RT Journal Article
SR Electronic
T1 Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 838
OP 851
DO 10.1124/jpet.301.3.838
VO 301
IS 3
A1 Ningaraj, Nagendra S.
A1 Rao, Mamatha
A1 Hashizume, Kazuhiro
A1 Asotra, Kamlesh
A1 Black, Keith L.
YR 2002
UL http://jpet.aspetjournals.org/content/301/3/838.abstract
AB 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 (KCa) channels. We modulated KCa 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 (Ki) to [14C]α-aminoisobutyric acid in the brain tumor area but not in normal brain tissue. The Ki 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 KCa channel antagonist, iberiotoxin. Immunoblot and immunolocalization studies demonstrate overexpression of KCa channels in tumor cells and capillaries compared with normal brain. The potentiometric assays demonstrate the functional activity of KCa 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 KCa channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. We conclude that KCachannels serve as a convergence point in the biochemical regulation of BTB permeability. The American Society for Pharmacology and Experimental Therapeutics