Bradykinin selectively modulates the blood-tumor barrier via calcium-induced calcium release.
To investigate the underlying mechanism for the selective modulation of permeability of the blood-tumor barrier by small dose of BK, we established cell lines of rat brain microvascular endothelial cells (BMECs) and astrocytes by primary culture from neonatal rats. BMECs, astrocytes, or C6 glioma cells were treated with BK, and changes of intracellular NO and intracellular calcium level were measured with a fluorescent spectrophotometer. Similarly to the observations in astrocytes, although the initial application of BK easily triggered a ryanodine-mediated calcium-induced calcium release (CICR), we also detected a long-lasting intracellular nitric oxide (NO) elevation in C6 glioma cells upon BK treatment. However, BMECs are not the direct target of BK. Further study showed that ryanodine-mediated CICR contributes greatly to the secondary NO elevation induced by BK treatment. With an in vitro blood-tumor barrier (BTB) model, we demonstrated that NO generated in C6 glioma cells might act as an intercellular messenger and play an important role in the selective modulation of permeability of BMECs by BK. In conclusion, BK triggered CICR in C6 glioma cells, and the associated NO generation might be the underlying mechanism for the selective modulation of BTB permeability by BK.
Wang
Yi-bao
YB
Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
Liu
Yun-hui
YH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006735:Horseradish Peroxidase; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D009569:Nitric Oxide; D006735:Horseradish Peroxidase; D001920:Bradykinin; D002118:Calcium