inhibit low-density lipoprotein (LDL) cholesterol oxidation, all of which could protect against atherogenesis and thrombus formation.