The blood-
brain tumor barrier (BTB) limits the delivery of therapeutic drugs to
brain tumors. We demonstrate in a rat
brain tumor (RG2) model an enhanced
drug delivery to
brain tumor following intracarotid infusion of
bradykinin (BK),
nitric oxide (NO) donors, or agonists of
soluble guanylate cyclase (sGC) and
calcium-dependent
potassium (K(Ca)) channels. We modulated K(Ca) channels by specific agonists and agents that produce NO and cGMP in situ to obtain sustained enhancement of selective
drug delivery to
brain tumors. Intracarotid infusion of BK or 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) significantly enhanced BTB permeability (K(i)) to [(14)C]
alpha-aminoisobutyric acid in the
brain tumor area but not in normal brain tissue. The K(i) increase achieved by BK,
NS-1619, NO donors, or the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzylindazole (YC-1) was significantly attenuated when coinfused with a K(Ca) channel antagonist,
iberiotoxin. Immunoblot and immunolocalization studies demonstrate overexpression of K(Ca) channels in
tumor cells and capillaries compared with normal brain. The potentiometric assays demonstrate the functional activity of K(Ca) channels in rat brain endothelial and
glioma cells. Additionally, we show that BK and
NS-1619 significantly increased the density of transport vesicles in the cytoplasm of
brain tumor capillary endothelia and
tumor cells. The cleft indices and cleft area indices in rat
tumor capillaries were significantly higher than in normal brain capillaries, and BK infusion did not alter these indices. These data demonstrate that the cellular mechanism for K(Ca) channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. We conclude that K(Ca) channels serve as a convergence point in the biochemical regulation of BTB permeability.