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Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (A.M.S.H., B.B., D.S.M.); and Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany (A.M.S.H., G.F.)

The ATP-driven xenobiotic transporter P-glycoprotein is a critical element of the blood-brain barrier. To study regulation of P-glycoprotein function, we measured specific transport [(3'-oxo-4-butenyl-4-methyl-threonine(1), (valine(2)) cyclosporin (PSC833)-sensitive] of the fluorescent cyclosporin A derivative [N-(4-nitrobenzofurazan-7-yl)-D-Lys⁸]-cyclosporin A (NBDL-CSA) into the lumens of isolated rat brain capillaries using confocal microscopy and quantitative image analysis. Luminal NBDL-CSA accumulation was rapidly and reversibly reduced in a concentration-dependent manner by 0.1 to 100 nM endothelin-1 (ET-1). In this concentration range, ET-1 did not affect junctional permeability. The ET_B receptor agonist sarafotoxin 6c also reduced transport. An ET_B receptor antagonist blocked effects of ET-1 and sarafotoxin 6c; an ET_A receptor antagonist was without effect. Consistent with this, immunostaining and Western blotting showed expression of the ET_B receptor in brain capillary membranes. NBDL-CSA transport was also reduced by sodium nitroprusside, a NO donor, and by phorbol ester, a protein kinase C (PKC) activator. Inhibition of NO synthase (NOS) or PKC abolished the ET-1 effects. Thus, ET-1, acting through an ET_B receptor, NOS, and PKC rapidly and reversibly reduced transport mediated by P-glycoprotein at the blood-brain barrier.

Address correspondence to: Dr. David S. Miller, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: miller{at}niehs.nih.gov

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