Role of endothelin in pial artery vasoconstriction and altered responses to vasopressin after brain injury.

Pial artery constriction following fluid-percussion injury to the brain is associated with elevated cerebrospinal fluid (CSF) vasopressin concentration in newborn pigs. It has also been observed that fluid-percussion injury reverses the function of vasopressin from that of a dilator to a constrictor. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, can be released by several stimuli, including vasopressin. The present study was designed to investigate the role of ET-1 in pial artery constriction and in the reversal of vasopressin from a dilator to a constrictor, which is observed after fluid-percussion injury. Brain injury of moderate severity (1.9-2.3 atm) was produced in anesthetized newborn pigs that had been equipped with a closed cranial window. Endothelin-1 elicited pial dilation at low concentrations and vasoconstriction at higher concentrations. Fluid-percussion injury reversed the process of dilation to that of constriction at the low ET-1 concentration and potentiated this constriction at high ET-1 concentrations (10% +/- 1%, -8% +/- 1%, and -15% +/- 1% vs. -6% +/- 1%, -17% +/- 1%, and -26% +/- 2% for 10(-12), 10(10),10(-8) M ET-1 before and after fluid-percussion injury, respectively). Vasopressin modestly increased CSF ET-1 concentration before fluid-percussion injury. Fluid-percussion injury markedly increased CSF ET-1 concentration and the ability of vasopressin to release ET-1 (20 +/- 2, 26 +/- 3, and 40 +/- 4 pg/ml vs. 93 +/- 6, 141 +/- 9, and 247 +/- 31 pg/ml for control, 40 pg/ml vasopressin, and 400 pg/ml vasopressin before and after fluid-percussion injury, respectively). An ET-1 antagonist, BQ 123 (10(-6) M) blunted pial artery constriction following fluid-percussion injury (146 +/- 5 microns -127 +/- 6 microns vs.144 +/- 5 microns-136 +/- 4 microns). The BQ 123 also blocked the reversal of vasopressin's function from that of a dilator to a constrictor after fluid-percussion injury (8% +/- 1%, 21% +/- 3%, and -5% +/- 1%, -14% +/- 2% vs. 8% +/- 1%, 21% +/- 2% and 4% +/- 1%, 2% +/- 1% for 40 and 4000 pg/ml vasopressin before and after fluid-percussion injury in the absence and presence of BQ 123, respectively). The BQ 123 blocked the constrictor component to ET-1, whereas it had no effect on the dilator component. These data show that ET-1 contributes to pial constriction after fluid-percussion injury. These data also indicate that vasopressin-induced release of ET-1 contributes to the reversal of vasopressin from a dilator to a constrictor following fluid-percussion injury. Furthermore, these data indicate that elevated CSF vasopressin and ET-1 interact in a positive feedback manner to promote pial artery constriction following fluid-percussion injury.