The effect of cerebrospinal fluid pressure on dural venous pressure in young rats.

In order to study cerebrospinal fluid (CSF) absorption across the dural sinus wall, the effect of CSF pressure (recorded from the cisterna magna) on dural venous pressure (recorded from the transverse sinus) was investigated in groups of rats at 2, 10, 20, and 31 days after birth and in adulthood. At normal resting pressures there was no positive pressure gradient between the CSF and sinus venous blood in 2-, 10-, and 20-day-old rats, but in 31-day-old and adult rats there was a positive gradient of 16 and 12 mm H2O, respectively. A series of constant-rate infusions of artificial CSF was made into the cisterna magna, and subsequent plateaus in both CSF and venous blood were recorded. The gradient of a plot of plateau pressure against infusion rate gave the overall resistance to absorption of the CSF for each age group, which was higher in 2- and 10-day-old rats than at three older ages. The effect on dural venous pressure was age-related, with the largest increase at 2 days, the smallest at 20 days, and no effect at 31 days or in adults. The pressure difference between CSF and sinus blood has been used to calculate resistance to absorption across the sinus wall. This showed that the high overall resistance to drainage in young rats can be largely accounted for by the rise in sinus pressure. It is concluded that drainage of CSF into the sinuses is greatly restricted in young animals.

Molecular factors influencing drug transfer across the blood-brain barrier.

A recently reported approach to the prediction of blood-brain drug distribution uses the general linear free energy equation to correlate equilibrium blood-brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; pi2H, solute dipolarity or polarizability; alpha2H and beta2H, the hydrogen bond acidity or basicity, and Vx, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood-brain barrier in the rat. The permeability (logPS) of the blood-brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol-water partition coefficients (logP(oct)) for comparison. It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.

The drainage of cerebrospinal fluid in hydrocephalic rats.

Cerebrospinal fluid plateau pressures and transverse sinus plateau pressures were measured in response to a series of constant-rate infusions into the CSF in 10-day-old control and hydrocephalic H-Tx rats. In control rats the venous pressure increased with CSF pressure but to a lesser extent and around 60% of the total resistance to absorption was due to the concurrent rise in venous pressure with a hydrostatic gradient maintained between CSF and venous blood. In hydrocephalic rats the same infusion rates resulted in an increase in venous pressure which was the same magnitude as the rise in CSF pressure, resulting in zero hydrostatic gradient from CSF to blood. This suggests that CSF drainage does not take place by this route in hydrocephalic rats and that alternative drainage routes must be operating.

Transport into retina measured by short vascular perfusion in the rat.

1. The short duration cerebrovascular perfusion method for measuring permeability of the blood-brain barrier has been adapted to measuring transport into the retina. 2. The method has been characterized on the one hand by comparing uptakes of radiotracers during HCO3(-)-buffered saline perfusion with those occurring after intravenous bolus injection of radioisotopes, and on the other by comparing uptake into retina with the uptake into frontal cerebral cortex. The mean permeability-surface area (PS) products (ml s-1 g-1) for [14C]urea and [14C]thiourea in the perfused retina were 1.2 +/- 0.26 x 10(-3) and 2.1 +/- 0.01 x 10(-3) respectively. The intravenous injection method gave comparable values for [14C]urea and [14C]thiourea of 1.6 +/- 0.28 x 10(-3) and 3.24 +/- 0.55 x 10(-3). The rates of uptake of the hydrophilic solutes were 2- to 7-fold greater than in brain. 3. Retinal and choroidal capillary perfusion fluid flow rates were measured using a diffusible flow marker ([14C]diazepam) and a particulate indicator (15 microns cerium141-labelled microspheres). Results using both flow markers confirmed that both capillary networks supplying the retina were being adequately perfused.

Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait.

BACKGROUND AND PURPOSE: Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1 hybrids derived from a SHRSP/WKY cross. METHODS: The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume. RESULTS: Infarct volumes measured by MRI in adult SHRSP (19.5 +/- 2.0%) and F1 hybrid rats (19.4 +/- 1.9%) were significantly greater than in WKY (11.1 +/- 2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F1 hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001). CONCLUSIONS: Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F1 hybrid rats and indicates a dominant mode of inheritance for this phenotype.