PULMONARY AND RENAL NEUTRAL ENDOPEPTIDASE IN CONGESTIVE HEART FAILURE

充血性心力衰竭(CHF)是一种病理状态 通过贪婪的钠滞留和浮肿的形成。确切的机制是 充血性心力衰竭钠重吸收夸大的背后并不是 澄清了。包括肾素在内的几种机制已经被牵连。 血管紧张素-醛固酮系统、交感神经系统和减肥药 心房利钠肽(ANP)是一种重要的心血管激素 钠水动态平衡的调节。中性内肽酶(NEP)， 是一种广泛分布的酶，主要存在于肾脏和 肺，并参与心钠素和其他相关多肽的降解。 我们研究了1)NEP抑制剂(NEP-I)对肾脏的影响 建立腹主动脉腔内瘘(ACF)诱发CHF后 2)NEP关键酶的表达、浓度和活性 代偿期大鼠肺、肾组织中ANP的降解 并分解了CHF。 对照组大鼠静脉注射NEP-I(40 mg/kg)。导致尿量增加 输出(UV)、绝对钠(UNaV)和部分钠(FeNa) 排泄物。等剂量NEP-I在代偿性脑损伤大鼠体内的应用 充血性心力衰竭引起显著的利钠和利尿作用，而在 失代偿性充血性心力衰竭时，肾脏反应明显减弱。 定量逆转录聚合酶链式反应(RT-PCR，21 周期)和免疫印迹分析使用多克隆抗体 NEP-显示NEP-mRNA和免疫反应水平显著 失代偿期大鼠肺组织低于代偿期和失代偿期 控制老鼠。这些结果进一步得到了NEP可视化的支持 明胶与十二烷基硫酸钠共聚聚丙烯酰胺凝胶的活性 (活性凝胶)。 这些发现表明：1)NEP-I可能是一种有效的治疗方法 该药适用于轻度但不严重的CHF病例。2)肾脏NEP活性为 不受严重心力衰竭的影响，而肺NEP活动 由于严重的心力衰竭而减少，很可能是对 保留ANP。3)CHF患者对ANP的迟钝反应不是由于 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.