ATP-dependent K+ channel activation reduces loss of opioid dilation after brain injury.

Abstract

ATP-dependent K+ (KATP) channel function is impaired after fluid percussion brain injury (FPI). Additionally, the nitric oxide (NO) releaser sodium nitroprusside and a cGMP analog elicit pial dilation via KATP channel activation, whereas opioids such as methionine enkephalin (Met) elicit pial dilation via NO and KATP channel activation. Decremented Met dilation contributes to reductions in pial artery diameter and altered cerebral hemodynamics after FPI. This study was designed to investigate the role of KATP channel activation before FPI in the loss of opioid dilation subsequent to FPI in newborn pigs equipped with a closed cranial window. FPI was produced by allowing a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw in the cranium. FPI blunted dilation to Met (7 +/- 1, 11 +/- 1, and 17 +/- 1% before FPI vs. 1 +/- 1, 4 +/- 1, and 6 +/- 1% after FPI for 10(-10), 10(-8), and 10(-6) M Met, respectively). Met-associated elevation in cerebrospinal fluid (CSF) cGMP was similarly blunted (350 +/- 12 and 636 +/- 12 fmol/ml before FPI vs. 265 +/- 5 and 312 +/- 17 fmol/ml after FPI for control and 10(-6) M Met, respectively). In piglets pretreated with cromakalim (10(-10) M) 20 min before FPI, Met dilation was partially restored (7 +/- 1, 10 +/- 1, and 15 +/- 1% before FPI vs. 4 +/- 1, 7 +/- 1, and 11 +/- 1% after FPI for 10(-10), 10(-8), and 10(-6) M Met, respectively). Met cGMP release was similarly partially restored (400 +/- 9 and 665 +/- 25 fmol/ml before FPI vs. 327 +/- 11 and 564 +/- 23 fmol/ml after FPI for control and 10(-6) Met, respectively). Cromakalim (10(-10) M) had no effect on pial diameter itself but prevented pial artery constriction by FPI (148 +/- 5 to 124 +/- 5 microns vs. 139 +/- 4 to 141 +/- 4 microns in the absence vs. presence of cromakalim pretreatment, respectively). In contrast, pretreatment with a subthreshold concentration of NS-1619, a calcium-dependent K+ channel agonist, did not restore vascular and biochemical parameters after FPI. These data indicate that prior KATP channel activation reduces the loss of opioid dilation after FPI.