Blood—Brain Barrier Permeability and Brain Concentration of Sodium, Potassium, and Chloride during Focal Ischemia

Abstract

Summary: 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 deter mine whether chloride is the principal anion that accumu lates 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 pro duced 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) gig dry wtlh. This was accompanied by a net increase in brain sodium (48 ± 12 j.Lmol/g dry wtlh) and a loss of potassium (34 ± 7 j.Lmol/g dry wt/h). The net rate of chloride accu mulation (16 ± 1 j.Lmol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions e2Na, 36CI, and 86Rb) and two passive permeability tracers WH]a-aminoisobutyric Numerous studies have emphasized the impor tance of cations in the development of brain edema during focal ischemia (Ito et aI., 1979;Schuier and Hossmann, 1980; Gotoh et aI., 1985; Young et aI., 1987; Betz et aI., 1989; Menzies et aI., 1993). For example, during the first 3-6 h of ischemia, water accumulation results from a net increase in brain sodium despite a significant loss of brain potassium (Gotoh et aI., 1985; Young et aI., 1987; Betz et aI., 1989; Menzies et aI., 1993). The rate at which soReceived November 9, 1992; final revision received July 13, 1993; accepted July 16, 1993.Address correspondence and reprint requests to Dr. A. L. Betz at D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718, U. S.A.Abbreviations used: AlB, a-aminoisobutyric acid; BBB, blood-brain barrier; MeAO, middle cerebral artery occlusion. 29acid eH]AIB) and e4C]urea} was determined. Permeabil ity to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36CI influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in isch emic brain. The BBB permeability to 22Na relative to that of eRJAIB was significantly increased in the ischemic cortex, the relative permeability to 86Rb was significantly decreased, and the relative permeability to 36CI was un changed. 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 accumula tion 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. Key Words: Brain edema Electrolyte transport-Middle cerebral artery occlu sion-Permeability-surface area product.

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

“…Future studies will need to evaluate the effectiveness of administering bumetanide after the onset of cerebral ischemia, as would occur in a clinical setting. A previous study showed that intravenous administration of the Na/H exchange inhibitor dimethylamiloride caused a 20% reduction in edema formation induced by permanent MCAO (Betz et al, 1995), and our own recent studies have shown that intravenous administration of the specific Na/H exchange inhibitor HOE-642 can also reduce edema formation in MCAO (Tran et al, 2004). Thus, a luminal Na/H exchanger may also contribute to edema formation during ischemia.…”

“…As predicted, MCAO caused a decrease in ADC values for the occluded hemisphere (increased edema formation), seen as a decrease in the left/right ADC ratios for all four regions evaluated. Previous studies have shown that permanent MCAO causes a net increase in brain water and a decrease in ADC values, and that the latter provides a very good index of brain swelling (Betz et al, 1994;Rudin et al, 2001). In these studies, we also used gravimetric methods (Menzies et al, 1993) to evaluate the effect of 180 minutes of permanent MCAO on brain water (Table 1).…”

“…Brain edema that forms during the early hours of ischemic stroke involves a net uptake of Na + and water from blood into brain across an intact blood-brain barrier (BBB) (Betz, 1996;Betz et al, 1994Betz et al, , 1995Menzies et al, 1990Menzies et al, , 1993Schielke et al, 1991) along with swelling of astrocytes (Bourke et al, 1980;Gotoh et al, 1985;Iadecola, 1999;Kempski et al, 1991;Kimelberg, 1995Kimelberg, , 1999. Previous studies have shown that BBB breakdown, allowing paracellular flux of solute and water into the brain, generally occurs after 3 to 6 hours of continuous reduction in blood flow, and that the majority of edema formation is accounted for by the net uptake of brain cations and water that occurs well before BBB breakdown (Betz, 1996).…”

Sodium time course using 23Na MRI in reversible focal brain ischemia in the monkey

“…Many reports in the literature have studied the increase in the TSC that occurs during acute stroke using small animal models of brain ischemia (2)(3)(4)(5)(6)(7)(8)(9). However, the majority of these studies used invasive direct tissue analysis with flame photometry in which each animal provided data at only a single time point, and therefore, the characterization of TSC over the time course of the stroke in individual animals was not possible.…”

“…The general consensus from studies in the literature is that the increase in TSC during focal brain ischemia is linear in nature (2)(3)(4)(5)(6)(7)(8)(9)(10). The studies found TSC increases during focal brain ischemia ranging from 16%/h to 35%/h for small animal models (2)(3)(4)(5)(6)(7)(8)(9) and TSC increases ranging from 2.7%/h to 12.7%/h for nonhuman primates (10,11). Because ischemia is associated with time-dependent increases in TSC, noninvasive techniques for the in vivo measurement of the sodium changes in acute stroke are highly desirable.…”