轻度和重度实验性心力衰竭时肾脏对急性中性内肽酶抑制的反应

Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure.

作者信息

Chen H H, Schirger J A, Chau W L, Jougasaki M, Lisy O, Redfield M M, Barclay P T, Burnett J C

机构信息

Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.

出版信息

Circulation. 1999 Dec 14;100(24):2443-8. doi: 10.1161/01.cir.100.24.2443.

DOI:10.1161/01.cir.100.24.2443

PMID:10595958

Abstract

BACKGROUND

Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS.

METHODS AND RESULTS

We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 microg. kg(-1). min(-1)) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT(1) receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT(1) receptor antagonism.

CONCLUSIONS

The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

摘要

背景

中性内肽酶24.11（NEP）是一种金属蛋白酶，在肾脏中含量最为丰富，可降解利钠肽，如心房利钠肽（ANP）。轻度充血性心力衰竭（CHF）的特征是循环中ANP增加，但肾素-血管紧张素-醛固酮系统（RAAS）未激活且无钠潴留。相比之下，重度CHF的特征是钠潴留以及ANP和RAAS的共同激活。

方法与结果

我们在4组麻醉犬中定义了NEP抑制剂坎多沙坦酯（8微克·千克-1·分钟-1）的急性心肾作用（正常组，n = 8；轻度CHF组，n = 6；重度CHF组，n = 5；重度CHF伴慢性AT1受体拮抗组，n = 5）。轻度CHF通过以180次/分钟的频率快速心室起搏10天产生，重度CHF通过以245次/分钟的频率快速心室起搏10天产生。在轻度CHF中，与对照动物或重度CHF动物相比，急性NEP抑制后尿钠排泄和肾小球滤过率最高。此外，仅在轻度CHF中观察到肾小球滤过率增加，同时伴有肾血流量增加、肾血管阻力降低和远端肾小管钠重吸收减少。尿ANP和cGMP排泄是ANP肾脏生物学作用的标志物，在轻度CHF中最高。在轻度CHF中观察到的肾脏作用在重度CHF中减弱，且慢性AT1受体拮抗不能恢复。