Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke

Martha E O'Donnell, Lien Tran, Tina I. Lam, Xiao Bo Liu, Steven E. Anderson

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Increased transport of Na+ across an intact blood-brain barrier (BBB) participates in edema formation during the early hours of cerebral ischemia. In previous studies, the authors showed that the BBB Na-K-Cl cotransporter is stimulated by factors present during ischemia, suggesting that the cotransporter may contribute to the increased brain Na+ uptake in edema. The present study was conducted to determine (1) whether the Na-K-Cl cotransporter is located in the luminal membrane of the BBB, and (2) whether inhibition of the BBB cotransporter reduces brain edema formation. Perfusion-fixed rat brains were examined for cotransporter distribution by immunoelectron microscopy. Cerebral edema was evaluated in rats subjected to permanent middle cerebral artery occlusion (MCAO) by magnetic resonance diffusion-weighted imaging and calculation of apparent diffusion coefficients (ADC). The immunoelectron microscopy studies revealed a predominant (80%) luminal membrane distribution of the cotransporter. Magnetic resonance imaging studies showed ADC ratios (ipsilateral MCAO/contralateral control) ranging from 0.577 to 0.637 in cortex and striatum, indicating substantial edema formation. Intravenous bumetanide (7.6-30.4 mg/kg) given immediately before occlusion attenuated the decrease in ADC ratios for both cortex and striatum (by 40-67%), indicating reduced edema formation. Bumetanide also reduced infarct size, determined by TTC staining. These findings suggest that a luminal BBB Na-K-Cl cotransporter contributes to edema formation during cerebral ischemia.

Original languageEnglish (US)
Pages (from-to)1046-1056
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume24
Issue number9
DOIs
StatePublished - Sep 2004

Fingerprint

Sodium-Potassium-Chloride Symporters
Bumetanide
Middle Cerebral Artery Infarction
Blood-Brain Barrier
Edema
Stroke
Immunoelectron Microscopy
Brain Edema
Brain Ischemia
Diffusion Magnetic Resonance Imaging
Membranes
Brain
Ischemia
Perfusion
Magnetic Resonance Imaging
Staining and Labeling

Keywords

  • Blood-brain barrier
  • Cerebral edema-Bumetanide
  • Cotransport
  • Stroke, Cerebral ischemia

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. / O'Donnell, Martha E; Tran, Lien; Lam, Tina I.; Liu, Xiao Bo; Anderson, Steven E.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 24, No. 9, 09.2004, p. 1046-1056.

Research output: Contribution to journalArticle

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