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題名 | Functional Comparison of Isothioureas on Nitric Oxide Synthase Isoforms in Rat Thoracic Aortas=Isothioureas在大鼠胸主動脈對一氧化氮合成酶異構型的功能性比較 |
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作者姓名(中文) | 陳秀珍; 吳錦楨; | 書刊名 | Journal of Medical Sciences |
卷期 | 22:3 2002.06[民91.06] |
頁次 | 頁119-125 |
分類號 | 364.64 |
關鍵詞 | 胸主動脈; 一氧化氮合成酶異構型; Isothioureas; Nitric oxide synthase; Rats; Thoracic aortas; |
語文 | 英文(English) |
英文摘要 | Background: Nitric oxide (NO) is a multifunctional messenger molecule generated by a family of enzymes, the NO synthase. Nitric oxide is overproduced in the pathophysiology of a variety of diseases including inflammation and circulatory shock. This enhanced formation of NO is due mainly to the induction of the inducible NO synthase isoform (iNOS). The vasodilator NO is produced by the endothelial NO synthase (eNOS). Constitutively expressed eNOS inhibitors are able to elicit vascular disorders such as hypertension or atherosclerosis. The inflammation-associated iNOS inhibitors show beneficial effects for chronic inflammation, circulatory shock and diabetes. Objective and Methods: We examined the S-substituted isothioureas, S-methylisothiourea (MITU), S-(2-aminoethyl)isothiourea (AEITU), S-ethylisothiourea (EITU) and S-isopropylisothiourea (IPPITU) under vasodilation to acetylcholine (ACh) or vasoconstriction to norepinephrine (NE) in thoracic aortas obtained from normal rats (as an indicator of eNOS activity) and on NE vasoconstriction in endothelium-denuded aortas obtained from rats treated with lipopolysaccharide (LPS) for 4 h (as an indicator of iNOS activity). Results: MITU and EITU are 3-5 times less potent than Nω-nitro--arginine methyl ester (L--NAME in inhibiting eNOS activity in these tissues. AEITU is almost equipotent with NG-methyl-arginine (L-NMA) and is 34 times less potent than L-NAME in inhibiting eNOS activity in vitro. A comparison of the potencies of these compounds on iNOS activity in the endothelium-denuded aortas of LPS-treated rats shows that EITU, IPPITU and MITU are 4-12 times more potent than L-NAME, while AEITU is equipotent to L-NMA in inhibiting iNOS activity in vitro. In addition, the EC50 ratio of eNOS/iNOSin S-substituted isothioureas is in the following order: EITU > MITU > AEITU > L-NMA > IPPITU > L-NAME. Conclusions: Our functional analysis of the S-substituted isothioureas in selectivity for NOS in blood vessels shows that IPPITU is a potent inhibitor of eNOS and iNOS with little selectivity towards either form (like L-NMA), while others (EITU > MITU > AEITU) are relatively selective inhibitors of iNOS activity. Thus, EITU may be useful as therapy for diseases that are associated with an enhanced formation of NO due to iNOS induction, e.g. inflammation, circulatory shock or diabetes. |
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