Effects of Renal Neutral Endopeptidase Inhibition on Sodium Excretion, Renal Hemodynamics and Neuro-hormonal 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 can-doxatril-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.

Beneficial Renal and Hemodynamic Effects of Omapatrilat in Mild and Severe Heart Failure

“…15,16 Although isolated ACE inhibition may produce transient, minor natriuresis in mild HF, 33 this is unlikely in severe HF, when GFR is low and often falls further with ACE inhibition. 15,20,34 These results are consistent with a recent study in mild HF that demonstrated augmentation of natriuresis by omapatrilat compared with pure ACE inhibitor (fosinoprilat). 18 In our study, despite significant hemodynamic changes and falling renal perfusion pressure, ERPF increased with omapatrilat, most markedly in mild HF.…”

“…While this pattern could be consistent with isolated ACE inhibition, the trend to improvement of GFR in severe HF is not an expected ACE inhibitor effect and presumably reflects neutral endopeptidase inhibition. 34 By contrast with these results, our previous studies in this severe HF model demonstrated a progressive decline in endogenous creatinine clearance with repeated doses of the ACE inhibitor captopril. 19 The beneficial renal hemodynamic effects of omapatrilat in this study may be mediated by local enhancement of ANP, BNP, or urodilatin levels within the kidney.…”

Combined Endopeptidase Inhibition and Adrenomedullin in Sheep With Experimental Heart Failure

“…16,17 In agreement with earlier studies, 1,13 ADM increased urinary cAMP and sodium excretion and more than maintained urinary output in the face of larger blood pressure reductions. In addition to any effects of NEP inhibition and ADM administration on tubular reabsorption and renal vascular resistance and increases in renal blood flow, 24 increased glomerular filtration (as assessed by increased creatinine clearance) appears to have contributed to the natriuretic effects observed with both treatments in the present study.…”

“…The hypotensive effect of ADM appears to be primarily due to a direct affect on arterial tone, 22 whereas the rise in CO presumably reflects a positive inotropic action 23 and the fall in cardiac afterload. Similar hemodynamic responses to separate ADM 1,13-15 and NEP inhibition 16,17 have previously been reported in HF. Combined treatment induced greater reductions in cardiac preload and afterload and increments in CO than during ADM infusion alone.…”

“…Similarly, augmentation of the natriuretic peptides, via exogenous administration and through prevention of enzymatic degradation by neutral endopeptidase (NEP), has proven to be favorable in the treatment of HF. 3,16,17 The present study was designed to test the hypothesis that combined administration of ADM and an NEP inhibitor will produce additional hemodynamic and renal benefits in HF beyond those achieved by either treatment separately.…”