Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas.
Intracarotid low dose bradykinin infusion can selectively increase permeability in brain tumor capillaries. However, the mechanism by which bradykinin selectively increases transport into brain tumors and not normal brain has not been clearly defined. This study therefore sought to determine whether the mechanism by which bradykinin increases tumor permeability specifically involves the bradykinin B2 receptor in brain tumor tissue. In permeability studies, 27 Wistar rats with RG2 gliomas were utilized and a unidirectional transport, Ki, of radiolabeled [14C] sucrose was determined using quantitative autoradiography. Bradykinin (10 microg kg-1 min-1) increased the transport of sucrose to tumors 2.1-fold compared to saline infusion alone (p<0.001). The uptake of sucrose in tumors was significantly inhibited by the bradykinin B2 receptor antagonist, d-Arg, [Hyp3, Thi5,8, d-Phe7]-bradykinin (p<0.01), but not by the B1 receptor antagonist, des-Arg9, [Leu8]-bradykinin. The distribution of B2 receptors in normal brain and tumor tissue was examined by immunohistochemistry using the B2 receptor antiserum, AS 424. High levels of B2 receptors were detected in intracerebral RG2 glioma and brain surrounding tumor (BST), but not in normal brain tissue. These results indicate that the permeabilizing effects of bradykinin are mediated through bradykinin B2 receptors, and that differences in distribution of B2 receptors between tumor tissue and normal brain may be responsible for the selective effects on tumor tissue.
Matsukado
K
K
Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Sugita
M
M
Black
K L
KL
D000818:Animals; D001345:Autoradiography; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism*; D002344:Carotid Body; D002478:Cells, Cultured; D005260:Female; D005910:Glioma / Q000378:metabolism*; D007150:Immunohistochemistry; D007267:Injections; D007700:Kinetics; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000378:metabolism*; D013238:Stereotaxic Techniques; D013395:Sucrose / Q000378:metabolism
D018002:Receptors, Bradykinin; D013395:Sucrose; D001920:Bradykinin