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 converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these 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 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease 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 levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.
Campbell
D J
DJ
St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Anastasopoulos
F
F
Duncan
A M
AM
James
G M
GM
Kladis
A
A
Briscoe
T A
TA
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000808:Angiotensinogen / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D004231:Diuresis; D004573:Electrolytes / Q000652:urine; D006321:Heart / Q000187:drug effects; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D004573:Electrolytes; D011480:Protease Inhibitors; D000808:Angiotensinogen; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin; D006152:Cyclic GMP; D001920:Bradykinin