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Experimental Biology and Medicine 231:1069-1074 (2006)
© 2006 Society for Experimental Biology and Medicine

CENTRAL NERVOUS SYSTEM

Prevention and Reversal of Vasospasm and Ultrastructural Changes in Basilar Artery by Continuous Infusion of CGS 35066 Following Subarachnoid Hemorrhage

Aij-Lie Kwan*,{dagger}, Chih-Lung Lin*, Chun-Po Yen*, William Winardi*, Yu-Feng Su*, Daniel Winardi*, Zen-Kong Dai{ddagger}, Arco Y. Jeng§, Neal F. Kassell{dagger}, Sheng-Long Howng* and Chih-Jen Wang*,1

* Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, 807 Taiwan; {dagger} Department of Neurosurgery, University of Virginia, Charlottesville, Virginia 22903; {ddagger} Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; and § Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07936

To whom requests for reprints should be addressed at 1 Department of Neurosurgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China. E-mail: a_lkwan{at}yahoo.com

Abstract

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.

Key Words: cerebral vasospasm • endothelin-converting enzyme • subarachnoid hemorrhage • CGS 35066 • electron microscopy






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