Prevention and reversal of vasospasm and ultrastructural changes in basilar artery by continuous infusion of CGS 35066 following subarachnoid hemorrhage.
Endothelin-1, a potent vasoconstrictive peptide, has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). The goal of this study was to evaluate the effect of continuous intravenous infusion of a highly selective endothelin-converting enzyme-1 inhibitor, CGS 35066, on the prevention and reversal of cerebral vasospasm following SAH. New Zealand white rabbits were subjected to SAH by injecting autologous arterial blood into the cisterna magna. Infusion of CGS 35066 at dosages of 1, 3, or 10 mg/kg/ day was initiated either 1 hr and 24 hrs later in the prevention and reversal protocols, respectively. Animals were sacrificed by perfusion-fixation 48 hrs after SAH induction. The cross-sectional areas of basilar arteries were measured using computer-assisted videomicroscopy. Ultrastructural changes in basilar arteries were determined using electron microscopy. CGS 35066 significantly prevented and reversed the arterial narrowing after SAH in all three groups. The mean cross-sectional areas of arteries from animals in both the prevention and reversal protocol groups that received 10 mg/kg/day of CGS 35066 did not differ significantly from those of the healthy controls. Histological studies of the basilar artery in the 10 mg/kg/day treatment group did not show pathomorphological changes, such as corrugation of the endothelium seen at 2 days after SAH induction or vacuole formation in the endothelial cells noted in the vehicle-treated SAH group. These findings suggest that CGS 35066 is a promising therapeutic agent for the prevention and reversal of cerebral vasospasm after SAH. It also prevents the pathological changes in vascular walls due to SAH.
Kwan
Aij-Lie
AL
Department of Neurosurgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China. a_lkwan@yahoo.com
Lin
Chih-Lung
CL
Yen
Chun-Po
CP
Winardi
William
W
Su
Yu-Feng
YF
Winardi
Daniel
D
Dai
Zen-Kong
ZK
Jeng
Arco Y
AY
Kassell
Neal F
NF
Howng
Sheng-Long
SL
Wang
Chih-Jen
CJ
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D001572:Benzofurans / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D063065:Organophosphonates / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000209:etiology*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*
D001572:Benzofurans; C404932:CGS 35066; D063065:Organophosphonates; D011480:Protease Inhibitors