Long-term treatment with neutral endopeptidase inhibitor improves cardiac function and reduces natriuretic peptides in rats with chronic heart failure.
OBJECTIVE
Increased secretion of atrial and brain natriuretic peptide (ANP and BNP) from hearts is known to exhibit favorable effects in patients and animals with heart failure, and inhibition of neutral endopeptidase (NEP), an enzyme that degrades ANP and BNP, may further increase these peptide levels. However, it is still unknown whether such elevation of the ANP and BNP may offer a therapeutic benefit to the progression of chronic heart failure (CHF). We examined the effects of ONO-9902, a novel NEP inhibitor, on changes in hemodynamic parameters, NEP activity and neurohumoral factors in rats with CHF induced by left coronary artery ligation (CAL).


METHODS
Male Wistar rats (220-240 g) were subjected to induction of acute myocardial infarction by CAL. Rats were orally treated with ONO-9902 (300 mg/kg/day) from the 1st to 6th week after the operation. Hemodynamic and/or biochemical assessments were performed at the 1st and 6th weeks after the operation.


RESULTS
A single administration of ONO-9902 inhibited the plasma and kidney NEP activities and thereby further augmented the elevation of plasma ANP concentration in rats with CAL at the 1st week after the operation. In rats with CAL at the 6th week after the operation, the left ventricular end-diastolic pressure (LVEDP) increased and cardiac output index (COI) decreased as compared with those of sham-operated rats. These changes were accompanied by marked increases in the plasma ANP, BNP and endothelin-1 (ET-1). Chronic treatment with ONO-9902 attenuated the increase in LVEDP and the decrease in COI. These changes were associated with a decrease in plasma ANP, BNP and ET-1 concentrations.


CONCLUSIONS
The results suggest that chronic treatment with NEP inhibitor improves depressed cardiac function in rats with CHF. ONO-9902 may offer a new and possible therapeutic approach in patients with CHF.
Maki
T
T
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, 192-0392, Tokyo, Japan.
Nasa
Y
Y
Yamaguchi
F
F
Yoshida
H
H
Mori
M
M
Takada
T
T
Horikawa
E
E
Okano
K
K
Takeo
S
S
D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000378:metabolism; D004745:Enkephalins; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018712:Analgesics, Non-Narcotic; D019332:Endothelin-1; D004745:Enkephalins; D004791:Enzyme Inhibitors; C104138:ONO 9902; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D015260:Neprilysin