PULMONARY AND RENAL NEUTRAL ENDOPEPTIDASE IN CONGESTIVE HEART FAILURE

充血性心力衰竭中的肺和肾中性内肽酶

• 批准号: 3757677
• 负责人: Z ABASSI
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3757677
• 关键词: SDS polyacrylamide gel electrophoresis; atrial natriuretic peptide; congestive heart failure; disease /disorder model; endopeptidases; heart disorder chemotherapy; kidney; laboratory rat; lung; polymerase chain reaction; protease inhibitor; sodium; western blottings

Congestive heart failure (CHF) is a pathological condition characterized by avid sodium retention and edema formation. The exact mechanism underlying the exaggerated sodium reabsorption in CHF has not been clarified. Several mechanisms have been implicated including the renin angiotensin aldosterone system, sympathetic nervous system and attenuated response to atrial natriuretic peptide (ANP), an important hormone in the regulation of sodium and water homeostasis. Neutral endopeptidase (NEP), is a widely distributed enzyme, found predominantly in the kidneys and lungs, and involved in the degradation of ANP and other related peptides. We investigated 1) The renal effects of NEP inhibitor (NEP-I) before and after the induction of CHF by creation of an aortocaval fistula (ACF) in rats; 2) The expression, concentration and activity of NEP, a key enzyme in the degradation of ANP, in lungs and kidneys of rats with compensated and decomposed CHF. In control rats, NEP-I (40 mg/kg, bolus, i.v.) caused increases in urine output (UV), and both absolute (UNaV) and fractional (FENa) sodium excretion. Infusion of the same dose of NEP-I into rats with compensated CHF induced remarkable natriuresis and diuresis, whereas in rats with decompensated CHF the renal responses were markedly blunted. Quantitative reverse transcription-polymerase chain reaction (RT-PCR, 21 cycles) and Western blot analysis using polyclonal antibodies against NEP-revealed that NEP-mRNA and immunoreactivity levels were significantly lower in lungs of decompensated rats than in those of compensated and control rats. These results were further supported by visualizing NEP activity using SDS polyacrylamide gel co-polymerized with gelatin (activity gel). These findings indicate that: 1) NEP-I may be a fruitful therapeutic agent in mild, but not severe cases of CHF. 2) Renal NEP activity is not affected by severe heart failure, whereas pulmonary NEP activity is reduced by severe CHF, most likely as a compensatory adaptation to preserve ANP. 3) The blunted response to ANP in CHF is not due to changes in endogenous renal NEP.

充血性心力衰竭（CHF）是一种病理状态，其特征是 由于强烈的钠潴留和水肿形成。 确切的机制 CHF 中钠重吸收过度的潜在原因尚未得到证实 澄清。 涉及多种机制，包括肾素 血管紧张素醛固酮系统、交感神经系统和弱化 对心房钠尿肽（ANP）的反应，心房钠肽是一种重要的激素 钠和水稳态的调节。 中性肽链内切酶（NEP）， 是一种分布广泛的酶，主要存在于肾脏和 肺，并参与 ANP 和其他相关肽的降解。 我们研究了 1) NEP 抑制剂 (NEP-I) 之前和之后的肾脏影响 通过创建主动脉腔静脉瘘 (ACF) 诱发 CHF 后 老鼠； 2）关键酶NEP的表达量、浓度和活性 代偿大鼠肺和肾中 ANP 的降解 并分解CHF。 在对照大鼠中，NEP-I（40 mg/kg，推注，静脉注射）导致尿液增加 输出 (UV)、绝对钠 (UNaV) 和分数 (FENa) 钠 排泄。 代偿大鼠输注相同剂量的NEP-I CHF 引起显着的尿钠排泄和利尿，而在患有 CHF 的大鼠中 失代偿性 CHF 的肾脏反应明显减弱。 定量逆转录聚合酶链反应（RT-PCR，21 循环）和使用多克隆抗体进行蛋白质印迹分析 NEP-显示 NEP-mRNA 和免疫反应水平显着 失代偿大鼠的肺中的氧含量低于代偿大鼠和代偿大鼠的肺 控制老鼠。 NEP 可视化进一步支持了这些结果 使用与明胶共聚的 SDS 聚丙烯酰胺凝胶进行活性 （活性凝胶）。 这些发现表明：1) NEP-I 可能是一种卓有成效的治疗方法 适用于轻度CHF病例，但不适用于严重CHF病例。 2) 肾脏 NEP 活性为 不受严重心力衰竭的影响，而肺 NEP 活性则受到影响 因严重的 CHF 而减少，很可能是一种补偿性适应 保留 ANP。 3) CHF 患者对 ANP 的反应迟缓并非由于 内源性肾 NEP 的变化。