Age dependent endothelin contribution to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury.

This study was designed to characterize the role of endothelin-1 (ET-1) in nociceptin/orphanin FQ (NOC/oFQ) induced impairment of NMDA cerebrovasodilation after fluid percussion brain injury (FPI) as a function of age in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Previous studies have observed that NOC/oFQ is released into CSF and contributes to impaired NMDA induced pial artery dilation following FPI to a greater extent in newborn vs juvenile pigs. Topical ET-1 (10(-10) M), a concentration approximating that observed in CSF following FPI in the newborn, increased CSF NOC/oFQ from 67 +/- 4 to 119 +/- 7 pg/ml under non FPI conditions. CSF NOC/oFQ was elevated within 60 min of FPI (70 +/- 3 to 444 +/- 51 pg/ml) but such release was attenuated by the ET-1 antagonist BQ123 in the newborn (66 +/- 3 to 145 +/- 10 pg/ml). CSF ET-1 and NOC/oFQ were not elevated as greatly in the juvenile following FPI and BQ123 correspondingly did not attenuate CSF NOC/oFQ release as much as in the newborn. Under non injury conditions, ET-1 (10(-10) M) coadministered with NMDA attenuated pial dilation to this excitatory amino acid. Following FPI in the newborn, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction and both NOC/oFQ and ET-1 receptor antagonists partially prevented such alterations (9 +/- 1 and 16 +/- 1, sham control; -7 +/- 1 and -12 +/- 1, FPI; -2 +/- 1 and -3 +/- 1, FPI-NOC/oFQ antagonist; and 2 +/- 1 and 5 +/- 1 %, FPI-ET-1 antagonist). NMDA induced pial dilation was only attenuated following FPI in the juvenile and modestly restored by NOC/oFQ and ET-1 receptor antagonists. These data show that ET-1, in concentrations present in CSF following FPI, contributes to the release of CSF NOC/oFQ following such an insult. The greater release of such ET-1 following FPI in the newborn contributes to the corresponding greater release of NOC/oFQ in the newborn vs the juvenile. Moreover, ET-1 also contributes to the impairment of NMDA cerebrovasodilation after brain injury to a greater extent in newborns vs juveniles. These data suggest that ET-1 contributes to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury in an age dependent manner.