Effect of long-term therapy with fasidotril, a mixed inhibitor of neprilysin and angiotensin-converting enzyme (ACE), on survival of rats after myocardial infarction.
OBJECTIVE
Two hormonal systems with opposite effects are activated in congestive heart failure: the renin-angiotensin system that promotes vasoconstriction, cardiac hypertrophy and salt retention, and the atrial natriuretic factor (ANF), which has vasorelaxant and natriuretic effects. It could be of therapeutic interest to associate prevention of angiotensin II formation, by inhibition of angiotensin I-converting enzyme (ACE), with potentiation of the ANF effects, by inhibition of neprilysin (NEP).


METHODS
The effects of long-term therapy with fasidotril, a mixed NEP/ACE inhibitor, were assessed in rats submitted to coronary artery ligation. Twenty-four hours after ligation, 172 rats were assigned to either placebo or fasidotril therapy (180 mg/kg/day, orally) for 40 weeks. The date of spontaneous death was recorded, myocardial infarct size was determined and rats were classified as having small, moderate or large infarcts.


RESULTS
In rats with moderate infarcts, fasidotril prolonged survival, 50% of the control rats dying during the 40-week observation period compared with 30% of treated rats (P = 0.04, log-rank test)). In rats with large infarcts, mortality was significantly reduced during the initial 25 weeks of therapy, during which 23.5% of animals died compared to 53.8% in untreated rats (P = 0.015). Cardiac hypertrophy was significantly attenuated by fasidotril for the three infarct sizes. Plasma renin activity was not increased by therapy, which presumably reflected the inhibition of renal renin secretion by endogenous ANF. Fasidotril therapy had no significant effects on arterial blood pressure and heart rate.


CONCLUSIONS
In addition to its beneficial effects on survival and cardiac hypertrophy, the lack of hypotensive effect of fasidotril is of interest by reducing the risk of renal hypoperfusion and differentiates the mixed inhibitor from selective ACE inhibitors.
Marie
C
C
Laboratoire de Pharmacodynamie, Faculté de Pharmacie, Dijon, France.
Mossiat
C
C
Gros
C
C
Schwartz
J C
JC
Lecomte
J M
JM
Bralet
J
J
D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016009:Chi-Square Distribution; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D015260:Neprilysin / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D015996:Survival Rate; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; C097293:aladotril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin; D000409:Alanine