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

• Published in: Journal of neuro-oncology 1998-05, Vol.37 (3), p.199-215
• Main Authors: FIKE, J. R, GOBBEL, G. T, MESIWALA, A. H, SHIN, H. J, NAKAGAWA, M, LAMBORN, K. R, SEILHAN, T. M, ELLIOTT, P. J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood flow; Blood Pressure - drug effects; Blood Pressure - radiation effects; Bradykinin; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Brain - diagnostic imaging; Brain - drug effects; Brain - radiation effects; Brain Edema - diagnostic imaging; Brain Edema - etiology; Cerebral blood flow; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - radiation effects; Computed tomography; Dogs; Edema; Hypotension; Injection; Intravenous administration; Male; Medical sciences; Miscellaneous; Neuropharmacology; Permeability; Pharmacology. Drug treatments; Radiation; Radiation Injuries, Experimental; Reference Values; Statistical analysis; Tomography, X-Ray Computed
• ISSN: 0167-594X; 1573-7373
• 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.