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(Stroke. 2004;35:1164.)
© 2004 American Heart Association, Inc.

Original Contributions

Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

From the Center for Neuropharmacology and Neuroscience (P.J.F.), Albany Medical College, Albany, New York and Ordway Research Institute (Y.J., H.K.K.), Albany, New York.

Correspondence to Paul J. Feustel, PhD, Center for Neuropharmacology and Neuroscience, MC136, Albany Medical College, Albany, New York. E-mail feustep{at}mail.amc.edu

Background and Purpose— Release of excitatory amino acids (EAA) is considered a cause of neuronal damage in ischemia. We investigated the sources and mechanisms of EAA release using microdialysis in regions of incomplete ischemia where perfusion was reduced by 50% to 80%, by applying inhibitors of volume-regulated anion channels (VRACs) and the GLT-1 glutamate transporter.

Methods— Reversible middle cerebral artery occlusion (rMCAo) was induced in anesthetized rats using the intraluminal suture technique. Microdialysate concentrations of glutamate, aspartate, and taurine were measured before, during 2 hours of rMCAo, and for 2 hours after rMCAo. Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or tamoxifen (50 µmol/L), a VRAC inhibitor, were administered continuously via the dialysis probes starting one hour prior to ischemia.

Results— During incomplete ischemia, dialysate glutamate levels averaged 1.74±0.31 µmol/L (SEM) in the control group (n=8), 2.08±0.33 µmol/L in the DHK group (n=7), and were significantly lower at 0.88±0.30 µmol/L in the tamoxifen group (n=9; P<0.05). As perfusion returned toward baseline levels, EAA levels declined in the vehicle and tamoxifen-treated animals but they remained elevated in the DHK-treated animals.

Conclusions— In contrast to previous results in severely ischemic regions, DHK did not reduce EAA release in less severely ischemic brain, suggesting a diminished role for transporter reversal in these areas. These findings also support the hypothesis that in regions of incomplete ischemia, release of EAAs via VRACs may play a larger role than reversal of the GLT-1 transporter.

Key Words: cerebral ischemia • astrocytes • anion transport • rats • reversible middle cerebral artery occlusion

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