Bumetanide Reduces Cerebral Edema Formation in Rats With Diabetic Ketoacidosis

  1. Tina I. Lam1,
  2. Steven E. Anderson1,
  3. Nicole Glaser2 and
  4. Martha E. O’Donnell1
  1. 1Department of Physiology and Membrane Biology, University of California, Davis, California
  2. 2Department of Pediatrics, University of California, Davis, California
  1. Address correspondence and reprint requests to Dr. Martha E. O’Donnell, Department of Physiology and Membrane Biology, School of Medicine, University of California, One Shields Avenue, Davis, CA 95616. E-mail: meodonnell{at}


The mechanisms responsible for cerebral edema formation in diabetic ketoacidosis (DKA) are not well understood, although evidence suggests ischemia as a contributing factor. Previous studies have shown that the Na-K-Cl cotransporter of cerebral microvascular endothelial cells and astrocytes is a major participant in ischemia-induced cerebral edema in stroke. The present study was conducted to test the hypothesis that the Na-K-Cl cotransporter also contributes to cerebral edema in DKA. Sprague-Dawley rats were administered streptozotocin to induce DKA, and then cerebral edema was assessed by determination of apparent diffusion coefficients (ADC) with magnetic resonance diffusion-weighted imaging. Cerebral ADC values in DKA rats were significantly reduced in both cortex and striatum compared with non-DKA control rats, indicating the presence of cerebral edema. Intravenous administration of bumetanide to DKA rats abolished the drop in cortical ADC values, while having no significant effect in the striatum. Insulin and saline treatment had no effect when given after bumetanide but increased both cortical and striatal ADC values when given before bumetanide. Evidence is also presented here that acetoacetate and β-hydroxybutyrate stimulate brain microvascular Na-K-Cl cotransporter activity. These findings suggest that the Na-K-Cl cotransporter contributes to brain edema in DKA.


    • Accepted November 10, 2004.
    • Received May 21, 2004.
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