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(Stroke. 2002;33:593.)
© 2002 American Heart Association, Inc.

Original Contributions

Phosphatidylinositol 3–Kinase Inhibitor Failed to Reduce Cerebral Vasospasm in Dog Model of Experimental Subarachnoid Hemorrhage

Hitoshi Kimura, MD; Kenroh Sasaki, PhD; Toshinari Meguro, MD John H. Zhang, MD, PhD

From the Departments of Neurosurgery (H.K., T.M., J.H.Z.) and Pharmacology and Toxicology (K.S.), University of Mississippi Medical Center, Jackson.

Correspondence to John H. Zhang, MD, PhD, Department of Neurosurgery, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail jzhang{at}neurosurgery.umsmed.edu

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.

Key Words: 1-phosphatidylinositol 3-kinase • subarachnoid hemorrhage • vasospasm, intracranial • wortmannin • dogs