trans-Resveratrol (t-RESV; 1-10 microM), a phenolic component of wines, had no effect on phenylephrine-(PE; 1 microM) and high KCl-(60 mM) induced contractions in endothelium-denuded rat aortic rings. However, it relaxed the contractile response produced by these vasoconstrictor agents in intact rat aorta. The vasorelaxing effects of t-RESV were completely inhibited by N(G)-nitro-L-arginine (L-NOARG; 0.1 mM) and methylene blue (10 microM), but they were unaffected by atropine (10 microM) and yohimbine (1 microM). The reversal effect produced by L-NOARG was antagonized by L-arginine but not by D-arginine (0.1 mM). t-RESV (1-10 microM) did not significantly modify rat aorta constitutive nitric-oxide synthase activity. However, this natural compound decreased NADH/NADPH oxidase activity in rat aortic homogenates. In addition, t-RESV (1-10 microM) was ineffective in scavenging superoxide anions (O(2)*) generated enzymatically by a hypoxanthine/xanthine oxidase (HX/XO) system and/or to inhibit XO. The above data demonstrate that the characteristic endothelium-dependent vasorelaxant effect of t-RESV in rat aorta seems to be caused by the inhibition of vascular NADH/NADPH oxidase and the subsequent decrease of basal cellular O(2)* generation and, therefore, of NO biotransformation. Under the assumption that t-RESV exhibits a similar behavior in human blood vessels and bearing in mind that an overactivity of NADH/NADPH oxidase has been found in a number of cardiovascular pathologies, the results obtained in this work suggest that t-RESV could play an important role in the cardioprotective effects induced by the long-term moderate wine consumption.