Multifaceted Effects of Selective Inhibitor of Phosphodiesterase III, Cilostazol, for Cerebral Vasospasm after Subarachnoid Hemorrhage in a Dog Model

Abstract

Background: Selective inhibition of phosphodiesterase type III (PDE III) may be involved in the pathophysiology of vasospasm and a PDE III inhibitor, cilostazol, is thus expected to attenuate vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effects of cilostazol on angiographic and morphological vasospasm. Method: Twenty-one mongrel dogs were divided into 4 groups: (1) control (n = 3); (2) SAH (n = 6); (3) SAH with low-dose treatment (n = 6), and (4) SAH with high-dose treatment (n = 6). We used the established double-hemorrhage model of SAH achieved by injecting autologous blood. Angiography was performed on day 0 and day 7. The animals were euthanized after a second angiogram, and Western blotting was performed to analyze phenotypic changes in smooth muscle cells of the basilar artery. The basilar artery was sectioned for immunohistochemistry of SM1, SM2 and SMemb to analyze phenotypic changes (SM1, SM2 for the contractile type of smooth muscle myosin heavy chain and SMemb for the synthetic type). Intact endothelial cells were counted under a microscope. Results: Severe vasospasm was obtained in the SAH group (42 ± 1%). Cilostazol attenuated angiographic vasospasm in both treatment groups (63 ± 2 and 74 ± 4%, respectively). Prevention of endothelial damage and phenotypic changes in smooth muscle cells were observed in both treatment groups (p < 0.05 vs. control, ANOVA). Conclusion: Cilostazol attenuates vasospasm following SAH in dogs by suppressing phenotypic changes in the basilar artery and preventing endothelial damage. Therefore, we anticipate that cilostazol may be useful in the management of vasospasm.