Phosphatidylinositol 3-kinase inhibitor failed to reduce cerebral vasospasm in dog model of experimental subarachnoid hemorrhage.
OBJECTIVE
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.
Kimura
Hitoshi
H
Department of Neurosurgery, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Sasaki
Kenroh
K
Meguro
Toshinari
T
Zhang
John H
JH
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002533:Cerebral Angiography; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017211:Treatment Failure; D014654:Vascular Patency / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one