The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n=5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially-30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n=5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p

Studies were performed in anesthetized dogs to determine plasma endothelin (ET) concentrations in the presence and absence of experimental congestive heart failure (CHF) produced by rapid ventricular pacing for 8 days. These studies were also designed to determine the effect of exogenous low-dose ET upon integrated cardiorenal and endocrine function in the presence and absence of CHF. In these studies, plasma ET was significantly elevated in CHF (3.25 +/- 0.39 pg/ml) compared with normal (1.03 +/- 0.21 pg/ml) or sham-operated (1.08 +/- 0.27 pg/ml) groups. Compared with the control group, which was characterized by a significant cardiorenal vasoconstrictor response to low-dose ET, a significant attenuation of the vasoconstrictor and antinatriuretic actions of ET was observed in the CHF group. Despite these differential responses, exogenous ET suppressed plasma renin activity (PRA) and activated aldosterone in both control and CHF groups. Thus these studies demonstrate for the first time that experimental CHF is characterized by elevated plasma ET in association with an attenuated cardiorenal response to exogenous ET. In contrast, low-dose ET inhibited PRC and activated aldosterone in the presence and absence of experimental CHF.

Cine nuclear magnetic resonance (NMR) imaging was used to serially measure cardiovascular function in 17 patients with New York Heart Association class II or III heart failure and left ventricular ejection fraction less than or equal to 45% who were treated for 3 months with benazepril hydrochloride, a new angiotensin-converting enzyme inhibitor, while continuing treatment with diuretic agents and digoxin. Interobserver reproducibilities for ejection fraction (r = 0.94, SEE 3.3%), end-systolic volume (r = 0.98, SEE 10.6 ml), end-diastolic volume (r = 0.99, SEE 8.29 ml), end-systolic mass (r = 0.96, SEE 15.4 g), end-systolic wall stress (r = 0.91, SEE 10 dynes.s.cm-5) and end-systolic stress/volume ratio (r = 0.85, SEE 0.13) demonstrated applicability of cine NMR imaging for the serial assessment of cardiovascular function in response to pharmacologic interventions in patients with heart failure. During 12 weeks of treatment with benazepril, ejection fraction increased progressively from 29.7 +/- 2.2% (mean +/- SEM) to 36 +/- 2.2% (p less than 0.05), end-diastolic volume decreased from 166 +/- 14 to 158 +/- 12 ml (p = NS), end-systolic volume decreased from 118 +/- 12 to 106 +/- 11 ml (p less than 0.05), left ventricular mass decreased from 235 +/- 13 to 220 +/- 12 g (p less than 0.05), end-systolic wall stress decreased 29% from 90 +/- 5 to 64 +/- 5 dynes.s.cm-5 (p less than 0.05), end-systolic pressure decreased from 92.6 +/- 3.7 to 78.8 +/- 5.3 (p less than 0.05) and end-systolic stress/volume ratio, a load-independent index of contractility, decreased from 0.83 +/- 0.05 to 0.67 +/- 0.06 (p less than 0.05), demonstrating that improved ejection fraction is due to afterload reduction.

Atrial natriuretic factor (ANF) is degraded by neutral endopeptidase. We hypothesized that neutral endopeptidase inhibition (NEP-I) increases sodium excretion and that this effect would be potentiated in the presence of an isolated increase in intrarenal ANF. In seven anesthetized dogs, ANF was infused into one renal artery to produce pathophysiologic concentrations in the supplemented kidney while the control kidney received physiologic circulating concentrations of ANF. In the control kidney, NEP-I (SQ 28,603) produced significant increases in urine flow, absolute sodium excretion and fractional sodium excretion while glomerular filtration rate (GFR) remained constant. These renal actions of NEP-I were associated with marked increases in urinary excretion of ANF and cyclic GMP consistent with decreased renal degradation and increased biologic activity of ANF. All of these effects were significantly greater in the supplemented kidney. The present study suggests that NEP-I produces natriuresis which appears to be independent of changes in GFR. In addition, while NEP-I mimics the renal action of pathophysiologic levels of ANF, NEP-I also potentiates the natriuretic effects of pathophysiologic concentrations of ANF as observed in congestive heart failure or hypertension.