Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase, in healthy subjects with hypovolemia.
OBJECTIVE
To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia.


METHODS
Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration.


RESULTS
The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05).


CONCLUSIONS
In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.
Chodjania
Yasmina
Y
Department of Pharmacology, Saint-Antoine Hospital, Assistance Publique-Hopitaux de Paris, France.
Tharaux
Pierre-Louis
PL
Ragueneau
Isabelle
I
Dussaule
Jean-Claude
JC
Picker
Jean-Luc
JL
Funck-Brentano
Christian
C
Jaillon
Patrice
P
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D020896:Hypovolemia / Q000097:blood / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D011422:Propionates / Q000494:pharmacology*; D012016:Reference Values; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006728:Hormones; D011422:Propionates; C111219:S 21402-1; D013438:Sulfhydryl Compounds