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Endothelin and Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: Pathogenesis and Treatment

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Abstract:

Endothelin (ET)-mediated vasoconstriction has been implicated in the pathophysiology of various disorders, e.g. hypertension, chronic heart failure, acute renal failure, pulmonary hypertension, and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. The potential involvement of ETs in cerebral vasospasm following SAH has triggered considerable interest in designing therapeutic strategies to inhibit biological effects of ET. Major approaches include: (a) reducing the levels of circulating ET- 1 by the the specific anti- ET- 1 antibodies, (b) antagonizing the ET receptors, and (c) suppressing the biosynthesis of ET- 1. To date, numerous antagonists of ETA and / or ETB receptors have been discovered, and some are under clinical evaluation. Inhibitors of endothelin-converting enzymes (ECEs), which catalyze the biosynthesis of ET-1, have also been synthesized. Two types of ECE-1 inhibitors have been evaluated in various animal disease models: dual ECE-1 / neutral endopeptidase 24.11 (NEP) inhibitors and selective ECE-1 inhibitors. In this article, the effects of ET receptor antagonists and ECE-1 inhibitors on the prevention and reversal of SAHinduced cerebral vasospasm in preclinical animal models are reviewed.

Keywords: cerebral vasospasm; endothelin; endothelin receptor antagonists; endothelin-converting enzyme inhibitors; subarachnoid hemorrhage

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043364919

Affiliations: Address correspondence and reprint requests to:, Aij-Lie Kwan, M.D., Ph.D., Department of Neurosurgery, Kaohsiung Medical University Hospital, No.100, Shih-Chuan 1st Road, Kaohsiung, Taiwan, Republic of China

Publication date: July 1, 2004

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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