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(Circulation. 1995;91:2036-2042.)
© 1995 American Heart Association, Inc.

Articles

The Role of Neutral Endopeptidase in Dogs With Evolving Congestive Heart Failure

Kenneth B. Margulies, MD; Paul L. Barclay, PhD; John C. Burnett, Jr, MD

From the Section of Cardiology (K.B.M.), Temple University School of Medicine, Philadelphia, Pa; Pfizer Central Research (P.L.B.), Sandwich, England; and the Department of Internal Medicine (J.C.B.), Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Kenneth B. Margulies, MD, Assistant Professor of Medicine, Room 318, OMS Bldg, Temple University School of Medicine, 3401 N Broad St, Philadelphia, PA 19140.

Background Recent studies suggest that neurohumoral mechanisms including decreased renal responses to increases in atrial natriuretic factor (ANF) play a central role in the progression from asymptomatic cardiac dysfunction to advanced congestive heart failure (CHF) with sodium retention, vasoconstriction, and reduced exercise tolerance. Recognizing that neutral endopeptidase 24.11 degrades ANF and may be enhanced in CHF, we hypothesized that chronic neutral endopeptidase inhibition (NEP-I) would potentiate renal responses to exogenous ANF and alter the temporal evolution of sodium retention in evolving CHF by potentiation of increased endogenous ANF.

Methods and Results We studied 13 conscious dogs with evolving CHF produced by rapid ventricular pacing at 250 beats per minute. Six of these dogs received NEP-I with candoxatril, 10 mg/kg PO BID, throughout evolving CHF. Responses to exogenous ANF, 10 µg/kg IV bolus, were assessed at baseline and after 6 days of CHF. Daily metabolic studies during evolving CHF with chronic NEP-I showed increased sodium excretion and renal cGMP generation consistent with enhanced renal activity of endogenous ANF compared with untreated controls. In addition, renal natriuretic and cGMP responses to exogenous ANF were intact in CHF with chronic NEP-I in contrast to markedly attenuated renal responses to exogenous ANF in untreated CHF. Despite enhanced ANF responsiveness and improved sodium balance in evolving CHF, a moderate degree of sodium retention was observed during chronic NEP-I in evolving CHF.

Conclusions Enzymatic degradation by neutral endopeptidase limits local renal responses to increases in endogenous and exogenous ANF in CHF independent of changes in systemic hemodynamics or augmented plasma concentrations of ANF. The moderate sodium retention observed during evolving CHF despite chronic NEP-I probably reflects the antinatriuretic effects of hemodynamic and humoral factors independent of ANF activity.

Key Words: heart failure • natriuretic peptides • sodium • atrial natriuretic factor

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