Brain catecholamines are involved in the regulation of biological functions including cardiovascular activity. The hypothalamus presents areas with high density of catecholaminergic neurons and the endothelin system. Two hypothalamic regions intimately related with the cardiovascular control are distinguished: the anterior (AHR) and posterior (PHR) hypothalamus considered as sympathoinhibitory and sympathoexcitatory regions, respectively. We previously reported that endothelins (ETs) are involved in the short-term tyrosine hydroxylase (TH) regulation in both the AHR and PHR. TH is crucial for catecholaminergic transmission and is tightly regulated by well characterized mechanisms. In the present study we sought to establish the effects and underlying mechanisms of ET-1 and ET-3 on TH long-term modulation. Results showed that in the AHR ETs decreased TH activity through ETB receptor activation coupled to the nitric oxide, phosphoinositide and CaMK-II pathways. They also reduced total TH level and TH phosphorylated forms (Ser 19 and 40). Conversely in the PHR, ETs increased TH activity through a G-protein coupled receptor, likely an atypical ET receptor or the ETC receptor, which stimulated the phosphoinositide and adenylyl cyclase pathways as well as CaMK-II. ETs also increased total TH level and the Ser 19, 31 and 40 phosphorylated sites of the enzyme. These findings support that ETs are involved in the long-term regulation of TH activity leading to reduced sympathoinhibition in the AHR and increased sympathoexcitation in the PHR. Present and previous studies may partially explain the cardiovascular effects produced by ETs when applied to the brain.