CONTROLLED MODULATION OF BBB PERMEABILITY USING THE BRADYKININ AGONIST, RMP-7

Previous studies have shown that the bradykinin agonist, RMP-7, can sa fely permeabilize the blood brain barrier (BBB) by activation of const itutive B2 receptors on endothelial cells. The paper describes a serie s of studies using quantitative autoradiography and intracarotid infus ions of RMP-7 to further elucidate the effect on BBB permeability. Bec ause earlier studies also demonstrated that even greater effects of RM P-7 were observed in the BBB associated with brain tumors, animal mode ls were employed so that comparisons could be made between the effects of RMP-7 within tumor, brain tissue proximal to tumor, and brain tiss ue distal from tumor. In the first study, the effect of RMP-7 on enhan cing the BBB permeation of three compounds of different physical chara cteristics was directly compared ([C-14]carboplatin, small, hydrophili c; [C-14]dextran, large, hydrophilic; [C-14]BCNU, small, lipophilic). RMP-7 increased permeability of the vascular barriers to both hydrophi lic compounds, carboplatin and dextran. While the effects of RMP-7 wer e observed on nontumor BBB, the greatest and most consistent effects w ere observed on the blood brain tumor barrier. This was true for both carboplatin and dextran, with progressively less effect seen as the di stance from tumor boundary increased. This topographic effect was more pronounced with the larger molecular weight compound, dextran. No eff ect of RMP-7 was seen in permeabilizing the BBB or the blood brain tum or barrier for the lipophilic drug, BCNU. In a second study, the gener ality of RMP-7's effects was established by demonstrating similar incr eases 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 in sight into the dynamics involved with eventual restoration of the BBB following RMP-7 administration. In one series, it was demonstrated tha t 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 inf usion was studied. These studies demonstrated that 60 min of continuou s 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 o f 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. (C) 1996 Academic Press, Inc.