Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases (CVDs). Endothelin type B (ET_B) receptors were involved in the pathogenesis of CVDs. However, Sirtuin 1(Sirt1) has potential protect roles for CVDs. The present study was designed to examine the hypothesis that homocysteine up-regulates ET_B receptors through down-regulation of Sirt 1. In vitro experiments were performed in rat superior mesenteric artery (SMA). The rat SMA was cultured in serum free medium for 24h in the presence and absence of homocysteine (Hcy) with or without resveroral (Res) (a Sirt 1agonist). In vivo, the rats received subcutaneous injections of Hcy in the presence of or absence of Res for 3 weeks. The contractile responses to sarafotoxin 6c (S6c) (an ET_B receptor agonist) were studied using a sensitive myograph. Levels of protein expression were determined using western blotting. The blood pressure of rat was measured via a noninvasive tail-cuff plethysmography method. We observed that Hcy increased the level of ET_B receptor protein expression and the ET_B receptor-mediated contractile responses induced by S6c, and decreased level of Sirt1 protein expression in SMA without endothelium in vitro. However, these effects were reversed by Res. Moreover, Res also blocked the up-regulation of acetylized p65 induced by Hcy. The in vivo study showed that HHcy down-regulated Sirt 1, and up-regulated acetylized p65 and ET_B receptor protein expression, and elevated the blood pressure of rats. However, Res could block these effects. In conclusion, this suggested that Hcy regulated ET_B receptor expression through sirt1/nuclear factor-κB signaling pathway.