Fike J R, Gobbel G T, Mesiwala A H, Shin H J, Nakagawa M, Lamborn K R, Seilhan T M, Elliott P J
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143, USA.
J Neurooncol. 1998 May;37(3):199-215. doi: 10.1023/a:1005874206814.
The effects of an intravenous (i.v.) injection of the bradykinin analog RMP-7 (100 ng/kg) were assessed in normal dogs and dogs with focal, radiation-induced brain lesions. A dose of 20 Gy was delivered to a point 0.75 cm from a removable interstitial 125I source; parameters relating to blood flow and permeability were quantified using computed tomography 2-8 weeks after irradiation. Blood flow-related endpoints included regional cerebral blood flow (rCBF), mean transit time of blood and vascular volume, while endpoints related to permeability included blood-to-brain transfer constant (Ki), brain-to-blood transfer constant and plasma volume. In unirradiated brain, an i.v. bolus of RMP-7 administered through the left cephalic vein induced a rapid and transient hypotension and a statistically significant increase in vascular volume; no alterations in any parameter related to permeability were observed. After irradiation, changes in rCBF after RMP-7 depended upon time after exposure, effects presumably due to changing morphology in the irradiated tissues. In the radiation lesions, significant increases in Ki were observed 5 minutes after injection of RMP-7, but those increases were not related to time after irradiation or alteration in blood flow-related parameters. Our results showed that RMP-7 selectively increased permeability in already damaged vasculature without affecting the extent or volume of radiation-induced vasogenic edema. These data suggest that RMP-7 may provide an effective means to enhance the delivery of compounds to an already compromised brain while not exacerbating the potential adverse effects of pre-existing vasogenic edema.
在正常犬和患有局灶性辐射诱导脑损伤的犬中评估了静脉注射缓激肽类似物RMP-7（100 ng/kg）的效果。将20 Gy的剂量给予距可移除间质¹²⁵I源0.75 cm处的一个点；在照射后2 - 8周使用计算机断层扫描对与血流和通透性相关的参数进行量化。与血流相关的终点包括局部脑血流量（rCBF）、血液平均通过时间和血管容积，而与通透性相关的终点包括血脑转运常数（Ki）、脑血转运常数和血浆容积。在未受照射的脑中，通过左头静脉静脉推注RMP-7会引起快速且短暂的低血压以及血管容积的统计学显著增加；未观察到与通透性相关的任何参数有改变。照射后，RMP-7注射后rCBF的变化取决于暴露后的时间，这些影响可能是由于受照射组织形态的改变。在辐射损伤中，注射RMP-7后5分钟观察到Ki显著增加，但这些增加与照射后的时间或血流相关参数的改变无关。我们的结果表明，RMP-7选择性地增加了已受损血管的通透性，而不影响辐射诱导的血管源性水肿的程度或体积。这些数据表明，RMP-7可能提供一种有效的方法来增强化合物向已受损脑的递送，同时不会加剧先前存在的血管源性水肿的潜在不良反应。
