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Background and Purpose Traumatic brain injury conveys significant morbidity and mortality to infants and children. In the newborn pig, opioids contribute to pial artery vasconstriction after fluid percussion injury (FPI). FPI attenuates vasodilation and cGMP production by methionine enkephalin (Met) and leucine enkephalin (Leu) and reverses dynorphin (Dyn) from a dilator to a constrictor. Superoxide anion (O 2 − ) production contributes to altered cerebral hemodynamics after FPI, and O 2 − scavengers partially restore decreased dilator responses after FPI. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, has been suggested to alter nitric oxide function and cGMP concentration. The present study was designed to determine the contribution of ET-1 to altered opioid-induced dilation after FPI and the role of O 2 − in such altered responses. Methods Injury of moderate severity (1.9 to 2.3 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase (SOD)–inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O 2 − generation. Results FPI increased cerebrospinal fluid ET-1 from 20±2 to 93±6 pg/mL (≈10 −10 mol/L). Topical ET-1 (10 −10 mol/L) increased SOD-inhibitable NBT reduction from 1±1 to 16±3 pmol/mm 2 , similar to previously reported NBT reduction after FPI (14±2 pmol/mm 2 ). BQ123 (10 −6 mol/L), an ET-1 antagonist, blunted the NBT reduction observed after FPI (4±1 pmol/mm 2 ). Met produced pial vasodilation that was attenuated by FPI and partially restored by BQ123 pretreatment (7±1%, 11±1%, and 17±1% versus 3±1%, 6±1%, and 9±2% versus 5±1%, 9±1%, and 14±2% for 10 −10 , 10 −8 , and 10 −6 mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Met-induced dilation was associated with increased cerebrospinal fluid cGMP, and these biochemical changes were likewise blunted by FPI and partially restored by BQ123 (357±12, 455±15, 500±19, and 632±11 versus 264±4, 267±4, 295±12, and 305±15 versus 309±19, 432±11, 529±10, and 593±4 pg/mL for resting conditions, 10 −10 , 10 −8 , and 10 −6 mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Similar partial restoration of vascular and biochemical parameters was observed for Leu and Dyn. Conclusions These data show that ET-1, in concentrations similar to that present in cerebrospinal fluid after FPI, increases O 2 − production. These data also indicate the opioid-induced vasodilation and cGMP production are partially restored after FPI by ET-1 receptor blockade. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI, at least in part, through elevated O 2 − production.