BACKGROUND Polyphenols in red wine are supposed to improve endothelial function. We investigated whether daily red wine consumption improves in-vivo vascular function by reducing endothelin-1 (ET-1). Additional pathways mediating this effect were studied using porcine coronary arteries (PCAs). METHODS Eighteen young healthy women drank red wine daily for 3 weeks. Vascular function was evaluated by determining forearm blood flow (FBF) responses to endothelium-dependent (acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside (SNP)) vasodilators. PCAs were suspended in organ baths and exposed to the endothelium-dependent vasodilator bradykinin, the nitric oxide (NO) donor S-nitroso-N-acetyl-L,L-penicillamine (SNAP) and/or red wine extract (RWE). RESULTS ACh-induced and SNP-induced FBF increases were equally enhanced after 3 weeks of red wine consumption, but an immediate enhancement (i.e., after drinking the first glass) was not observed. Vice versa, plasma ET-1 levels were not decreased after 3 weeks, but we observed an acute drop after drinking one glass of wine. RWE relaxed preconstricted PCAs in an endothelium-, NO-, and soluble guanylyl cyclase (sGC)/guanosine-3',5'-cyclic monophosphate (cGMP)-dependent manner. Short RWE exposure reduced the response to bradykinin and SNAP by inactivating sGC. This effect disappeared upon prolonged RWE exposure. CONCLUSIONS The enhanced FBF response following 3 weeks of red wine consumption, but not after one glass, reflects a change in smooth muscle sensitivity. Alterations in sGC responsiveness/activity, rather than changes in ET-1, appear to underlie this phenomenon.