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Regulation of blood-brain tumor barrier permeability by calcium-activated potassium channels.

Abstract
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.
AuthorsNagendra S Ningaraj, Mamatha Rao, Kazuhiro Hashizume, Kamlesh Asotra, Keith L Black
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 301 Issue 3 Pg. 838-51 (Jun 2002) ISSN: 0022-3565 [Print] United States
PMID12023511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Potassium Channels, Calcium-Activated
  • Bradykinin
Topics
  • Animals
  • Blood-Brain Barrier (drug effects, physiology)
  • Bradykinin (administration & dosage, pharmacokinetics)
  • Brain Neoplasms (drug therapy, metabolism)
  • Capillary Permeability (drug effects, physiology)
  • Cells, Cultured
  • Drug Delivery Systems (methods)
  • Potassium Channels, Calcium-Activated (physiology)
  • Rats
  • Rats, Wistar
  • Xenograft Model Antitumor Assays (methods, statistics & numerical data)

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