Abstract
Brain edema formation during the early stages of focal cerebral ischemia is associated with an increase in both sodium content and blood–brain barrier (BBB) sodium transport. The goals of this study were to determine whether chloride is the principal anion that accumulates in ischemic brain, how the rate of BBB transport of chloride compares with its rate of accumulation, and whether the stimulation seen in BBB sodium transport is also seen with other cations. Focal ischemia was produced by occlusion of the middle cerebral artery (MCAO) in anesthetized rats. Over the first 6 h after MCAO, the amount of brain water in the center of the ischemic cortex increased progressively at a rate of 0.15 ± 0.02 (SE) g/g dry wt/h. This was accompanied by a net increase in brain sodium (48 ± 12 μmol/g dry wt/h) and a loss of potassium (34 ± 7 μmol/g dry wt/h). The net rate of chloride accumulation (16 ± 1 μmol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions (22Na, 36Cl, and 86Rb) and two passive permeability tracers {[3H]α-aminoisobutyric acid (3H]AIB) and [14C]urea} was determined. Permeability to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36Cl influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in ischemic brain. The BBB permeability to 22Na relative to that of [3H]AIB was significantly increased in the ischemic cortex, the relative permeability to 86Rb was significantly decreased, and the relative permeability to 36Cl was unchanged. These results indicate that the stimulation in BBB sodium transport is specific for sodium. Further, chloride accumulates with sodium in brain during the early stages of ischemia; however, its rate of accumulation is low compared with its rate of transport from blood to brain. Therefore, inhibition of BBB sodium transport is more likely to reduce edema formation than is inhibition of BBB chloride transport.
This study demonstrates that chloride is the principal anion that accompanies the accumulation of sodium in ischemic brain, but its rate of accumulation in brain is much less than its rate of movement into brain, and therefore inhibition of chloride uptake would have little effect on brain edema formation. There is a specific acceleration of blood-to-brain sodium transport during ischemia that is not seen with another positively charged ion, 86Rb. This is consistent with stimulation of brain capillary Na,K-ATPase activity in response to the elevated extracellular potassium concentration. Inhibition of potassium influx across the BBB would probably be more successful in lessening edema formation than accelerating potassium efflux. However, inhibition of blood-to-brain sodium transport is likely to be a more effective approach to reducing brain edema formation during the early stages of cerebral ischemia.