Endothelin-converting enzyme inhibitor versus cerebrovasospasm
Cerebral vasospasm remains a major problem where patients suffer from the subarachnoid haemorrhage (SAH). Endothelin (ET) has demonstrated to play a substantial role in the pathophysiology of cerebral vasospasm after SAH. The potential involvement of endo
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Endothelin-converting enzyme inhibitor versus cerebrovasospasm W. Winardi1 , A. L. Kwan2;3 , C. L. Lin2;4 , A. Y. Jeng5 , K. I. Cheng4;6 1
Bronx High School of Science, Bronx, U.S.A. Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 Department of Pharmacology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Cardiovascular Diseases Research, Norvartis Institute for BioMedical Research, East Hanover, New Jersey, U.S.A. 6 Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2
Summary Cerebral vasospasm remains a major problem where patients suffer from the subarachnoid haemorrhage (SAH). Endothelin (ET) has demonstrated to play a substantial role in the pathophysiology of cerebral vasospasm after SAH. The potential involvement of endothelins in SAH-induced vasospasm has triggered considerable interest in therapeutic strategies to inhibit their biological effects. One promising approach to block the biosynthesis of endothelins is through the suppression of the proteolytic conversion of the precursor peptide (big ET-1) to its vasoactive form (ET-1) by the phosphoramidon-sensitive membrane-associated metallopeptidase of endothelin-converting enzyme (ECE) inhibitor. Therefore, ECE-1 inhibitors represent as logical candidates for blocking the activation of ET-1 and for limiting spastic constriction. According to their potencies for inhibiting three different types of metalloprotease, ECE-1 inhibitors can be categorized into three types of ECE-1 inhibitors: dual ECE-1=neutral endopeptidase 24.11 (NEP) inhibitors, triple ECE-1=NEP=angiotensin-converting enzyme (ACE) inhibitors, and selective ECE-1 inhibitors. However, only dual ECE-1=NEP and selective ECE-1 inhibitors have been evaluated in animal models of cerebral vasospasm following SAH. Due to the different characteristics of these compounds, the therapeutic effects of ECE-1 inhibitors for preventing and reversing SAH-induced vasospasm are discussed here. Keywords: Cerebral vasospasm; endothelin-1; endothelin-converting enzyme-1; subarachnoid haemorrhage.
Introduction Cerebral vasospasm remains a major problem where patients suffer from SAH. Two vasoactive substance activations, nitric oxide synthase [7] and ET-1 [7, 13, 20, 22], have been implicated in the development of SAHinduced cerebrovasospasm. However, from current basic
Correspondence: K. I. Cheng, Department of Anesthesiology, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan. e-mail: [email protected]
evidence and clinical observations, ET-1 have accrued and suggested a substantial role in the pathophysiology of cerebral vasospasm after SAH [13, 20, 22]. Multiple steps of post-translational processing are required for a large prepropeptide composed of 212 amino acids to form active 21-amino acid polypeptide ETs. The final conversion step for the cleavage of the inactive precursor big ETs (approx
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