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Increased brain uptake and brain to blood efflux transport of C-14-GABA in spontaneously hypertensive rats

机译：自发性高血压大鼠脑摄取和C-14-GABA的脑外血转运增加

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The brain uptake and brain to blood efflux transport of C-14-GABA were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats using 20 min bilateral in situ brain perfusion in rats anesthetized using urethane. The volume of distribution (Vd) of C-14-GABA into cerebrospinal fluid (CSF) and brain regions (cortex, diencephalon, cerebellum, and brain stem) was significantly greater in SHR than in the corresponding regions in WKY rats (p < 0.05). The estimated Vd value of C-14-GABA in CSF of SHR was 3.4 fold greater than that in WKY. Also compared to WKY, the Vd of C-14-GABA into cerebellum and cortex of SHR was 15.3 fold and 19.4 fold greater, respectively. Although the study of blood-brain barrier (BBB) integrity using H-3-mannitol revealed increased paracellular permeability at the brain capillaries of SHR when compared to WKY rats, this was found to be only partially responsible for the increased C-14-GABA uptake. The study of brain to blood efflux transport of C-14-GABA (after loading of brain with C-14-GABA by vascular perfusion) revealed that the half-time of elimination was significantly shorter in SHR (5.35 +/- 0.66 min) than in WKY rats (14.83 +/- 1.94 min), (p < 0.001). HPLC analysis revealed that GABA concentrations in brain extracts and CSF of SHR were similar to those in WKY rats (p > 0.05). The faster efflux in SHR might be, at least partially, responsible to compensate for increased uptake of this neurotransmitter and to preserve the protective function of BBB towards GABA. The protective function of the BCSFB towards GABA appears to be also preserved, since systemic infusion of GABA within a wide range of administered doses (0.004-5.00 mg/kg) produced an increase in GABA CSF concentration from around 0.5 mu M to only 11 mu M, and the obtained pattern of CSF GABA concentrations under these conditions did not differ between SHR and WKY rats, as revealed by HPLC. (c) 2006 Elsevier Inc. All rights reserved.
机译：研究了自发性高血压大鼠（SHR）和血压正常的Wistar Kyoto（WKY）大鼠的C-14-GABA的脑吸收和脑到血液的外流转运，并使用氨基甲酸乙酯麻醉的大鼠进行了20分钟的双侧原位脑灌注。在SHR中，C-14-GABA进入脑脊液（CSF）和大脑区域（皮质，间脑，小脑和脑干）的分布体积（Vd）明显大于WKY大鼠的相应区域（p <0.05 ）。 SHR CSF中C-14-GABA的估计Vd值比WKY高3.4倍。与WKY相比，C-14-GABA进入小脑和SHR皮质的Vd分别大15.3倍和19.4倍。尽管使用H-3-甘露醇对血脑屏障（BBB）完整性的研究表明，与WKY大鼠相比，SHR的脑毛细血管旁细胞通透性增加，但发现这仅部分导致C-14-GABA升高摄取。对C-14-GABA进行脑到血液外排运输的研究（通过血管灌注在脑中装载C-14-GABA后）表明，SHR的消除半衰期明显较短（5.35 +/- 0.66分钟）比WKY大鼠（14.83 +/- 1.94分钟）（p <0.001）。 HPLC分析显示，SHR的脑提取物和CSF中的GABA浓度与WKY大鼠相似（p> 0.05）。 SHR中较快的外排可能至少部分负责补偿这种神经递质的摄取增加，并保持BBB对GABA的保护功能。 BCSFB对GABA的保护功能似乎也得以保留，因为在各种给药剂量（0.004-5.00 mg / kg）中全身性输注GABA会使GABA CSF浓度从约0.5μM增加到仅11μm M，以及在这些条件下获得的CSF GABA浓度模式在SHR和WKY大鼠之间没有差异，如HPLC所揭示。 （c）2006 Elsevier Inc.保留所有权利。

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