期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 289, 期 6, 页码 C1492-C1501出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00257.2005
关键词
edema; blood-brain barrier; bumetanide; cell volume
资金
- NINDS NIH HHS [R01 NS039953, NS-039953] Funding Source: Medline
Brain edema that forms during the early stages of stroke involves increased transport of Na+ and Cl- across an intact blood-brain barrier (BBB). Our previous studies have shown that a luminal BBB Na+-K+-Cl- cotransporter is stimulated by conditions present during ischemia and that inhibition of the cotransporter by intravenous bumetanide greatly reduces edema formation in the rat middle cerebral artery occlusion model of stroke. The present study focused on investigating the effects of hypoxia, which develops rapidly in the brain during ischemia, on the activity and expression of the BBB Na+-K+-Cl- cotransporter, as well as on Na+-K+-ATPase activity, cell ATP content, and intracellular volume. Cerebral microvascular endothelial cells (CMECs) were assessed for Na+-K+-Cl- cotransporter and Na+-K+-ATPase activities as bumetanide-sensitive and ouabain-sensitive Rb-86 influxes, respectively. ATP content was assessed by luciferase assay and intracellular volume by [H-3]-3-O-methyl-D-glucose and [C-14]-sucrose equilibration. We found that 30-min exposure of CMECs to hypoxia ranging from 7.5% to 0.5% O-2 (vs. 19% normoxic O-2) significantly increased cotransporter activity as did 7.5% or 2% O-2 for up to 2 h. This was not associated with reduction in Na+-K+-ATPase activity or ATP content. CMEC intracellular volume increased only after 4 to 5 h of hypoxia. Furthermore, glucose and pyruvate deprivation increased cotransporter activity under both normoxic and hypoxic conditions. Finally, we found that hypoxia increased phosphorylation but not abundance of the cotransporter protein. These findings support the hypothesis that hypoxia stimulation of the BBB Na+-K+-Cl- cotransporter contributes to ischemia-induced brain edema formation.
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