1 886 



lIAMJllllllK OF PHYSIOLOGY 



NEUROPHYSIOLOGY III 



pH of the interstitial fluid. The neuronal environment 

 seems rather secure against H + concentration changes 

 in the plasma. On the other hand, changes in plasma 

 CO» are rapidly reflected in a changed interstitial pH 

 as this readily diffusible lipoid soluble gas passes into 

 the extravascular fluid and becomes hydra ted. It is 

 interesting to speculate whether this lack of local 

 control by the central nervous system over CO2 

 movement may not represent an 'Achilles heel' of the 

 blood-brain homeostatic mechanism, necessitating 

 precise regulation of blood pCOs by the respiratory 

 center to prevent disastrous shifts in pH of the neu- 

 ronal milieu. In this regard, Swanson et al. (144) 

 studied the effect on the EEG of differential regulation 

 of CO» and pH, and demonstrated in unanesthetized 

 curarized cats that increased arterial pCO» with 

 lowered blood pH produced EEG slowing progressing 

 to rolling 3 per sec. activity with intermittent flatten- 

 ing. Hypoventilation produced progressively higher 

 amplitudes and 5 to 6 cps activity with a typical 

 sharp configuration. Lowering blood pH without 

 appreciably changing arterial pCO> by intravenous 

 MCI infusions produced no significant EEG altera- 

 tion. Intravenous Na^COs and NaHCO :l both raised 

 arterial pH, but NajCOs lowered arterial pC02 

 producing hyperventilation-like EEG abnormalities, 

 while NaHCOj raised the pCOs producing EEG 

 changes similar to those of CO; breathing. 



Furthermore, it is possible for the pH of the cerebral 

 cortex to vary independently of the blood, as shown 

 by Dusser de Barenne et al. (33). They found that in 

 dogs the pi! of the cortex passively followed that of 

 the arterial blood when the COs content of the latter 

 was varying due to alterations in the ventilation, but 

 that as soon as changes occurred in the functional 

 activity of the cortex, its pi I altered independently 

 of that of the arterial blood. Similarly Tschirgi et al. 

 (149) demonstrated local changes in cerebral cortex 

 pH of as much .is 0.5 units lasting 2-4 min. which 

 accompanied waxes of cortical spreading depression 

 or convulsions in eats and rabbits. 



Transbarria Melabolu Pump 



As indicated in figure 4, there appears to be a con- 

 tinuous net movement of water and solutes from the 



vascular compartment into the extravascular com- 

 partments ol the central nervous svstem which is 

 balanced, at least in part, In a net movement of 

 watei and solutes from the subarachnoid space 

 through the arachnoid villi back into the blood 

 stream (see Davson's chapter on intracranial fluids 

 in this volume). As discussed previously, the thermo- 



dynamic analysis of this fluid formation requires 

 local metabolic energy to account for the electrolyte 

 composition of the cerebrospinal fluid (fig. 3), but the 

 nature of this metabolic "pump' and its role in regu- 

 lating the neuronal milieu have remained obscure. 



Tschirgi and co-workers (148) reported that the 

 carbonic anhydrase inhibitor acctazoleamide 

 (2 - acetylamino - 1 ,3,4 - thiadiazolc - 5 - sulfon- 

 amide) given intravenously to cats and rabbits pro- 

 duced a threefold reduction in rate of cerebrospinal 

 fluid flow in an open drainage system, or a decline of 

 approximately 30 per cent in intracranial pressure in 

 a closed system. Subsequent studies (148; unpublished 

 observations) revealed that this effect was unrelated 

 to altered blood COs tension, blood pH, altered renal 

 excretion or circulatory hemodynamics, and it 

 therefore was interpreted as resulting from inhibition 

 of the intrinsic carbonic anhydrase of the central 

 nervous system. This effect of acctazoleamide has 

 been confirmed in cats by Kister (92) who also 

 showed that two compounds having close structural 

 and chemical relations to acctazoleamide, but without 

 activity against carbonic anhydrase, were ineffective 

 in reducing flow rate of cerebrospinal fluid. Knapp 

 et al. (95) demonstrated a similar reduction in cere- 

 brospinal fluid pressure following acctazoleamide in 

 the cat, but were unable to measure a significant 

 decrease in normal monkeys, due perhaps to the 

 extremely low pressure (15 mm H 2 0) which they 

 observed in their animals prior to administration of 

 the drug. In both cats and monkeys, these authors 

 recorded an initial transient increase in cerebrospinal 

 fluid pressure which the) attribute to increased 

 plasma carbon dioxide and consequent intracranial 

 vascular dilatation. Coppen & Russell (26) reported 

 an initial pressure increase in epileptic patients given 



acctazoleamide, but did not observe .1 subsequent fall 

 below preinjection control levels during their 2-hr 

 pel iod of observation. 

 Carbonic anhydrase occurs in a variety oi secretory 



tissues, including stomach, pancreas, kidney and 



ciliary body of the eye (27), and is known to be 

 present in appreciable amounts throughout the cen- 

 tral nervous system (7). Acctazoleamide has been 

 reported specifically to inhibit this enzyme, which 

 catalyses the reaction COs + H 2 <± H>C0 3 

 (116), and to alter secretory activity in those tissues 

 where carbonic anhydrase occurs and which are 

 known to possess .1 secretory function (85). 



On the basis of these observations, Tschirgi (147) 

 has postulated a mechanism diagrammed in figure 8, 

 whereby X.i* and CI could be transported from the 

 plasma into the extravascular fluids of the central 



