Pharmaceutical Research

, Volume 16, Issue 9, pp 1360–1365

Cereport™ (RMP-7) Increases the Permeability of Human Brain Microvascular Endothelial Cell Monolayers1

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

DOI: 10.1023/A:1018938722768

Cite this article as:
Mackic, J.B., Stins, M., Jovanovic, S. et al. Pharm Res (1999) 16: 1360. doi:10.1023/A:1018938722768

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 [I4C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000).

Results. Cereport increased the HBMEC permeability to [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 [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.

Cereportbradykinin B2 receptorhumanbrain endotheliumpermeability

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Jasmina B. Mackic
    • 1
  • Monique Stins
    • 2
  • Suzana Jovanovic
    • 1
  • Kwang Sik Kim
    • 2
  • Raymond T. Bartus
    • 3
  • Berislav V. Zlokovic
    • 1
  1. 1.Department of Neurological SurgeryUSC School of MedicineLos Angeles
  2. 2.Division of Infectious Diseases Childrens HospitalUSC School of MedicineLos Angeles
  3. 3.Alkermes Inc.Cambridge