PMID- 11823675
OWN - NLM
STAT- MEDLINE
DCOM- 20020221
LR  - 20191210
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Linking)
VI  - 33
IP  - 2
DP  - 2002 Feb
TI  - Phosphatidylinositol 3-kinase inhibitor failed to reduce cerebral vasospasm in 
      dog model of experimental subarachnoid hemorrhage.
PG  - 593-9
AB  - BACKGROUND AND PURPOSE: Phosphatidylinositol 3-kinase (PI3-kinase) is involved in 
      smooth muscle contraction induced by growth factors and/or G protein-coupled 
      receptor agonists. To evaluate the role of PI3-kinase in the pathogenesis of 
      delayed vasospasm, we applied 2 PI3-kinase inhibitors to an established canine 
      double-hemorrhage model of experimental subarachnoid hemorrhage. METHODS: 
      Twenty-four dogs underwent double blood injections via the cisterna magna on days 
      0 and 2. The dogs were killed on day 7. Dogs were treated with either vehicle 
      (dimethyl sulfoxide), wortmannin, or LY294002 once per day on day 2 through day 
      6. Angiography was performed before blood injection and before the dogs were 
      killed. The basilar arteries were collected for morphology, Western blot 
      analysis, and PI3-kinase activity. RESULTS: The residual diameter of the basilar 
      arteries in the dimethyl sulfoxide treatment group, which was compared with day 0 
      angiogram, decreased markedly on day 7 (the percentage of the residual diameter 
      was 47.8+/-0.8%). Wortmannin and LY294002 did not significantly change residual 
      diameter on day 7. Both PI3-kinase inhibitors abolished PI3-kinase activity 
      compared with the vehicle treatment group. However, both PI3-kinase inhibitors 
      failed to significantly attenuate PI3-kinase protein expression (Western blot) 
      (P>0.05, ANOVA). CONCLUSIONS: Delayed treatment, which was to mimic the clinical 
      situation, with PI3-kinase inhibitors failed to reverse vasospasm. PI3-kinase may 
      not play an important role in the delayed vasospasm. The possible effect of 
      PI3-kinase inhibitors in the early stage of vasospasm was not investigated in the 
      present study.
FAU - Kimura, Hitoshi
AU  - Kimura H
AD  - Department of Neurosurgery, University of Mississippi Medical Center, Jackson 
      39216-4505, USA.
FAU - Sasaki, Kenroh
AU  - Sasaki K
FAU - Meguro, Toshinari
AU  - Meguro T
FAU - Zhang, John H
AU  - Zhang JH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Basilar Artery/drug effects/pathology
MH  - Blotting, Western
MH  - Brain/drug effects/pathology/physiopathology
MH  - Cerebral Angiography
MH  - Chromones/pharmacology
MH  - Disease Models, Animal
MH  - Dogs
MH  - Enzyme Inhibitors/*pharmacology
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/analysis
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Subarachnoid Hemorrhage/complications/*drug therapy/pathology/physiopathology
MH  - Treatment Failure
MH  - Vascular Patency/drug effects
MH  - Vasospasm, Intracranial/*drug therapy/etiology/pathology/physiopathology
MH  - Wortmannin
EDAT- 2002/02/02 10:00
MHDA- 2002/02/22 10:01
CRDT- 2002/02/02 10:00
PHST- 2002/02/02 10:00 [pubmed]
PHST- 2002/02/22 10:01 [medline]
PHST- 2002/02/02 10:00 [entrez]
AID - 10.1161/hs0202.103398 [doi]
PST - ppublish
SO  - Stroke. 2002 Feb;33(2):593-9. doi: 10.1161/hs0202.103398.