title: Phosphodiesterase inhibitor modulation of brain microvascular endothelial cell barrier properties.
abstract: OBJECTIVE
  Brain microvascular disorders, including cerebral microscopic hemorrhage, have high prevalence but few treatment options. To develop new strategies for these disorders, we analyzed the effects of several phosphodiesterase (PDE) inhibitors on human brain microvascular endothelial cells (HBECs).
  
  
  METHODS
  We modified barrier properties and response to histamine of HBECs using cilostazol (PDE3 inhibitor), rolipram (PDE4 inhibitor), and dipyridamole (non-specific PDE inhibitor).
  
  
  RESULTS
  Cilostazol and dipyridamole altered the distribution of endothelial F-actin. Cilostazol increased expression of tight junction protein claudin-5 by 118% compared to control (p<.001). Permeability to albumin was decreased by cilostazol (21% vs control, p<.05), and permeability to dextran (70Kd) was decreased by both cilostazol (37% vs control, p<.001) and dipyridamole (44% vs control, p<.0001). Cilostazol increased trans-endothelial electrical resistance (TEER) after 12h by 111% compared to control (p<.0001). Protein kinase A (PKA) inhibitors H89 and KT5720 attenuated the TEER increase by cilostazol. Transient increased permeability in response to histamine was significantly mitigated by cilostazol, but not by other PDE inhibitors.
  
  
  CONCLUSIONS
  These findings demonstrate distinctive effects of cilostazol and other PDE inhibitors on HBECs, including enhanced barrier characteristics and mitigation of response to histamine. PKA-mediated effects of cilostazol were prominent in this model. These in vitro findings are consistent with therapeutic potential of PDE inhibitors in human brain microvascular disorders.
authors: Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA, United States.
authors: Shuo
authors: S
authors: Liu
authors: Chuanhui
authors: C
authors: Yu
authors: Fan
authors: F
authors: Yang
authors: Annlia
authors: A
authors: Paganini-Hill
authors: Mark J
authors: MJ
authors: Fisher
mesh_terms: D000199:Actins / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D000077407:Cilostazol; D062507:Claudin-5 / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000199:Actins; D002227:Carbazoles; D062507:Claudin-5; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D013777:Tetrazoles; C057416:KT 5720; D004176:Dipyridamole; D006632:Histamine; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000077407:Cilostazol