Kugiyama K, Sugiyama S, Matsumura T, Ohta Y, Doi H, Yasue H
Division of Cardiology, Kumamoto University School of Medicine, Japan.
Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):1080-7. doi: 10.1161/01.atv.16.8.1080.
Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.
中性内肽酶24.11（NEP）广泛分布于体内，可水解并使多种内源性血管活性肽失活，其中一些肽可改变动脉壁中细胞的各种功能。最近发现NEP存在于血管内皮中。本研究的目的是评估通过每日给予UK79300（坎多沙坦）（一种口服活性NEP抑制剂（NEPI））对高胆固醇喂养兔子动脉粥样硬化病变发展的慢性NEP抑制作用。雄性新西兰白兔按以下方式喂养8周：正常兔饲料（正常组，n = 15）、1.5%胆固醇饲料（胆固醇组，n = 15）或含NEPI（20 mg·kg-1·d-1）的1.5%胆固醇饲料（胆固醇+NEPI组，n = 15）。在饮食期结束时，发现NEPI治疗可抑制斑块覆盖的主动脉表面积（表面积百分比：胆固醇组为59±6，胆固醇+NEPI组为36±7，P <.01），并降低主动脉中胆固醇和胆固醇酯的含量。NEPI还使血浆总胆固醇比胆固醇组兔子降低了27%（1781±130 mg/dL）。与胆固醇组兔子相比，通过分离的主动脉对乙酰胆碱的内皮依赖性舒张来评估的内皮功能在胆固醇+NEPI组兔子中得以保留。胆固醇组兔子血浆和主动脉匀浆颗粒部分中的NEP酶活性分别比正常组兔子增加了3.1倍和3.9倍，但胆固醇+NEPI组兔子中的活性显著低于胆固醇组兔子。UK73967（UK79300的活性形式）或磷酰胺部分逆转了胆固醇组兔子分离的胸主动脉环对外源性添加的C型利钠肽（CNP）和P物质（已知在内皮中内源性存在的NEP底物）反应的动脉粥样硬化性舒张功能损害。结果表明NEP活性增加在动脉粥样硬化形成中起重要作用，并且NEPI可能在预防动脉粥样硬化方面具有治疗用途。血浆胆固醇的降低以及内源性释放的CNP、P物质或可能具有抗动脉粥样硬化作用的其他激肽在动脉中的降解抑制可能至少部分有助于NEPI对动脉粥样硬化病变的抑制作用。
