Physiologic consequences of vasopeptidase inhibition in humans: effect of sodium intake.
The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.
Azizi
Michel
M
Clinical Investigation Center 9201, Assistance Publique des Hôpitaux de Paris/INSERM, Hôpital Européen Georges Pompidou, Paris, France. micel.azizi@egp.ap-hop-paris.fr
Lamarre-Cliche
Maxime
M
Labatide-Alanore
Agnès
A
Bissery
Alvine
A
Guyene
Than Tam
TT
Ménard
Joël
J
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000097:blood; D016232:Endothelins / Q000097:blood; D017328:Fosinopril / Q000494:pharmacology; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000652:urine; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000097:blood; D011725:Pyridines / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D011725:Pyridines; D012982:Sodium, Dietary; D013841:Thiazepines; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin; C058504:goralatide; D017328:Fosinopril