QUANTIFICATION OF LOCAL CAPILLARY TRANSFER IN THE CNS

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The central nervous system is made up of many regions which, in turn, are composed of smaller units such as nuclei, tracts, and layers. Recent evidence clearly shows that there are regional and local differences in blood flow and glucose utilization within the CNS (e.g. 24), but no systematic efforts to look for local differences in capillary transfer have been made. The main objective of this proposal is to determine if there are regional and local differences in transfer across CNS capillaries (i.e. local differences in the blood-brain barrier) and to investigate the mechanism(s) of transfer across this structure. The major experimental work will be the measurement of blood-to-brain influx constants (Ki) for 14 organic compounds with a multiple-time/graphical analysis approach (34). Experiments of varying duration will be performed by intravenously administering a 14C-labeled compound, determining the compound's time-course in plasma, measuring its local uptake by quantitative autoradiography, and assessing the compound's local Ki values by graphing. If local and/or regional Ki differences are found, then related differences in the uptake of substances such as drugs, peptides, and toxins are also highly likely. Using experimentally measured values of local blood flow, local PS products (the operational expression of capillary permeability) will be calculated from the Ki data. The mechanism(s) of local transcapillary influx will be examined by plotting these PS products as functions of their apparent solubility and diffusivity in the membrane (8,9,27). This analysis should point out both the mechanisms of blood-to-tissue influx and the physicochemical properties of organic compounds which set their local capillary penetrability. The multiple-time/graphical analysis also products estimates of the vascular volume, including the capillary endothelium, in which the compound distributes before completely crossing the blood-brain barrier and yields information on the mechanism of movement into and through the capillary endothelium. Finally, the distribution of these compounds into parts of the CNS which lack tight capillaries (for example, the circumventricular organs) will be quantitated from the experimental data. This quantitation of blood-tissue exchange may be especially useful for understanding the uptake and release of hormones and other messenger substances in these areas of the CNS.