15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Brain-Injuries

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca(2+), and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis that cyclosporine A (CsA), which blocks both mPTP and CaN, ameliorates the persistent reduction of cerebral blood flow (CBF), impaired vascular reactivity, and a persistent rise in the cerebral metabolic rate of oxygen (CMRO(2)) following CSD. In addition to CsA, we used the specific mPTP blocker NIM811 and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO(2), and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD; the rise in CMRO(2) was unchanged. Our data suggest that blockade of mPTP formation and CaN activation may prevent persistent CBF reduction and vascular dysfunction after CSD.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Brain; Brain Injuries; Cerebrovascular Circulation; Cortical Spreading Depression; Cyclosporine; Enzyme Inhibitors; Immunosuppressive Agents; Male; Oxygen; Rats; Rats, Wistar; Tacrolimus; Vasoconstrictor Agents

Previous studies have observed that fluid percussion brain injury (FPI) elevated the CSF concentration of the opioid nociceptin/orphanin FQ (NOC/oFQ). In separate studies, FPI impaired pial artery dilation to the prostaglandins PGI2 and PGE2. This study was designed to investigate the following: (1) role of NOC/oFQ in impaired dilation to PGI2 and PGE2, (2) the effects of FPI on vasoconstriction to the TXA2 mimic U46619 and PGF2alpha, and (3) the role of NOC/oFQ in such FPI induced effects on U46619 and PGF(2alpha). Lateral FPI was induced in newborn pigs equipped with a closed cranial window. PGI2 (1, 10, 100 ng/ml) vasodilation was blunted by FPI and fully restored by the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH2 (10(-6)M) (9 +/- 1, 13 +/- 1, and 19 +/- 1 vs. 2 +/- 1, 4 +/- 1, and 5 + 1 vs 7 +/- 1, 12 +/- 2, and 17 +/- 3% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGE2. In contrast, U46619 (1, 10 ng/ml) induced vasoconstriction was potentiated by FPI but returned to the response observed prior to FPI by [F/G] NOC/oFQ (1-13) NH2 ( -8 +/- 1 and -14 +/- 1 vs. -15 +/- 1 and -25 +/- 1 vs. -7 +/- 1 and -12 +/- 2% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGF(2alpha). Coadministration of NOC/oFQ (10(-10)M), the CSF concentration observed after FPI, with agonists under nonbrain injury conditions blunted PGI2 and PGE2 vasodilation, but potentiated U46619 and PGF2alpha vasoconstriction similarly to that observed after FPI. These data show that FPI blunted PGI2 and PGE2 vasodilation but potentiated U46619 and PGF2alpha vasoconstriction. Additionally, these data show that administration of a NOC/oFQ receptor antagonist prevented such FPI associated events. NOC/oFQ administrated in a concentration observed after FPI produced blunted dilator prostaglandin and potentiated vasoconstriction prostaglandin vascular responses under nonbrain injury conditions. Finally, these data suggest that NOC/oFQ alters prostaglandin cerebrovascular action following brain injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blood Chemical Analysis; Blood Pressure; Brain Injuries; Cerebrovascular Circulation; Dinoprostone; Epoprostenol; Female; Male; Nociceptin; Opioid Peptides; Swine; Vasoconstrictor Agents

Traumatic injury is the leading cause of death for infants and children, and mortality is increased with head injury. Previous studies have shown that pial arteries constricted and that responses to several nitric oxide (NO)-dependent dilator stimuli were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of K+ channels is a major regulator of membrane potential. Recent data show that the NO releasers sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) and 8-bromo-cGMP elicit dilation via ATP-sensitive K+ channel (KATP) activation. The present study was designed to investigate the effect of FPI on KATP channel function.. Chloralose-anesthetized newborn pigs equipped with a closed cranial window were connected to a percussion device that consisted of a saline-filled cylindrical reservoir and a metal pendulum. Brain injury of moderate severity (1.9 to 2.1 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Pial artery diameter was measured with a video microscaler. Data were analyzed by repeated measures ANOVA. An alpha level of P < .05 was considered significant.. FPI blunted dilation to cromakalim (10(-8), 10(-6) mol/L), a KATP agonist (10 +/- 1% and 27 +/- 2% versus 3 +/- 1% and 7 +/- 2% before and after FPI, respectively, n = 8). Similarly, FPI blunted dilation to calcitonin gene-related peptide, an endogenous KATP activator. FPI also blunted dilator responses to SNP, S-nitroso-N-acetylpenicillamine, and 8-bromo-cGMP (10(-6) to 10(-8) mol/L) (10 +/- 1% and 20 +/- 1% versus 2 +/- 1% and 8 +/- 2% for SNP before and after FPI; 9 +/- 1% and 16 +/- 1% versus 2 +/- 1% and 4 +/- 1% for 8-bromo-cGMP before and after FPI, respectively, n = 8). In contrast, responses to papaverine and brain natriuretic peptide were unchanged after FPI.. These data show that KATP channel function is impaired after FPI. Furthermore, these data suggest that impaired function of mechanisms distal to NO synthase contribute to altered cerebral hemodynamics after FPI.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Animals, Newborn; Blood; Brain Injuries; Cerebral Arteries; Cyclic AMP; Cyclic GMP; Female; Male; Nitric Oxide; Pia Mater; Potassium Channels; Swine; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Wounds, Nonpenetrating