Comparison of cerebrospinal fluid transport in fetal and adult sheep.

We quantified cerebrospinal fluid (CSF) transport (conductance) and CSF outflow resistance in late-gestation fetal and adult sheep using two methods, a constant pressure infusion method and a bolus injection technique into the lateral ventricles. No significant differences in CSF conductance (fetus 0.013 +/- 0.002, adult 0.014 +/- 0.003 ml x min(-1) x cm H(2)O(-1)) or CSF outflow resistance (fetus 83.7 +/- 9.8, adult 84.7 +/- 19.7 cm H(2)O x ml(-1) x min) were observed. To confirm CSF transport to plasma in fetal animals, (125)I- or (131)I-labeled human serum albumin (HSA) was injected into the lateral ventricles. The tracer entered fetal plasma with an average mass transport rate of 1.91 +/- 0.47% injected/h (n = 9). In two fetuses, we monitored the tracer appearance in plasma and cervical and thoracic duct lymph after injection of radioactive HSA into the ventricular CSF. As was the case in adult animals, fetal tracer concentrations increased in all three compartments over time, with the highest concentrations measured in lymph collected from the cervical lymphatics. These results 1) indicate that global CSF transport parameters in the late-gestation fetus and adult sheep are similar and 2) suggest an important role for extracranial lymphatic vessels in CSF transport before birth.

Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep.

We estimated the volumetric clearance of cerebrospinal fluid (CSF) through arachnoid villi and extracranial lymphatics in conscious sheep. Catheters were inserted into both lateral ventricles, the cisterna magna, multiple cervical lymphatics, thoracic duct, and jugular vein. Uncannulated cervical vessels were ligated. 125I-labeled human serum albumin (HSA) was administered into both lateral ventricles. 131I-HSA was injected intravenously to permit calculation of plasma tracer loss and tracer recirculation into lymphatics. From mass balance equations, total volumetric absorption of CSF averaged 3.37 +/- 0.38 ml/h, with 2.03 +/- 0.29 ml/h (approximately 60%) removed by arachnoid villi and 1.35 +/- 0.46 ml/h (approximately 40%) cleared by lymphatics. With projected estimates for noncannulated ducts, total CSF absorption increased to 3.89 +/- 0.33 ml/h, with 1.86 +/- 0.49 ml/h (48%) absorbed by lymphatics. Additionally, we calculated total CSF drainage to be 3.48 +/- 0.52 ml/h, with 54 and 46% removed by arachnoid villi and lymphatics, respectively, using previously published mass transport data from our group. We employed estimates of CSF tracer concentrations that were extrapolated from relationships observed in the study reported here. We conclude that 40-48% of the total volume of CSF absorbed from the cranial compartment is removed by extracranial lymphatic vessels.

Neurogenic modification of the vulnerability of the blood-brain barrier during acute hypertension in conscious rats.

To study the possible influence of sympathetic adrenergic tone on the blood-brain barrier function during acute hypertension in conscious unrestrained rats with indwelling catheters in the aorta and a jugular vein the blood pressure was increase by noradrenaline, 6-hydroxydopamine (6-OHDA) or baclofen. One or 60 min later the rats were sacrificed and the extravasation of 125I labelled albumin determined in the brain. After i.v. injection of noradrenaline the baroreceptor reflex will decrease the sympathetic tone whereas the blood pressure increased induced by the other two drugs is accompanied by an increased sympathetic activity. One minute after a corresponding rise in blood pressure the albumin content in the brain was considerably lower in rats given 6-OHDA than in those given noradrenaline. 60 min after the injection of 6-OHDA or baclofen the extravasation in the brain did not differ despite a considerably more rapid increase in pressure after 6-OHDA. Pretreatment with clonidine increased the blood-brain barrier dysfunction in rats given 6-OHDA but not in those given baclofen, probably because the slower rise in pressure facilitates myogenic autoregulation. It is concluded that neurogenic influences on vessel tone can modify the response of the blood-brain barrier during acute hypertension in conscious rats.

Prevention of protein extravasation in the brain by an anion transport inhibitor in acute experimental hypertension in rats.

Acute experimental hypertension induces protein leakage in the brain. The protein is thought to be, at least to a great extent, transported through the endothelial cells by pinocytosis. An anion transport inhibitor, 4 acetamido-4-isothiocyano-stilbene-2,2'-disulfonic acid, markedly reduced adrenaline or bicuculline-induced leakage of 125IHSA and Evans blue-albumin in all areas of the rat brain. The preventive effect of dexamethasone was less pronounced and no effect was seen of haloperidol.

Evidence for the movement of fluid, macromolecules and ions from the brain extracellular space to the CSF.

This report examines the effect of decreasing serum osmolality on movement into the ventricular system of fluid and of test material injected into the brain. Trace quantities of 22NaCl and 125I-labeled cat serum albumin (CSA) were injected into cerebral white matter of cats. The rates of cerebrospinal fluid volume flow, and appearance of 22Na and 125I-CSA were measured in the effluent fluid using ventriculocisternal perfusion before and while serum osmolality was acutely decreased by the intravenous infusion of a 60 mOsm sucrose solution. As compared to the control period, at the end of the infusion serum osmolality decreased from 321 +/- 4.2 mOsm to 283 +/- 4.0 mOsm and CSF volume flow increased from 21.8 +/- 2.3 microliter/min to 54.9 +/- 4.1 microliter/min (means +/- S.E.). The slope of the regression line describing 22Na influx went from 1.04 to 1.79, while for 125I the slope went from 0 to 1.38. These results suggest that a common pathway may exist for the movement, through the brain and into the ventricular system, of water, ions and large molecules.

Transfer of I125-albumin from blood into brain and cerebrospinal fluid in newborn and juvenile rats.

Human fetuses, rabbit fetuses and newborn rats have a relatively high concentration of protein in cerebrospinal fluid (csf) as compared with the adult. The present study was undertaken in an attempt to evaluate whether this high protein concentration in newborn rats is caused by a high permeability of the blood-brain-csf barrier to protein or by a low production rate of csf. The results suggest that the high concentration protein in csf in newborn rats is due to a low rate of production of csf rather than to an increased transfer of protein across the blood-brain-csf barrier.

Interferon administered in the cerebrospinal space and its effect on rabies in rabbits.

Because combined administration of intramuscular and intravenous interferon has been partially successful in the incubationary treatment of rabies, the effect of direct interferon administration into the cerebrospinal fluid space was tested. After injecting 1,800 U of interferon into the cisterna magna or the lateral ventricle, periodic samples, obtained by cisternal taps, showed that 1 to 5% remained after 24 h, as opposed to the known clearance of interferon from the bloodstream to this level within minutes. The distributions of interferon and (131)I-labeled albumin were similar as demonstrated by kinetics of clearance monitored over 24 h. Beginning with and after experimental infection of rabbits, daily intraventricular injections of one million units of interferon were given for as long as 3 weeks. Interferon was prepared from cell culture fluids after pressure dialysis and chromatography on Sephadex G-100. This intensive treatment did not prevent encephalitis, but prolonged the length of the incubation period by one- to two-thirds. The outcome after intraventricular administration was not as favorable as when one million units equally divided between intramuscular and intravenous injections were given at the time of challenge. Interferon administered in the subarachnoid space in this fashion is apparently inadequate to protect the rabbit against rabies. Its role as an adjunct measure, or other methods of administration in the nervous system, remains to be examined.