QUANTIFICATION OF LOCAL CAPILLARY TRANSFER IN THE CNS

中枢神经系统由许多区域组成，而这些区域又是 由更小的单位组成的，如核、束和层。近期 证据清楚地表明，在 中枢神经系统内的血流量和葡萄糖利用率(例如24)，但没有 寻找局部毛细转移差异的系统性努力已经 已经做好了。这项提案的主要目标是确定是否有 跨中枢神经系统毛细血管转移的区域和局部差异(即 血脑屏障的局部差异)，并调查 跨这个结构的调剂机制(S)。主要的实验 工作将是测量14个月的血到脑内流常数(KI) 采用多次/图形分析方法的有机化合物(34)。 不同持续时间的实验将通过静脉注射进行 给药~(14)C标记的化合物，测定化合物的 在血浆中的时间过程，通过定量测量其局部摄取 放射自显影，并通过图表评估化合物的局部KI值。 如果发现本地和/或区域KI差异，则相关差异 在对药物、多肽和毒素等物质的吸收方面， 很有可能。使用实验测量的局部血流量值， 本地PS产品(毛细血管渗透性的运算表达式) 将从KI数据中计算出来。地方性机制(S) 通过绘制这些PS产物的图来检查跨毛细血管内流 它们在膜中的表观溶解度和扩散系数的函数 (8，9，27)。这一分析应该指出两种机制 血液到组织的内流与有机物质的物理化学性质 使它们的局部毛细血管渗透性。这个 多时间/图形分析也产生了对血管的估计 体积，包括毛细血管内皮细胞，其中化合物 在完全穿过血脑屏障之前分布，并产生 关于进入和通过毛细管的运动机制的信息 内皮细胞。最后，这些化合物在不同部位的分布 缺乏紧密毛细血管的中枢神经系统(例如，脑室周围 器官)将从实验数据中定量。这一量化 血液-组织交换的研究可能特别有助于理解 体内激素和其他信使物质的摄取和释放 中枢神经系统的区域。

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.