Age-Dependent Impairment of K ATP Channel Function Following Brain Injury

Abstract

Previous studies observed that endothelin-1 (ET-1) contributed to ATP-sensitive K⁺ (K_ATP) channel impairment 1 h following fluid percussion brain injury (FPI) in the newborn pig. The present study was designed to determine the effect of FPI on K_ATP channel activity as a function of time in newborn (1–5 days old) and juvenile (3–4 weeks old) pigs equipped with a closed cranial window. FPI of moderate severity (1.9–2.1 atm) was produced by using a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. Cromakalim, a K_ATP agonist, produced dilation that was blunted for at least 72 h post FPI, but dilator responsiveness was restored within 168 h post FPI in the newborn pig (15 ± 1% and 27 ± 2% vs. 5 ± 1% and 11 ± 1% vs. 13 ± 1% and 26 ± 2% for responses to 10⁻⁸, 10⁻⁶ M cromakalim before, and 72 and 168 h after FPI). Similar inhibited responses were observed for calcitonin gene–related peptide, 8-Bromo cGMP, and the nitric oxide (NO) releasers SNP and SNAP. In contrast, cromakalim-induced dilation was blunted for at least 4 h, but dilator responsiveness was restored within 8 h post FPI in the juvenile pig (15 ± 1% and 27 ± 1% vs. 9 ± 1% and 15 ± 2% vs. 18 ± 1% and 28 ± 1% for 10⁻⁸, 10⁻⁶ M cromakalim before, and 4 and 8 h post FPI). Similar inhibition of dilations of other agonists also occurred in the juvenile. CSF ET-1 increased to a greater level and remained elevated for a longer period of time in the newborn compared to the juvenile pig. BQ123, an ET-1 antagonist, pretreatment partially restored decremented agonist induced dilation following FPI in the newborn and juvenile pig (5 ± 1% and 11 ± 1% vs. 11 ± 1% and 21 ± 1% for responses to 10⁻⁸, 10⁻⁶ M cromakalim 72 h post FPI in the newborn in the absence and presence of BQ123). These data indicate that K_ATP channel function is impaired to a greater extent and for a longer time period in the newborn versus the juvenile pig. These data also show that ET-1 contributes to such impaired vascular responsiveness to a greater extent in the newborn versus the juvenile pig. These data furthermore suggest that the newborn is more sensitive to traumatic vascular injury than the juvenile.