QUANTIFICATION OF LOCAL CAPILLARY TRANSFER IN THE CNS

中枢神经系统由许多区域组成，这些区域依次 由更小的单位如核、束和层组成。 最近 证据清楚地表明，区域和地方差异， CNS内的血流量和葡萄糖利用（例如24），但没有 为了寻找毛细血管转移的局部差异， 被制造了。 本提案的主要目的是确定是否存在 是跨CNS毛细血管转移的区域和局部差异（即， 血脑屏障的局部差异），并研究 通过此结构转移的机制。 主要实验 工作将是测量14小时的血脑流入常数（Ki）。 有机化合物的多时间/图形分析方法（34）。 不同持续时间的实验将通过静脉内给药进行。 施用14C-标记的化合物，测定化合物的 血浆中的时间过程，通过定量测定其局部摄取 放射自显影，并通过作图评估化合物的局部Ki值。 如果发现局部和/或区域Ki差异，则相关差异 在药物、肽和毒素等物质的摄取中， 很有可能 使用局部血流的实验测量值， 局部PS产品（毛细血管渗透率的运算表达式） 将根据Ki数据计算。 当地机制 将通过将这些PS产物绘制为 它们在膜中的表观溶解度和扩散系数的函数 （8、9、27）。 这种分析应该指出两种机制， 血液到组织的流入和有机物的理化性质 这些化合物设置其局部毛细血管渗透性。 的 多时间/图形分析还产生血管的估计 体积，包括毛细血管内皮，其中化合物 在完全穿过血脑屏障之前分布， 关于移动进入和通过毛细管的机制的信息 内皮细胞 最后，将这些化合物分布到 缺乏紧密毛细血管的CNS（例如，脑室周围 器官）将从实验数据中定量。 这种定量 血液组织交换的研究可能对理解 激素和其他信使物质的摄取和释放， CNS的区域。

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.