PULMONARY AND RENAL NEUTRAL ENDOPEPTIDASE IN CONGESTIVE HEART FAILURE

充血性心力衰竭（CHF）是一种病理状态， 钠潴留和水肿形成。 的确切机制 CHF中钠重吸收过度的基础尚未被证实， 明确了 有几种机制与此有关， 血管紧张素醛固酮系统，交感神经系统和减弱 心房钠尿肽（ANP），一种重要的激素， 调节钠和水的体内平衡。 中性内肽酶（NEP）， 是一种广泛分布的酶，主要存在于肾脏中， 参与ANP等相关肽的降解。 我们研究了：1）NEP抑制剂（NEP-Ⅰ）治疗前和治疗后对肾脏的影响。 在通过建立下腔静脉瘘（ACF）诱导CHF后， 2）NEP的表达、浓度和活性 在代偿性心绞痛大鼠肺、肾组织中， 分解了CHF 在对照大鼠中，NEP-I（40mg/kg，推注，i.v.）导致尿量增加 输出（UV）以及绝对钠（UNaV）和分数钠（FENa） 排泄 将相同剂量的NEP-I输注到代偿性 CHF引起显著的尿钠排泄和利尿，而在 在失代偿性CHF中，肾反应明显减弱。 定量逆转录-聚合酶链反应（RT-PCR，21 循环）和Western印迹分析，使用针对 NEP-显示NEP-mRNA和免疫反应性水平显着升高 失代偿大鼠肺中的含量低于代偿和 对照组大鼠。 这些结果得到了NEP可视化的进一步支持 活性使用SDS聚丙烯酰胺凝胶与明胶共聚 （活性凝胶）。 这些结果表明：1）NEP-I可能是一种有效的治疗药物， 在轻度但不严重的CHF病例中使用。 2)肾脏NEP活性为 不受严重心力衰竭的影响，而肺NEP活性 严重CHF降低，最有可能作为代偿性适应 保留ANP。 3)CHF患者对ANP的反应迟钝不是由于 内源性肾NEP的变化。

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.