CHEMICAL ENVIRONMENT OF THE CENTRAL NERVOUS SYSTEM 



1887 



fig. 8. Diagram illustrating proposed mechanism for con- 

 verting central nervous system metabolically produced C0 2 

 into carbonic acid with subsequent exchange for plasma 

 Na + and CI - . [From Tschirgi 1 147).] 



nervous system by an exchange mechanism operating 

 via metabolically produced C0 2 (147, fig. 40). 

 It is proposed that a fraction of the COs produced 

 by central nervous cellular metabolism does not 

 diffuse into the blood as molecular CO2 but is rapidly 

 hydrated to carbonic acid in the presence of carbonic 

 anhydrase. This reaction could most reasonably occur 

 within a cellular structure immediately adjacent to 

 the capillary wall separating the blood from the extra- 

 vascular compartments and, for this reason, is pro- 

 posed to exist within the neuroglial perivascular 

 membrane. A further mechanism is suggested within 

 this membrane, which can selectively exchange the 

 H + and HCO.r ions thus formed for other electro- 

 lytes, largely Na + and Cl~ from the plasm, 1. The Na + 

 and Cl~ ions thus obtained would be then introduced 

 into the interstitial fluid of the nervous system. Be- 

 cause of the relative impermeability of this barrier to 

 free diffusion of electrolytes, a net increase of two os- 

 mols of NaCl in the central nervous system inter- 

 stitial fluid will result from each mol of CO -J thus 

 hydrated and exchanged. Water, which moves freely 

 among all the intracranial compartments (see above), 

 enters from the plasma to establish osmotic equilib- 

 rium. Insofar as Na + and Cl~ are thus transferred into 

 the interstitial fluid and cerebrospinal fluid from the 

 plasma preferentially, at a rate greater in proportion 

 to their plasma concentration than other electrolytes, 

 then the cerebrospinal fluid and interstitial fluid will 

 have a higher NaCl concentration than plasma, but 

 will maintain isotonicity (fig. 3). 



This mechanism is hypothesized to exist through- 

 out the entire parenchymal perivascular membrane 

 of the central nervous system, including the choroid 

 plexus, with the exception of the arachnoid villi in 

 the dural sinuses (fig. 4), thus providing a hydrostatic 

 pressure gradient to drive interstitial fluid outward 

 through the pial surface of the nervous system into 

 the subarachnoid space, and cerebrospinal fluid 

 through the ventricular system into the cisterna 

 magna and thence over the convexity of the brain. 

 The net influx of intracranial extravascular electro- 

 lytes and water is envisioned as moving into the sub- 

 arachnoid space and back into the blood stream, 

 largely through the arachnoid villi, at a rate deter- 

 mined by, among other factors, the COj production 

 nf the central nervous system. 



The maximum rate of net extravascular fluid pro- 

 duction predicted by this hypothesis can be calculated 

 for man on the assumption that all the COs produced 

 by the central nervous system is hydrated and ex- 

 changed for XaCl and that the blood-brain barrier 

 is otherwise completely impermeable 10 Na + and 

 CI - . Since it is highly unlikeK thai either of these 

 conditions is actually achieved, the calculated results 

 would be expected to be lii«_;h Accepting a CO2 

 production of 46 ml per min. by the human brain 

 (91), I',", ml per min. of isotonic XaCl could be 

 moved from the plasma into the extravascular com- 

 partments. This figure gre.nK exceeds the generally 

 accepted values for rate of cerebrospinal fluid produc- 

 tion (112), .md the proposed mechanism is therefore 

 capable of producing the observed water movement. 



On the basis nf this hypothesis, it is possible to 

 account for the decrease in intracranial fluid forma- 

 tion after acetazoleamide administration in the fol- 

 lowing manner. Carbonic anhydrase inhibition in the 

 central nervous system allows essentiall) all of the 

 metabolic COs produced by the cells to diffuse freely 

 into the blood plasma before any appreciable hydra- 

 tion to H + and HCO3 - has occurred. Therefore, 

 after acetazoleamide inhibition of the intrinsic central 

 nervous system carbonic anhydrase, the H + and 

 IIC0 3 ~ available for exchange with plasma Na + 

 and CI - diminishes and, since this represents a de- 

 creased rate of production of osmotically active 

 particles in the extravascular fluids, the net move- 

 ment of water from the plasma is proportionately 

 reduced. 



This mechanism for the transfer of Na + across a 

 cellular membrane by exchange for metabolically 

 produced H + with the accompaniment of osmotically 

 obligate water is essentially identical with that pro- 

 posed by Pitts (124) for kidney tubular reabsorption 



