Bradykinin-induced blood-brain tumor barrier permeability increase is mediated by adenosine 5'-triphosphate-sensitive potassium channel.
Bradykinin has been shown to selectively transiently increase the permeability of the blood-brain barrier (BBB). This study was performed to determine whether ATP-sensitive potassium (K(ATP)) channels mediate the increase in permeability of brain tumor microvessels induced by BK. Using a rat brain glioma (C6) model, we found increased expression of K(ATP) channels at tumor sites via Western blot analysis, after intracarotid infusion of bradykinin at a dose of 10 microg/kg/min for 15 min. A significant increase (73.58%) of the integrated density value (IDV) of the K(ATP) channel Kir6.2 subunit was observed in rats with glioma after 10 min of bradykinin perfusion. The over-expression of K(ATP) channels with bradykinin was significantly attenuated by the K(ATP) channel antagonist glibenclamide. Immunohistochemistry and immunolocalization experiments showed that the over-expression of K(ATP) channels was more obvious near tumor capillaries of 10 microm in diameter. I(KATP) modulation by bradykinin in cultured C6 cells was also studied using the patch-clamp technique in a whole-cell configuration. Administration of bradykinin led to a significant opening of K(ATP) channels in a time-dependent manner. This led to the conclusion that the bradykinin-mediated BBB permeability increase is due to accelerated formation of K(ATP) channels, which are thus as an important target in the biochemical regulation of this process.
Zhang
Hua
H
Department of Neurobiology, China Medical University, Shenyang, 110001, Liaoning Province, P.R. China.
Gu
Yan Ting
YT
Xue
Yi Xue
YX
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism* / Q000503:physiopathology; D005905:Glyburide / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009362:Neoplasm Metastasis / Q000188:drug therapy; D018408:Patch-Clamp Techniques / Q000379:methods; D010539:Permeability / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D000099161:Kcnj11 Channel
D000255:Adenosine Triphosphate; D001920:Bradykinin; D005905:Glyburide; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel