Blood‐Brain Barrier Na/HCO3 Cotransporters: Evidence for a Role in Ischemia‐induced Brain Na Uptake

Abstract

Increased Na transport across the blood‐brain barrier (BBB) contributes to brain edema during the early hours of ischemic stroke. Our previous studies show that BBB Na‐K‐Cl cotransporter and Na/H exchange are stimulated by ischemic factors and inhibition of these Na transporters by bumetanide and HOE642, respectively, greatly attenuates Na uptake and edema in the rat middle cerebral artery occlusion (MCAO) model of stroke. In the present study, we examined the possibility that one or more Na/HCO3 cotransporters (NBCs) are present at the BBB and contribute to ischemia‐induced brain edema. NBC protein expression and activity were evaluated using Western blot and microspectroflurometric assays, respectively. We found the expression of NBCe1C and NBCn1 in bovine cerebral microvascular endothelial cells (CMEC) and freshly isolated rat brain microvessels. We also observed a Na‐ and HCO3‐dependent, HOE642‐insensitive H+ flux in CMEC that is comprised of both DIDS‐sensitive and DIDS‐insensitive components, indicating the presence of both NBCe1 and NBCn1 activity in the cells. Finally, localized 23Na MR spectroscopy was used to assess brain Na uptake in rats subjected to MCAO. We found that MCAO‐induced Na uptake was significantly reduced by DIDS (40 mg/kg, iv). These findings support the hypothesis that BBB NBCe1C and/or NBCn1 participate in ischemia‐induced brain Na uptake and edema formation.Supported by NINDS