The atriopeptidase inhibitor UK 69,578 increases atrial natriuretic factor and causes a natriuresis in normal humans.
The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.
Jardine
A G
AG
Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow, Scotland.
Connell
J M
JM
Northridge
D
D
Dilly
S G
SG
Cussans
N J
NJ
Davidson
G
G
Doyle
J
J
Leckie
B L
BL
Lever
A F
AF
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D009320:Atrial Natriuretic Factor / Q000097:blood*; D002219:Carbamates / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine
D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011422:Propionates; D000804:Angiotensin II; D000450:Aldosterone; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D012964:Sodium; D012083:Renin; D015260:Neprilysin