SUMMARY1. The purpose of the experiments was to discover whether the turnover of 22Na in the c.s.f., which is largely determined by its rate of secretion, is affected in the same manner by inhibitors or accelerators of active transport as the turnover in the brain tissue since there is reason to believe that the composition of the extracellular fluid of brain is controlled by active processes.2. Although acetazolamide (Diamox) inhibits rate of secretion of c.s.f. and the turnover of 22Na in this fluid it does not appreciably affect the turnover of 22Na in the brain tissue of either rat or rabbit, the small inhibition observed being probably secondary to the effects on the c.s.f.3. Ouabain inhibits secretion of c.s.f. and turnover of 22Na in this fluid, but it, also, has no effect on turnover of 22Na in the brain tissue alone or in combination with Diamox.4. Amphotericin B and amiloride, the anti-aldosterone spirolactone S.C. 114266, all inhibited secretion of c.s.f. without affecting turnover of 22Na in the brain tissue; actinomycin D, puromycin and cycloheximide, however, had no effect on secretion of c.s.f.5. Vasopressin inhibited secretion of c.s.f. and turnover of 22Na in this fluid but increased the turnover in the brain by some 16 %. 6. In the ventriculo-cisternally perfused rabbit, replacement of 80 % of the NaCl in the perfusion fluid by choline chloride caused a slowing of the passage of 22Na from blood into the perfusion fluid.
The transport of thyroxine from the bloodstream to the brain and the synthesis and secretion of transthyretin (formerly called prealbumin) were studied in rats and in sheep choroid plexus perfused in vitro. Rat choroid plexus contained 4.4 micrograms and rat liver 0.39 micrograms transthyretin mRNA per gram wet tissue. The specific radioactivity of transthyretin isolated from cerebrospinal fluid of rats 60 min after intravenous injection of [14C]leucine was greater than 50 times that of transthyretin from serum. After adding [14C]leucine to the perfusion medium of an in vitro perfused sheep choroid plexus, highly radioactive transthyretin was isolated from freshly secreted cerebrospinal fluid collected from the exposed choroid plexus surface. Secretion of newly synthesized transthyretin into the perfusion medium could not be demonstrated. After intravenous injection of [125I]-thyroxine into rats, a maximum in the curve of radioactivity in tissue plotted against time after injection was observed first for choroid plexus, thereafter for cerebrospinal fluid, and still later for cortex and striatum. Based on the obtained data, a hypothesis is derived for the mechanism of the transport of thyroid hormones from the bloodstream to the brain involving transthyretin synthesized in choroid plexus and secreted into the cerebrospinal fluid.
1. The penetration of a metabolically inert, small molecular radius lipid insoluble substance ([(13)C] and [(4)H]sucrose), from blood into brain and c.s.f., has been studied in developing sheep from 50 days gestation (term, 150 days) through to the new-born stage. Around 50 days gestation sucrose accumulated rapidly into brain and c.s.f., and reached a steady-state level in brain of about 12% of the plasma level by 3 hr. By 60 days sucrose penetrated less freely into brain and c.s.f.; the brain steady-state level was 10% by 4(1/2) hr. A large decrease in sucrose penetration occurred by 70 days gestation, and by 123 days (just before the time when a foetal lamb becomes viable) both the rate of penetration and the brain steady-state level of sucrose were similar to those of the adult of other species.2. The rate of c.s.f. secretion at different ages has been estimated by dye dilution during ventriculo-cisternal perfusion. The turnover of c.s.f. in 60 day foetuses was high (1.36%/min.g wet weight brain). From 123 days gestation to the adult stage the turnover was much lower, 0.02%/min.g at 123 and 137 days gestation and 0.01%/min.g in the adult ewe.3. A simple new method for measuring c.s.f. volume is described. The volume at 51 days was estimated to be 0.14 ml., S.E. +/- 0.03, n = 4 (brain weight = 0.87 g +/- 0.11), at 59 days it was 0.45 ml., S.E. +/- 0.04, n = 6 (brain weight = 2.0 g +/- 0.1) and near term it was 7.28 ml S.E. +/- 1.29, n = 4 (brain weight 42.0 g +/- 0.5).4. The results are discussed in relation to possible changes in permeability of the cerebral capillary endothelium, the sink effect of c.s.f., and changes in extracellular space of the brain during its development. It is concluded that the high rate of penetration and raised brain steady-state level of sucrose in immature sheep foetuses is probably due to immaturity of a permeability barrier at the level of the cerebral capillary endothelium or its associated glial processes. Some clinical implications of these findings are considered briefly.
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