Cocaine-induced increase in the permeability function of human vascular endothelial cell monolayers.
The effects of cocaine on endothelial cell macromolecular transport, electrical resistance, and morphology were assessed. In confluent endothelial monolayers grown on microporus filters, cocaine (0.01 to 1 mmol/L) induced a rapid concentration-dependent increase in permeability to peroxidase and low density lipoprotein. Along with increased transport, the cocaine effect was paralleled by a decrease in transendothelial electrical resistance. Alterations in membrane resistance were fully reversible following washout of the drug, providing evidence that cocaine does not cause permanent injury to the integrity of the monolayer. Cocaines major metabolites, benzoylecgonine and ecgonine methyl ester, had minimal effect on electrical resistance properties, whereas monolayer impedance was markedly depressed by the novel cocaine/alcohol metabolite, cocaine ethyl ester (cocaethylene). Morphologic studies of cocaine-treated endothelial cells revealed a marked disruption of F-actin and the formation of intercellular gaps; no evidence of cell lysis and/or detachment was noted. Forskolin, a potent activator of adenylate cyclase known to promote the endothelial cell barrier function, impaired cocaine-induced changes in electrical resistance and morphology. Cocaine, however, had no effect on resting levels of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) in confluent endothelial monolayers. In summary, the results indicate that cocaine directly induces structural defects in the endothelial cell barrier which enhance the transport of macromolecular tracers, the mechanism does not appear to involve intracellular cAMP.
Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC, 20306-6000, USA.
F D
FD
Kolodgie
P S
PS
Wilson
W J
WJ
Mergner
R
R
Virmani
D000199:Actins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000199:Actins; D008077:Lipoproteins, LDL; D014662:Vasoconstrictor Agents; D005576:Colforsin; C005618:benzoylecgonine; D000242:Cyclic AMP; D009195:Peroxidase; C066444:cocaethylene; D003042:Cocaine; C034524:ecgonine methyl ester