title: Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats.
abstract: OBJECTIVE
  It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery. Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR).
  
  
  METHODS
  Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser(1177)-phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N(5)-(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia.
  
  
  RESULTS
  In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N(5)-(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin.
  
  
  CONCLUSIONS
  These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. oyama@medone.med.osaka-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Oyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yagita
authors.forename: Miki
authors.initials: M
authors.lastname: Kawamura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Emi
authors.initials: E
authors.lastname: Omura-Matsuoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply; D002560:Cerebrovascular Circulation / Q000187:drug effects; D000077407:Cilostazol; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000188:drug therapy / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D013777:Tetrazoles; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000077407:Cilostazol; D001241:Aspirin