The goal of this proposal is to determine the mechanisms responsible for the transport of ions across the blood-brain barrier (BBB) and to understand how these processes are regulated. The BBB is formed by capillary endothelial cells which control the flux of solutes between blood and brain, thus regulating the composition of the brain's interstitial fluid. To accomplish this task, the capillary endothelium acts similarly to an epithelium actively transporting ions and water across its cells. The ion transporters are likely to be important for maintaining the Na and K homeostasis with the brain for optimal neuronal activity. When this mechanism is disrupted, neuronal dysfunction and/or brain edema results. In the previous grant period, the investigator showed that the blood to brain Na transport plays an important role in the development of brain edema during ischemia. These results led the investigator to postulate that the concentration of K in the brain interstitial fluid (Ke) is an important modulator for Na transport into the brain. An increase in Ke would increase K extrusion into the capillaries and accelerate the flux of Na from the blood into the brain. The present proposal is an effort to test this hypothesis by simultaneously measuring Ke (with K-sensitive electrodes), Na and CI transport under three conditions where Ke is elevated: a) reperfusion following complete cerebral ischemia; b) incomplete cerebral ischemia and c) severe hypoglycemia. He will investigate the importance of Na, K-ATPase, sodium channels and sodium co-transport systems in the blood to brain Na transport. For this purpose, he will use conditions in which the capillary Na, K-ATPase system is up- or down-regulated and by administering potent inhibitors of the Na channels or Na-CI transport.
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