The ability of endothelins 1 and 3 (ET-1 and ET-3) to reduce neuronal norepinephrine release through ETB receptor activation involving nitric oxide (NO) pathways in the rat anterior hypothalamus region (AHR) was previously reported. In the present work, we studied the effects of ET-1 and -3 on tyrosine hydroxylase (TH) activity and the possible involvement of NO pathways. Results showed that ET-1 and -3 (10 nM) diminished TH activity in AHR and this effect was blocked by a selective ETB receptor antagonist (100 nM BQ-788), but not by a ETA receptor antagonist (BQ-610). To confirm these results, 1 mu M IRL-1620 (ETB agonist) reduced TH activity whereas 300 nM sarafotoxin S6b falled to modify it. N-omega-Nitro-L-arginine methyl ester (10 mu M), 7-nitroindazole (10 mu M), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-ona (10 mu M), KT5823 (2 mu M), inhibitors of nitric oxide synthase, neuronal nitric oxide synthase, NO-sensitive-guanylyl cyclase, and protein kinase G, respectively, did not modify the reduction of TH activity produced by ETs. In addition, both 100 mu M sodium nitroprusside and 50 mu M 8-bromoguanosine-3',5'-cyclic monophosphate (NO donor and guanosine-3',5'-cyclic monophosphate analog, respectively) diminished TH activity. Present results showed that ET-1 and ET-3 diminished TH activity through the activation of ETB receptors involving the NO/guanosine-3',5'-cyclic monophosphate/protein kinase G pathway. Taken jointly present and previous results it can be concluded that both ETs play an important role as modulators of norepinephrine neurotransmission in the rat AHR. (c) 2005 Elsevier Inc. All rights reserved.