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 (KATP) 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 KATP channels at tumor sites via Western blot analysis, after intracarotid infusion of bradykinin at a dose of 10 μg/kg/min for 15 min. A significant increase (73.58%) of the integrated density value (IDV) of the KATP channel Kir6.2 subunit was observed in rats with glioma after 10 min of bradykinin perfusion. The over-expression of KATP channels with bradykinin was significantly attenuated by the KATP channel antagonist glibenclamide. Immunohistochemistry and immunolocalization experiments showed that the over-expression of KATP channels was more obvious near tumor capillaries of 10 μm in diameter. IKATP 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 KATP channels in a time-dependent manner. This led to the conclusion that the bradykinin-mediated BBB permeability increase is due to accelerated formation of KATP channels, which are thus as an important target in the biochemical regulation of this process.