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Cerebrovascular effects of the bradykinin analog RMP-7 in normal and irradiated dog brain

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Abstract

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.

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Authors and Affiliations

  1. Brain Tumor Research Center, Department of Neurological Surgery, School of Medicine, University of California, San Francisco, California, 94143

    John R. Fike, Glenn T. Gobbel, Ali H. Mesiwala, Hyung J. Shin, Minoru Nakagawa, Kathleen R. Lamborn & Theresa M. Seilhan

  2. Department of Radiation Oncology, School of Medicine, University of California, San Francisco, California, 94143

    John R. Fike

  3. Department of Radiology, School of Medicine, University of California, San Francisco, California, 94143

    John R. Fike

  4. Department of Neurology, School of Medicine, University of California, San Francisco, California, 94143

    Glenn T. Gobbel

  5. Alkermes Inc., Cambridge, MA, 02139, USA

    Peter J. Elliott

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  1. John R. Fike
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  7. Theresa M. Seilhan
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  8. Peter J. Elliott
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Fike, J.R., Gobbel, G.T., Mesiwala, A.H. et al. Cerebrovascular effects of the bradykinin analog RMP-7 in normal and irradiated dog brain. J Neurooncol 37, 199–215 (1998). https://doi.org/10.1023/A:1005874206814

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