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 mode led by myocardial infarction (MI) in rats. MI is a model also characte rized by sodium retention despite the elevated plasma ANP levels, show ing 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 (K-i = 1.7 +/- 0.3 nM) and an giotensin-converting enzyme (K-i = 4.2 +/- 0.5 nM). Inhibition of neut ral endopeptidase protects endogenous ANP, and inhibition of angiotens in-converting enzyme blocks angiotensin II production, whereas inhibit ion of both peptidases is required to protect endogenous bradykinin (B K). Induction of MI in rats, by ligation of the left coronary artery, increased the base-line plasma ANP, cyclic GMP (cGMP) and renin concen trations, 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/k g bolus plus 25 mg/kg/hr i.v.) decreased the mean blood pressure and i ncreased natriuresis in MI rats what ever the degree of MI. S21402 (RB 105) induced an increase in plasma renin in MI rats despite the elevat ed base-line levels. S21402 (RB105) did not alter the plasma 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 an d BK was also increased by S21402 (RB105), proportionally to the infar ction size. Whatever the degree of MI, S21402 (RB105) was able to indu ce natriuresis, characterized by a desensitization of ANP-induced rena l responses. Inhibition of both angiotensin-converting enzyme and neut ral endopeptidase by potentiating endogenous ANP and BK and blocking a ngiotensin II production could be an interesting therapeutic approach in heart failure.