title: Effects of renal neutral endopeptidase inhibition on sodium excretion, renal hemodynamics and neurohormonal activation in patients with congestive heart failure.
abstract: We investigated the effects of inhibiting endogenous atrial natriuretic factor (ANF) metabolism on renal hemodynamics, sodium excretion and neurohormones in 12 patients with New York Heart Association functional class II congestive heart failure (CHF) due to left ventricular systolic dysfunction. In a randomized, placebo-controlled, double-blinded fashion, 8 patients received a single oral dose of candoxatril, an inhibitor of renal neutral endopeptidase, and 4 patients received placebo. Candoxatril treatment increased plasma ANF by 70 +/- 71 pg/ml (p < 0.015 vs. placebo) and plasma cGMP by 7.9 +/- 2.7 pmol/ml (p < 0.001 vs. placebo), with maximal effects at 3.5 h. Urinary cGMP more than doubled (p = 0.025 vs. placebo). Candoxatril increased urinary sodium by 2.7 +/- 2.0 mEq/h (p < 0.05 vs. placebo) and significantly elevated filtration fraction with no significant effect on glomerular filtration rate, renal plasma flow or lithium clearance. A significant reduction in aldosterone concentration with a similar trend in plasma renin activity was noted in candoxatril-treated patients. Thus in patients with moderate heart failure, renal neutral endopeptidase inhibition increases urinary sodium excretion. The lack of an effect on renal hemodynamics suggests that this natriuresis results from ANF-mediated inhibition of tubular sodium reabsorption. These findings justify additional investigation into potential clinical benefit of endopeptidase inhibition in patients with CHF.
authors.affiliation: Department of Medicine, Tufts University School of Medicine, New England Medical Center Hospital, Boston, Mass., USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Kimmelstiel
authors.forename: R
authors.initials: R
authors.lastname: Perrone
authors.forename: L
authors.initials: L
authors.lastname: Kilcoyne
authors.forename: J
authors.initials: J
authors.lastname: Souhrada
authors.forename: J
authors.initials: J
authors.lastname: Udelson
authors.forename: J
authors.initials: J
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: de Bold
authors.forename: J
authors.initials: J
authors.lastname: Griffith
authors.forename: M A
authors.initials: MA
authors.lastname: Konstam
mesh_terms: D000328:Adult; D000368:Aged; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000187:drug effects*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004311:Double-Blind Method; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011188:Potassium / Q000652:urine; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012964:Sodium / Q000652:urine
chemical_list: D007189:Indans; D011422:Propionates; D011480:Protease Inhibitors; D009320:Atrial Natriuretic Factor; D012964:Sodium; C062766:candoxatril; D017869:Cyclic GMP-Dependent Protein Kinases; D015260:Neprilysin; D011188:Potassium