Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage

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✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy.

Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

Article Information

Current address for Dr. Kwan: Kaohsiung Medical College Hospital, Kaohsiung, Taiwan.Address reprint requests to: Kevin S. Lee, Ph.D., Department of Neurological Surgery, Box 420, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. email: ksl3h@virginia.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Bar graph showing the effect of CGS 26303 on cerebral vasospasm in cross-sectional areas in the prevention study. The average luminal area (mean ± SEM) of cross sections of basilar arteries is shown for each group of animals. The degree of vasospasm was reduced significantly in the groups treated with CGS 26303 (F5,45 = 19.998). *p < 0.01 for comparisons with the SAH plus vehicle group using Fisher's protected LSD test.

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    Bar graph showing the effect of CGS 26303 on cerebral vasospasm in cross-sectional areas in the reversal study. The average luminal area (mean ± SEM) of cross sections of basilar arteries is shown for each group of animals. The degree of vasospasm was reduced significantly in the group treated with 30 mg/kg CGS 26303 (F5,38 = 17.099). *p < 0.01 for comparisons with the SAH plus vehicle group using Fisher's protected LSD test.

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