EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION AND COMBINED ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE INHIBITION ON ANGIOTENSIN AND BRADYKININ PEPTIDES IN RATS

The combination of neutral endopeptidase 24.11 (NEP) and angiotensin c onverting enzyme (ACE) inhibition is a candidate therapy for hypertens ion and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NE P inhibition and combined NEP and ACE inhibition on the levels of thes e peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10 , 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 day s. Ecadotril produced diuresis, natriuresis, increased urine cyclic gu anosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril red uced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation o f these effects of separate NEP and ACE inhibition. in addition, perin dopril potentiated the ecadotril-mediated diuresis, natriuresis and de crease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II le vels in plasma and lung. These data indicate that summation of the eff ects of separate NEP and ACE inhibition provides the basis for the the rapeutic efficacy of their combination. Whereas potentiation by perind opril of the diuretic and natriuretic effects of ecadotril may contrib ute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibi tion.