Blood-brain barrier sodium transport: Relationship to interstitial fluid potassium concentration.

Abstract

Cerebral ischemia results in an increase in brain sodium (Na) content which accounts for most of the increase in water content in the first 24 hours of ischemia. Na transport across the blood-brain barrier (BBB) appears to be rate limiting for the development of cerebral edema and may be mediated by channels and transporters such as the Na,K-ATPase. Brain capillary Na,K-ATPase, which is located on the abluminal membrane of the endothelial cell is exposed to high interstitial fluid potassium concentrations ((K) $\sb{\rm ISF}$) during brain ischemia. To assess the potential significance of this on BBB Na transport, the K-activation kinetics of the Na,K-ATPase in isolated brain capillaries and synaptosomes were determined. Results showed that brain capillary K uptake and Na efflux were activated by (K) in the pathophysiological range. K and Na flux rates were half-maximal at 3.8 and 4.2 mM, respectively, whereas K uptake into synaptosomes was half-maximal at 0.47 mM extracellular (K). Blood to brain transport of $\sp{22}$Na and $\sp3$H-aminoisobutyric acid(AIB) were measured during partial ischemia in the rat to determine if Na permeability was increased in tissue where (K) $\sb{\rm ISF}$ was elevated. At 2.5 hours following middle cerebral artery occlusion, the permeability-surface area product (PS) for Na and the PS-Na/PS-AIB ratio, were increased in ischemic tissue, demonstrating a relative increase (51%) in BBB Na permeability. The permeability of the BBB to Na was studied during insulin-induced severe hypoglycemia to determine if a relationship between Na permeability and (K) $\sb{\rm ISF}$ could be demonstrated in another brain injury model where (K) $\sb{\rm ISF}$ is elevated. The results showed that the PS ratio, Na/AIB increased 71% during the period of elevated (K) $\sb{\rm ISF}$ compared to values determined before this stage and following normalization of (K) $\sb{\rm ISF}$ by glucose administration. These data support the hypothesis that BBB Na permeability is increased in ischemia due to activation of the Na,K-ATPase by (K) $\sb{\rm ISF}$. The BBB ion transporters are potential targets for therapeutic approaches to brain edema.