Multifaceted effects of selective inhibitor of phosphodiesterase III, cilostazol, for cerebral vasospasm after subarachnoid hemorrhage in a dog model.
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.


METHODS
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).


CONCLUSIONS
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.
Yamaguchi-Okada
Mitsuo
M
Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan. mitsuyama42@msn.com
Nishizawa
Shigeru
S
Mizutani
Atsushi
A
Namba
Hiroki
H
D000284:Administration, Oral; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology; D002533:Cerebral Angiography; D000077407:Cilostazol; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005260:Female; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*
D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D018995:Myosin Heavy Chains; D000077407:Cilostazol