Phosphatidylinositol 3-kinase inhibitor failed to reduce cerebral vasospasm in dog model of experimental subarachnoid hemorrhage

Abstract

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.