Cerebrovascular effects of the bradykinin analog RMP-7 in normal and irradiated dog brain.
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.
Fike
J R
JR
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143, USA.
Gobbel
G T
GT
Mesiwala
A H
AH
Shin
H J
HJ
Nakagawa
M
M
Lamborn
K R
KR
Seilhan
T M
TM
Elliott
P J
PJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000528:radiation effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000528:radiation effects*; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000209:etiology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000528:radiation effects*; D004285:Dogs; D008297:Male; D011833:Radiation Injuries, Experimental; D012016:Reference Values; D014057:Tomography, X-Ray Computed
C089876:RMP 7; D001920:Bradykinin