Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by S21402 (RB105) in rats with experimental myocardial infarction.
The vasoconstrictor angiotensin II and atrial natriuretic peptide (ANP) are oppositely involved in the development of heart failure, as modeled by myocardial infarction (MI) in rats. MI is a model also characterized by sodium retention despite the elevated plasma ANP levels, showing a desensitization of responses to ANP. S21402 (RB105) {N-[2S,3R-(2-mercaptom-ethyl-1-oxo-3-phenylbutyl) L-alanine]} is a dual inhibitor that inhibits both neutral endopeptidase (Ki = 1.7 +/- 0.3 nM) and angiotensin-converting enzyme (Ki = 4.2 +/- 0.5 nM). Inhibition of neutral endopeptidase protects endogenous ANP, and inhibition of angiotensin-converting enzyme blocks angiotensin II production, whereas inhibition of both peptidases is required to protect endogenous bradykinin (BK). Induction of MI in rats, by ligation of the left coronary artery, increased the base-line plasma ANP, cyclic GMP (cGMP) and renin concentrations, which were related to the degree of MI (moderate and severe MI rats). Urinary excretion of ANP, cGMP and BK was also increased in MI rats and was linked to the infarction size. S21402 (RB105) (25 mg/kg bolus plus 25 mg/kg/hr i.v.) decreased the mean blood pressure and increased natriuresis in MI rats whatever the degree of MI. S21402 (RB105) induced an increase in plasma renin in MI rats despite the elevated base-line levels. S21402 (RB105) did not alter the plasma in ANP in MI rats. However, plasma cGMP was increased by the dual inhibitor, as a function of the infarction severity. Urinary excretion of ANP, cGMP and BK was also increased by S21402 (RB105), proportionally to the infarction size. Whatever the degree of MI, S21402 (RB105) was able to induce natriuresis, characterized by a desensitization of ANP-induced renal responses. Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by potentiating endogenous ANP and BK and blocking angiotensin II production could be an interesting therapeutic approach in heart failure.
Gonzalez
W
W
U367 Institut National de la Santé et de la Recherche Médicale, Paris, France.
Beslot
F
F
Laboulandine
I
I
Fournié-Zaluski
M C
MC
Roques
B P
BP
Michel
J B
JB
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015260:Neprilysin / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; C086898:N-(2-(mercaptomethyl)-3-phenylbutanoyl)-L-alanine; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D000409:Alanine