Cereport™ (RMP-7) Increases the Permeability of Human Brain Microvascular Endothelial Cell Monolayers1 Article DOI:
Cite this article as: Mackic, J.B., Stins, M., Jovanovic, S. et al. Pharm Res (1999) 16: 1360. doi:10.1023/A:1018938722768 Abstract . To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability. Purpose . HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [ Methods I4C]-inulin (MW. 5,200) and [ 3H]-dextran (MW. 70,000). . Cereport increased the HBMEC permeability to [ Results l4C]-inulin, but not to [ 3H]-dextran. The effect was transient, maximal at 15 min (i.e., 79.3% increase), and polarized to the basolateral membrane. An inverted U, dose-response curve was observed with active concentrations of Cereport from 0.01 to 0.5 nmol/L, the plateau maximal effect between 0.5 and 10 nmol/L, and loss of activity at the highest concentration, i.e., 20 nmol/L. Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 μmol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 μmol/L) enhanced by 31 % (p < 0.05) the effect of 0.1 nmol/L Cereport. Unlabeled Cereport displaced [ 12 5I]-bradykinin and/or [ 125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side. . Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its effects can be further modulated through changes in cAMP and cGMP second messenger systems. Conclusions Cereport bradykinin B2 receptor human brain endothelium permeability REFERENCES
B. V. Zlokovic and M. L. J. Apuzzo. Strategies to circumvent vascular barriers of the central nervous system.
B. V. Zlokovic and M. L. J. Apuzzo. Cellular and molecular neurosurgery: Pathways from concept to reality—Part II: Vector systems and delivery methodologies for gene therapy of the central nervous system.
D. R. LeMay, M. Kittaka, E. M. Gordon, B. Gray, M. Stins, J. G. McComb, S. Jovanovic, P. Tabrizi, M. H. Weiss, R. Bartus, W. F. Anderson, and B. V. Zlokovic. Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.
Human Gene Therapy
R. T. Bartus, P. J. Elliot, R. Dean, N. J. Hayward, T. L. Nagle, M. R. Huff, P. A. Snodgrass, and D. G. Blunt. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7.
R. T. Bartus. The blood-brain barrier as a target for pharmacological modulation.
Drug Disc. And Devel.
G. Riley, N. Kim, V. Watson, Y. P. Gobon, C. P. LeBel, K. L. Black, and R. T. Bartus. Intraarterial administration of carboplatin and the blood brain barrier permeabilizing agent, RMP-7: a toxicologic evaluation in swine.
E. Sanovich, R. T. Bartus, P. M. Friden, R. L. Dean, H. Q. Le, and M. W Brightman. Pathway across blood-brain barrier opened by the bradykinin agonist, RMP-7.
P. J. Elliot, J. B. Mackic, W. F. Graney, R. T. Bartus, and B. V. Zlokovic. RMP-7, a bradykinin agonist, increases permeability of blood-ocular barriers in the guinea-pig.
Invest. Ophthalmol. Vis. Sci.
P. J. Elliot, R. T. Bartus, J. B. Mackic, and B. V. Zlokovic, Intravenous infusion of RMP-7 increases ocular uptake of ganciclovir.
M. Sugita and K. T. Black. Cyclic-GMP-specific phosphodiesterase inhibition and intracarotid bradykinin infusion enhances permeability into brain tumors.
K. L. Black, T. Cloughesy, S. C. Huang, Y. P. Gobin, Y. Zhou, J. Grous, G. Nelson, K. Farahani, C. K. Hoh, and M. Phelps. Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas.
P. J. Elliot, N. J. Hayward, R. L. Dean, and R. T. Bartus. Dissociation of blood-brain barrier permeability and the hypotensive effects of the bradykinin B2 agonist RMP-7.
S. R. Doctorow, S. M. Abelleira, L. A. Curry, R. Heller-Harrison, J. Kozarich, B. Malfroy, L. McCarrol, K. G. Morgan, A. R. Morrow, G. F. Musso, J. Smart, J. A. Straub, B. Turnbull, and C. A. Gloff. The bradykinin analog RMP-7 increases intracellular free calcium levels in rat brain microvascular endothelial cells.
J. Pharmacol Exp. Ther.
J. A. Straub, A. Akiyama, and P. Parmar. In vitro plasma metabolism of RMP-7.
A. Untenberg, M. Wahl, and A. Baethmann. Effects of bradykinin on permeability and diameter of pial vessels in vivo.
J. Cereb. Blood Flow Metab.
M. Wahl, E. T. Whalley, A. Unterberg, L. Schilling, A. A. Parsons, A. Baethmann, and A. R. Young. Vasomotor and permeability effects of bradykinin in the cerebral microcirculation.
K. Matsukado, M. Sugita, and K. L. Black. Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas.
P. J. Elliott, N. J. Hayward, M. R. Huff, T. L. Nagle, K. L. Black, and R. T. Bartus. Unlocking the blood-brain barrier: a role for RMP-7 in brain tumor therapy.
P. Walker, D. Anthony, and V. H. Perry. Differences in intracerebral and peripheral bradykinin-induced plasma extravasation in rat.
Soc. Neuroscience Abstracts
D. M. Raidoo, R. Ramsaroop, S. Naidoo, W. Muller-Esterl, and K. D. Bhoola. Kinin receptors in human vascular tissue: their role in atheromatous disease.
J. B. Mackic, M. Stins, J. G. McComb, M. Calero, J. Ghiso, K. S. Kim, S. D. Yan, D. Stern, A. M. Schmidt, B. Frangione, and B. V. Zlokovic. Human blood-brain barrier receptors for Alzheimer's amyloid-
: Assymetrical binding, endocytosis and transcytosis at the apical side of brain microvascular endothelial cell monolayer.
J. Clin. Invest.
Y. Persidsky, M. Stins, D. Way, M. H. Witte, M. Weinand, K. S. Kim, P. Bock, H. E. Gendelman, and M. Fiala. A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis.
M. Fiala, M. F. Stins, D. J. Looney, P. Shapshank, A. Diagne, M. C. Graves, D. L. Way, O. Martinez, M. H. Witte, M. Weinard, and K. S. Kim. Penetration of HIV-1 across a blood-brain barrier model is enhanced by tumor necrosis factor α.
M. F. Stins, F. Gilles, and K. S. Kim. Selective expression of adhesion molecules on human brain microvascular endothelial cells.
T. Raub, S. L. Kuentzel, and G. A. Sawada. Permeability of bovine brain microvessel endothelial cells in vitro.
Exp. Cell. Res.
K. Audus and R. Borchardt. Characterization of an in vitro blood-brain barrier model system for studying drug transport and metabolism.
Y. Z. Ziylan, P. J. Robinson, and S. I. Rapoport. Differential blood-brain barrier permeabilities to [
C]sucrose and [
H]inulin after osmotic opening in the rat.
L. Rakic, B. V. Zlokovic, H. Davson, M. B. Segal, D. Begley, M. N. Lipovac, and D. M. Mitrovic. Chronic amphetamine intoxication and the blood-brain barrier permeability to inert polar molecules studied in the vascularly perfused guinea pig brain.
J. Neurol. Sci.
S. Vijaykumar, S. Takito, C. Hikita, and Q. Al-Awqati. Hensin remodels the apical cytoskeleton and induces columnarization of intercalated epithelial cells: Processes that resemble terminal differentiation.
J. Cell Biol.
Z. Chen, M. Zandonatti, D. Jakubowski, and H. S. Fox. Brain capillary endothelial cells express MBEC1, a protein that is related to the Clostridium perfringens enterotoxin receptors.
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