Inhibition of the Metabolism of Atrial Natriuretic Factor Causes Diuresis and Natriuresis in Chronic Heart Failure

Abstract

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.

Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

“…Many inhi bitors of NEP have been developed. They increase the endogenous ANP plasma level in normal volunteers and in experimental animals (218-221), or in congestive heart failure models (222,223) and in cirrhotic patients with ascites (224), in association with an increase in urine volume and mean urinary sodium excretion. NEP does not contribute to the kinin hydrolysis in plasma (225).…”

Omapatrilat: Neurohormonal and Pharmacodynamic Profile When Administered with Furosemide

“…15 Currently, however, no strong clinical evidence supports a role for selective NEP inhibitors alone in the treatment of heart failure. Positive hemodynamic effects have usually been limited to a modest decrease in right atrial and pulmonary capillary wedge pressure, [16][17][18] sometimes with a transient increase in cardiac index, 18 but with no improvement in arterial pressure, heart rate, or total peripheral resistance. [16][17][18] In animal studies, however, when selective NEP inhibitors were administered with ACE inhibitors, there were additional hemodynamic and renal benefits compared with those achieved with either alone.…”

Effect of Chronic Neutral Endopeptidase Inhibition on Cardiac Hypertrophy after Experimental Myocardial Infarction

“…Neutral endopeptidase (NEP) is a major ANP-degrading enzyme, [9][10][11] and a new therapeutic approach has been developed by inhibiting the enzyme and potentiating the effects of endogenous ANP. [12][13][14][15] Beneficial acute hemodynamic and renal effects of (±)-candoxatrilat (UK69578), an NEP inhibitor, have been reported in patients with congestive heart failure. 12,13 Furthermore, reports about the effects of NEP inhibitors on cardiovascular remodeling have been published recently.…”

“…[12][13][14][15] Beneficial acute hemodynamic and renal effects of (±)-candoxatrilat (UK69578), an NEP inhibitor, have been reported in patients with congestive heart failure. 12,13 Furthermore, reports about the effects of NEP inhibitors on cardiovascular remodeling have been published recently. 16,17 In patients with myocardial infarction, progressive left ventricular dilatation begins soon after myocardial infarction 18 and left ventricular volume is the most powerful predictor of prognosis.…”

“…Candoxatril is an orally active indanyl ester prodrug of the compound candoxatrilat (UK73967), the active isomer of the racemic mixture known as (±)-candoxatrilat (UK69578). 12,13 …”