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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021157-03
Application #
3402032
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1984-07-01
Project End
1991-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Bereczki, D; Wei, L; Otsuka, T et al. (1993) Hypercapnia slightly raises blood volume and sizably elevates flow velocity in brain microvessels. Am J Physiol 264:H1360-9
Hans, F J; Wei, L; Bereczki, D et al. (1993) Nicotine increases microvascular blood flow and flow velocity in three groups of brain areas. Am J Physiol 265:H2142-50
Gesztelyi, G; Finnegan, W; DeMaro, J A et al. (1993) Parenchymal microvascular systems and cerebral atrophy in spontaneously hypertensive rats. Brain Res 611:249-57
Tajima, A; Hans, F J; Livingstone, D et al. (1993) Smaller local brain volumes and cerebral atrophy in spontaneously hypertensive rats. Hypertension 21:105-11
Bereczki, D; Wei, L; Otsuka, T et al. (1993) Hypoxia increases velocity of blood flow through parenchymal microvascular systems in rat brain. J Cereb Blood Flow Metab 13:475-86
Fenstermacher, J D (1992) The blood-brain barrier is not a ""barrier"" for many drugs. NIDA Res Monogr 120:108-20
Bereczki, D; Wei, L; Acuff, V et al. (1992) Technique-dependent variations in cerebral microvessel blood volumes and hematocrits in the rat. J Appl Physiol 73:918-24
Tajima, A; Nakata, H; Lin, S Z et al. (1992) Differences and similarities in albumin and red blood cell flows through cerebral microvessels. Am J Physiol 262:H1515-24
Otsuka, T; Wei, L; Acuff, V R et al. (1991) Variation in local cerebral blood flow response to high-dose pentobarbital sodium in the rat. Am J Physiol 261:H110-20
Nakata, H; Shimizu, A; Tajima, A et al. (1991) The effects of chronic serum sickness on albumin distribution and glucose utilization in rat brain. Acta Neuropathol 81:312-7

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