✓ 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 µm−127 ± 6 µm vs. 144 ± 5 µm−136 ± 4 µm). 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.
The Role of Endothelial Dysfunction in the Development of Cardiotoxic Action of Cytostatics in Patients with Lymphoproliferative Diseases
