Cereport(TM) (RMP-7) increases the permeability of human brain microvascular endothelial cell monolayers

Jasmina B. Mackic, Monique Stins, Suzana Jovanovic, Kwang Sik Kim, Raymond T. Bartus, Berislav V. Zlokovic

Research output: Contribution to journalArticle

Abstract

Purpose. To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability. Methods. HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [14C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000). Results. Cereport increased the HBMEC permeability to [14C]-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 [125I]-bradykinin and/or [125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)1360-1365
Number of pages6
JournalPharmaceutical Research
Volume16
Issue number9
DOIs
StatePublished - Oct 4 1999
Externally publishedYes

Keywords

  • Bradykinin B2 receptor
  • Brain endothelium
  • Cereport
  • Human
  • Permeability

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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