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

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 m onolayer permeability was determined with [C-14]- inulin (MW. 5,200) and [H -3]-dextran (MW. 70,000). Results. Cereport increased the HBMEC permeability to [C-14]-inulin, but no t to [H-3]-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 mu mol/L) aboli shed Cereport effects, while cGMP-specific PDES inhibitor, zaniprast (50 mu mol/L) enhanced by 31% (p < 0.05) the effect of 0.1 nmol/L Cereport. Unlab eled Cereport displaced [I-125]-bradykinin and/or [I-125]-Cereport from the basolateral side. There was no specific Cereport binding to the epical sid e. Conclusions. Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its ef fects can be further modulated through changes in cAMP and cGMP second mess enger systems.