Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure.
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.
Northridge
D B
DB
Department of Cardiology, Western Infirmary, Glasgow, Scotland.
Jardine
A G
AG
Findlay
I N
IN
Archibald
M
M
Dilly
S G
SG
Dargie
H J
HJ
D000328:Adult; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000009:adverse effects / Q000627:therapeutic use; D002303:Cardiac Output, Low / Q000378:metabolism / Q000503:physiopathology*; D002908:Chronic Disease; D003509:Cyclohexanecarboxylic Acids; D004231:Diuresis / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011422:Propionates / Q000009:adverse effects / Q000627:therapeutic use; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine
D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011422:Propionates; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D012964:Sodium; D012083:Renin; D015260:Neprilysin