Hh. Chen et al., Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure, CIRCULATION, 100(24), 1999, pp. 2443-2448
Citations number
31
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is l
ocalized in the greatest abundance in the kidney and degrades natriuretic p
eptides, such as atrial natriuretic peptide (ANP). Mild congestive heart fa
ilure (CHF) is characterized by increases in circulating ANP without activa
tion of the renin-angiotensin-aldosterone system (RAAS) or sodium retention
. In contrast, severe CHF is characterized by sodium retention and coactiva
tion of both ANP and the RAAS.
Methods and Results-We defined the acute cardiorenal actions of the NEP inh
ibitor candoxatrilat (8 mu g.kg(-1).min(-1)) in 4 groups of anesthetized do
gs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chroni
c AT(1) receptor antagonism, n=5). Mild CHF was produced by rapid ventricul
ar 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 grea
test in response to acute NEP inhibition compared with the response in eith
er control animals or those with severe CHF. Furthermore, an increase in gl
omerular filtration rate was observed only in mild CHF in association with
increases in renal blood flow and decreases in renal vascular resistance an
d distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, marke
rs for renal biological actions of ANP, were greatest in mild CHF. The rena
l actions observed in mild CHF were attenuated in severe CHF and not restor
ed by chronic AT(1) receptor antagonism.
Conclusions-The results of the present study demonstrate that acute NEP inh
ibition in mild CHF results in marked increases in renal. hemodynamics and
sodium excretion that exceed that observed in control animals and severe CH
F. These studies underscore the potential therapeutic role for NEP inhibiti
on 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 acti
vated RAAS.