CHEMICAL ENVIRONMENT OF THE CENTRAL NERVOUS SYSTEM 



1867 



stitial fluid directly from central nervous tissue, it was 

 assumed to resemble extracellular fluid of other tissues 

 and to be the primary, if not exclusive reservoir for 

 the 'extracellular' ions, Na + and CI - . Using these 

 two assumptions, the approximate volume of the 

 interstitial space could be calculated by analyzing 

 central nervous tissue for Na+ or Cl~ and computing 

 the volume of solution represented by each ion in the 

 concentration predicted by the Gibbs-Donnan equi- 

 librium for an ultrafiltrate of plasma. Brain contains 

 about 35 mEq of Cl~ per kg and about 57 mEq of 

 Na + per kg. If we consider the concentration of Cl~ in 

 the cerebrospinal fluid — which at equilibrium closely 

 resembles plasma ultrafiltrate — to represent the con- 

 centration of that ion in the interstitial fluid, then the 

 volume of extracellular water is about 30 per cent 

 of the brain wet weight. This figure is similar to that 

 calculated for liver, and nearly twice that in muscle 

 (log). However, a similar calculation using the 

 figures for [Na + ] instead of [CI - ] reveals a significantly 

 larger space (approximately 35 per cent), and it is 

 necessary to conclude that either the Q concentra- 

 tion in the interstitial fluid is less than assumed, or 

 that some of the brain Na + is intracellular. For 

 reasons which are as much articles of faith as logical 

 necessities, it is generally agreed that the latter is 

 more probable. In general, the CI - of vertebrate 

 nerves behaves as if it were extracellularl) situated 

 (5), and brain slices appear to be relatively imperme- 

 able to both sodium and chloride (35). Although the 

 rate of equilibration of intravenous Na + and Cl - 

 with central nervous tissue is much slower than with 

 other tissues (see the discussion of the blood-brain 

 barrier below), the Na+ and CI - of brain in vivo 

 do respond as extracellular ions to plasma changes 

 when a sufficiently long period of time is allowed for 

 these changes to be reflected in the central nervous 

 system (167, 169). Flexner & Flexner (42) have shown 

 that the chloride concentration of the developing 

 guinea pig cerebral cortex decreases by 40 per cent 

 between the fortieth day of gestation and term. Dur- 

 ing this same period, the concentration of sodium 

 decreases by only a fraction of this amount. These 

 workers conclude that, during this period of func- 

 tional onset within the developing central nervous 

 system, sodium has become an intracellular constit- 

 uent of at least some central structures. 



Values ranging between 25 per cent and 40 per 

 cent (38) for interstitial space in the central nervous 

 system have been widely quoted in the literature 

 and depend primarily on the assumptions mentioned 

 previously. Whether the concentration of the 'extra- 



cellular' ion in the interstitial fluid is assumed to be 

 equal to its concentration in the plasma, an ultrafil- 

 trate of plasma or the cerebrospinal fluid, does not 

 markedly alter this figure. 



Woodbury (167) has approached the question of 

 central nervous system fluid compartments through a 

 careful analysis of rates of accumulation in the central 

 nervous system of various radiotracer inorganic ions. 

 He first determined that brain chloride is in complete 

 equilibrium with plasma by decreasing plasma 

 chloride concentration with intraperitoneal injections 

 of isomolar glucose solutions and determining brain 

 chloride concentration. The per cent change in brain 

 chloride equaled the per cent change in plasma 

 chloride for as much as 30 per cent decrease. Simi- 

 larly, increasing plasma chloride with 20 mEq per kg 

 of NaCI intrapcritoneally increased brain chloride 

 proportionately. On this basis, the author assumes 

 that brain chloride is distributed only in the extra- 

 cellular fluid and that the chloride space is an ade- 

 quate measure of the total extracellular volume 

 in brain. 



Using the equations developed l>v Solomon (136), 

 Woodbury has determined that the curve for uptake 

 of radiochloride by the brain of rats can be resolved 

 into two components; one with .1 1 1.1 If time of lij min. 

 and the other with a half time of 25 hr. Radiosulfatc 

 (S I ),), on the other hand, equilibrates with only 3.9 

 per cent of the total brain volume during the first 16 

 hr. after intraperitoneal administration. Subsequently 

 the sulfate space appears to increase, but this is attrib- 

 uted to 'binding 1 of the sulfate b) the tissues. Be- 

 fore this 'binding' process occurs, the rate of uptake of 

 sulfate can be resolved into a single component with 

 a half time of 8u min., which is believed to correspond 

 to the rapid component of the chloride uptake curve. 

 The curve for uptake of radiosodium resolves into 

 three components, two with half times of 90 min. and 

 23 hr. corresponding to the two chloride components, 

 and a third with a half time of 13 min. This latter 

 component is similar to a fast component in the 

 uptake of potassium, and is therefore postulated 

 to represent movement into the intracellular com- 

 partment. 



From these results, Woodbury proposes that the 

 interstitial volume of the central nervous system, 

 represented by the chloride space (25 per cent of the 

 brain total water), is composed of two 'phases,' a 

 rapid phase (4 per cent) into which sulfate movement 

 is restricted and a slow phase (21 per cent) which 

 can be entered from the rapid phase by some solutes, 

 such as Cl~~. In addition, the intracellular compart- 



