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Renal and vascular effects of S21402, a dual inhibitor of angiotensin‐converting enzyme and neutral endopeptidase, in healthy subjects with hypovolemia
Author(s) -
Chodjania Yasmina,
Tharaux PierreLouis,
Ragueneau Isabelle,
Dussaule JeanClaude,
Picker JeanLuc,
FunckBrentano Christian,
Jaillon Patrice
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.124521
Subject(s) - captopril , endocrinology , medicine , blood pressure , hydrochlorothiazide , atrial natriuretic peptide , renin–angiotensin system , ace inhibitor , hypovolemia , diuretic , angiotensin converting enzyme , cyclic guanosine monophosphate , plasma renin activity , angiotensin ii , pharmacology , nitric oxide
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 [(2 S )‐2‐{(2 S ,3 R )‐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 ceptopril 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. Clinical Pharmacology & Therapeutics (2002) 71 , 468–478; doi: 10.1067/mcp.2002.124521