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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels

Nagendra S. Ningaraj, Mamatha Rao, Kazuhiro Hashizume, Kamlesh Asotra and Keith L. Black
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 838-851; DOI: https://doi.org/10.1124/jpet.301.3.838
Nagendra S. Ningaraj
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Mamatha Rao
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Kazuhiro Hashizume
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Kamlesh Asotra
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Keith L. Black
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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 (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.

Footnotes

  • ↵1 Present address: Yamanashi Medical University, Department of Neurosurgery, Nakakoma-gun, Yamanashi Prefecture, Japan 409-3898

  • This work was supported by National Institutes of Health Grants NS32103, NS25554, RR13707, and a Jacob Javits Award to K.L.B.

  • Abbreviations:
    BTB
    blood-brain tumor barrier
    BK
    bradykinin
    B2
    BK type 2
    KCa
    calcium-dependent potassium
    sGC
    soluble guanylate cyclase
    RMP-7
    lobradimil
    IBTX
    iberiotoxin
    NS-1619
    1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one
    BBB
    blood brain barrier
    db-cGMP
    dibutyryl cGMP
    HRP
    horseradish peroxidase
    YC-1
    3-(5′-hydroxymethyl-2′furyl)-1-benzylindazole
    ODQ
    1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one
    [14C]AIB
    [14C]α-aminoisobutyric acid
    DEA-NONOate
    (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl) amino]
    PAPA-NONOate
    2-(N,N-diethylamino)-diazonolate-2-oxide
    PBS
    phosphate-buffered saline
    LDF
    laser-Doppler flowmetry
    CBF
    cerebral blood flow
    QAR
    quantitative autoradiographic
    DMEM
    Dulbecco's modified Eagle's medium
    RBE
    rat brain endothelial
    TBS
    Tris/HCl-buffered saline
    FITC
    fluorescein isothiocyanate
    TRITC
    tetramethylrhodamine B isothiocyanate
    DiBAC4(3)
    bisoxonal Dye, bis-(1,3-dibutylbarbuturic acid) trimethineoxonol
    MAP
    mean arterial blood pressure
    3D
    three-dimensional
    HOE140
    d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]-BK
    • Received January 10, 2002.
    • Accepted February 4, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels

Nagendra S. Ningaraj, Mamatha Rao, Kazuhiro Hashizume, Kamlesh Asotra and Keith L. Black
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 838-851; DOI: https://doi.org/10.1124/jpet.301.3.838

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels

Nagendra S. Ningaraj, Mamatha Rao, Kazuhiro Hashizume, Kamlesh Asotra and Keith L. Black
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 838-851; DOI: https://doi.org/10.1124/jpet.301.3.838
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