ET-1 Contributes to Age-Dependent G Protein Impairment after Brain Injury

Abstract

Previous studies have observed that endothelin-1 (ET-1) concentration is elevated in CSF and contributes to impaired cerebral hemodynamics following fluid percussion brain injury (FPI) in an age-dependent manner. This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussin toxin-sensitive G protein, mastoparan and mastoparan-7, as a function of age and the role of ET-1 in such effects in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Mastoparan (10^-8, 10^-6 M) elicited pial artery dilation that was blunted more by FPI in newborn versus juvenile pigs (9 ± 1 and 16 ± 1 vs. 3 ± 1 and 5 ± 1%, newborn; 9 ± 1 and 15 ± 1 vs. 6 ± 1 and 9 ± 1%, juvenile). Similar results were observed for mastoparan-7, but the inactive analogue mastoparan-17 had no effect on pial diameter. BQ123 (10^-6 M), an ET-1 antagonist, partially restored impaired mastoparan dilation after FPI in the newborn but not in the juvenile (3 ± 1 and 5 ± 1 vs. 7 ± 1 and 11 ± 1%, newborn; 6 ± 1 and 9 ± 1 vs. 6 ± 1 and 10 ± 1%, juvenile). These data show that G protein activation elicits cerebrovasodilation that is blunted following FPI in an age-dependent manner. These data suggest that ET-1 contributes to the impairment of G protein-mediated vasodilation in an age-dependent manner after FPI.