PMID- 16547169
OWN - NLM
STAT- MEDLINE
DCOM- 20060626
LR  - 20220409
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 317
IP  - 3
DP  - 2006 Jun
TI  - Cilostazol suppresses superoxide production and expression of adhesion molecules 
      in human endothelial cells via mediation of cAMP-dependent protein 
      kinase-mediated maxi-K channel activation.
PG  - 1238-45
AB  - This study shows whether increased intracellular cAMP level by cilostazol is 
      directly coupled to its maxi-K channel activation in human endothelial cells. 
      Cilostazol (1 microM) increased the K+ currents in the human endothelial cells by 
      activating maxi-K channels, which was abolished by iberiotoxin (100 nM), a maxi-K 
      channel blocker. On incubation of human coronary artery endothelial cells with 
      tumor necrosis factor-alpha (TNF-alpha) (50 ng/ml), monocyte adhesion 
      significantly increased with increased superoxide generation and expression of 
      vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 
      (MCP-1) accompanied by increased degradation of inhibitory kappaBalpha in 
      cytoplasm and activation of nuclear factor-kappaB p65 in nucleus. All these 
      variables were significantly suppressed by cilostazol (10 microM), which was 
      antagonized by iberiotoxin (1 microM) and 
      (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-l] 
      [1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) (300 nM, 
      cAMP-dependent protein kinase inhibitor), but not by 
      (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindo-lo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic 
      acid methyl ester (KT 5823) (300 nM, cGMP-dependent protein kinase inhibitor). In 
      the human endothelial cells transfected with siRNA-targeting maxi-K channels, 
      cilostazol did not suppress the superoxide generation, VCAM-1 and MCP-1 
      expressions, and monocyte adhesion as contrasted with the wild-type cells. These 
      findings were similarly evident with 
      (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one 
      (BMS-204352), a maxi-K channel opener, and forskolin and dibutyryl cAMP. In 
      conclusion, increased cAMP level by cilostazol is directly coupled to its maxi-K 
      channel opening action via protein kinase activation in human endothelial cells, 
      thereby suppressing TNF-alpha-stimulated superoxide production and expression of 
      adhesion molecules.
FAU - Park, So Youn
AU  - Park SY
AD  - Department of Pharmacology, College of Medicine, Pusan National University, 
      10-Ami-Dong 1-Ga, Seo-Gu, Busan 602-739, Korea.
FAU - Lee, Jeong Hyun
AU  - Lee JH
FAU - Kim, Chi Dae
AU  - Kim CD
FAU - Lee, Won Suk
AU  - Lee WS
FAU - Park, Won Sun
AU  - Park WS
FAU - Han, Jin
AU  - Han J
FAU - Kwak, Yong-Geun
AU  - Kwak YG
FAU - Kim, Ki Young
AU  - Kim KY
FAU - Hong, Ki Whan
AU  - Hong KW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060317
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Chemokine CCL2)
RN  - 0 (Large-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tetrazoles)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 11062-77-4 (Superoxides)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - N7Z035406B (Cilostazol)
SB  - IM
MH  - Cell Adhesion/drug effects
MH  - Cell Line
MH  - Chemokine CCL2/metabolism
MH  - Cilostazol
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Endothelial Cells/cytology/*drug effects/enzymology/metabolism
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Ion Channel Gating/drug effects/genetics
MH  - Large-Conductance Calcium-Activated Potassium Channels/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
MH  - Superoxides/*metabolism
MH  - Tetrazoles/*pharmacology
MH  - Transfection
MH  - Vascular Cell Adhesion Molecule-1/*biosynthesis
EDAT- 2006/03/21 09:00
MHDA- 2006/06/27 09:00
CRDT- 2006/03/21 09:00
PHST- 2006/03/21 09:00 [pubmed]
PHST- 2006/06/27 09:00 [medline]
PHST- 2006/03/21 09:00 [entrez]
AID - jpet.105.098509 [pii]
AID - 10.1124/jpet.105.098509 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2006 Jun;317(3):1238-45. doi: 10.1124/jpet.105.098509. Epub 
      2006 Mar 17.