Bartus R T, Elliott P J, Dean R L, Hayward N J, Nagle T L, Huff M R, Snodgrass P A, Blunt D G
Alkermes Inc., Cambridge, Massachusetts 02139, USA.
Exp Neurol. 1996 Nov;142(1):14-28. doi: 10.1006/exnr.1996.0175.
Previous studies have shown that the bradykinin agonist, RMP-7, can safely permeabilize the blood brain barrier (BBB) by activation of constitutive B2 receptors on endothelial cells. The paper describes a series of studies using quantitative autoradiography and intracarotid infusions of RMP-7 to further elucidate the effect on BBB permeability. Because earlier studies also demonstrated that even greater effects of RMP-7 were observed in the BBB associated with brain tumors, animal models were employed so that comparisons could be made between the effects of RMP-7 within tumor, brain tissue proximal to tumor, and brain tissue distal from tumor. In the first study, the effect of RMP-7 on enhancing the BBB permeation of three compounds of different physical characteristics was directly compared ([14C]carboplatin, small, hydrophilic; [14C]dextran, large, hydrophilic; [14C]BCNU, small, lipophilic). RMP-7 increased permeability of the vascular barriers to both hydrophilic compounds, carboplatin and dextran. While the effects of RMP-7 were observed on nontumor BBB, the greatest and most consistent effects were observed on the blood brain tumor barrier. This was true for both carboplatin and dextran, with progressively less effect seen as the distance from tumor boundary increased. This topographic effect was more pronounced with the larger molecular weight compound, dextran. No effect of RMP-7 was seen in permeabilizing the BBB or the blood brain tumor barrier for the lipophilic drug, BCNU. In a second study, the generality of RMP-7's effects was established by demonstrating similar increases in permeability to carboplatin in both inbred (Fischer 344) and outbred (Wistar) rat strains, implanted with varying tumor cell lines. Finally, several additional studies were performed to gain greater insight into the dynamics involved with eventual restoration of the BBB following RMP-7 administration. In one series, it was demonstrated that the BBB begins to close nearly immediately upon withdrawal of RMP-7, with complete restoration occurring within minutes. In another series, tachyphylaxis or desensitization resulting from continuous RMP-7 infusion was studied. These studies demonstrated that 60 min of continuous RMP-7 infusion resulted in complete, spontaneous restoration of the barrier to both carboplatin and dextran. Moreover, the desensitization appears to be linked to the initial activation of the receptors in a way which suggests that obligatory desensitization may exist as part of a more complete response. These data are discussed as they relate to practical issues to enhance delivery of drugs across the BBB, as well as more fundamental issues involving the function of the BBB and its interaction with the brain.
先前的研究表明，缓激肽激动剂RMP-7可通过激活内皮细胞上的组成型B2受体安全地使血脑屏障（BBB）通透性增加。本文描述了一系列使用定量放射自显影和颈内动脉注射RMP-7的研究，以进一步阐明其对BBB通透性的影响。由于早期研究还表明，在与脑肿瘤相关的BBB中观察到RMP-7的作用更大，因此采用了动物模型，以便比较RMP-7在肿瘤内、肿瘤近端脑组织和肿瘤远端脑组织中的作用。在第一项研究中，直接比较了RMP-7对三种不同物理特性化合物（[14C]卡铂，小分子、亲水性；[14C]右旋糖酐，大分子、亲水性；[14C]卡莫司汀，小分子、亲脂性）增强BBB通透性的影响。RMP-7增加了血管屏障对亲水性化合物卡铂和右旋糖酐的通透性。虽然在非肿瘤性BBB上观察到了RMP-7的作用，但在血脑肿瘤屏障上观察到的作用最大且最一致。卡铂和右旋糖酐都是如此，随着与肿瘤边界距离的增加，作用逐渐减弱。这种地形效应在分子量较大的化合物右旋糖酐上更为明显。对于亲脂性药物卡莫司汀，未观察到RMP-7对BBB或血脑肿瘤屏障通透性的影响。在第二项研究中，通过证明在植入不同肿瘤细胞系的近交系（Fischer 344）和远交系（Wistar）大鼠中，对卡铂的通透性有类似增加，确定了RMP-7作用的普遍性。最后，进行了几项额外的研究，以更深入地了解RMP-7给药后BBB最终恢复所涉及的动力学。在一系列研究中，证明了在停用RMP-7后，BBB几乎立即开始关闭，并在几分钟内完全恢复。在另一系列研究中，研究了连续注射RMP-7导致的快速耐受性或脱敏作用。这些研究表明，连续注射RMP-7达60分钟可使卡铂和右旋糖酐的屏障完全自发恢复。此外，脱敏似乎与受体的初始激活有关，这表明强制性脱敏可能作为更完整反应的一部分而存在。本文讨论了这些数据与增强药物跨BBB递送的实际问题以及涉及BBB功能及其与脑相互作用的更基本问题的关系。
