Effect of long-term therapy with fasidotril, a mixed inhibitor of neprilysin and angiotensin-converting enzyme (ACE), on survival of rats after myocardial infarction

被引:16
作者
Marie, C [1 ]
Mossiat, C
Gros, C
Schwartz, JC
Lecomte, JM
Bralet, J
机构
[1] Fac Pharm, Lab Pharmacodynam, F-21033 Dijon, France
[2] Ctr Paul Broca, INSERM, U109, Unite Neurobiol & Pharmacol, Paris, France
[3] Lab Bioprojet, Paris, France
关键词
myocardial infarction; angiotensin-converting enzyme; neprilysin; fasidotril; rat;
D O I
10.1016/S0008-6363(98)00257-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Conclusion: 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. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:544 / 553
页数:10
相关论文
共 68 条
  • [41] ANGIOTENSIN INHIBITION POTENTIATES THE RENAL RESPONSES TO NEUTRAL ENDOPEPTIDASE INHIBITION IN DOGS WITH CONGESTIVE-HEART-FAILURE
    MARGULIES, KB
    PERRELLA, MA
    MCKINLEY, LJ
    BURNETT, JC
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1991, 88 (05) : 1636 - 1642
  • [42] Effect of prolonged inhibition of neutral endopeptidase on cardiac hypertrophy in rats with myocardial infarction
    Marie, C
    Mossiat, C
    Gros, C
    Monteil, T
    Bralet, J
    [J]. CARDIOVASCULAR DRUGS AND THERAPY, 1996, 10 (05) : 593 - 598
  • [43] Marie C, 1995, J PHARMACOL EXP THER, V275, P1324
  • [44] MODULATION OF THE NATRIURETIC RESPONSE TO ATRIAL-NATRIURETIC-PEPTIDE BY ALTERATIONS IN PERITUBULAR STARLING FORCES IN THE RAT
    MENDEZ, RE
    DUNN, BR
    TROY, JL
    BRENNER, BM
    [J]. CIRCULATION RESEARCH, 1986, 59 (06) : 605 - 611
  • [45] HORMONAL AND CARDIAC EFFECTS OF CONVERTING ENZYME-INHIBITION IN RAT MYOCARDIAL-INFARCTION
    MICHEL, JB
    LATTION, AL
    SALZMANN, JL
    CEROL, MD
    PHILIPPE, M
    CAMILLERI, JP
    CORVOL, P
    [J]. CIRCULATION RESEARCH, 1988, 62 (04) : 641 - 650
  • [46] THE NEUTRAL ENDOPEPTIDASE INHIBITOR, SCH-34826, REDUCES LEFT-VENTRICULAR HYPERTROPHY IN SPONTANEOUSLY HYPERTENSIVE RATS
    MONOPOLI, A
    ONGINI, E
    CIGOLA, E
    OLIVETTI, G
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1992, 20 (03) : 496 - 504
  • [47] NEUROHORMONAL INHIBITION AND HEMODYNAMIC UNLOADING DURING PROLONGED INHIBITION OF ANF DEGRADATION IN PATIENTS WITH SEVERE CHRONIC HEART-FAILURE
    MUNZEL, T
    KURZ, S
    HOLTZ, J
    BUSSE, R
    STEINHAUER, H
    JUST, H
    DREXLER, H
    [J]. CIRCULATION, 1992, 86 (04) : 1089 - 1098
  • [48] INHIBITION OF RENIN RELEASE FROM RAT-KIDNEY SLICES BY ANGIOTENSINS
    NAFTILAN, AJ
    OPARIL, S
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1978, 235 (01): : F62 - F68
  • [49] NORTHRIDGE DB, 1989, LANCET, V2, P591
  • [50] INFLUENCE OF CHRONIC CAPTOPRIL THERAPY ON THE INFARCTED LEFT-VENTRICLE OF THE RAT
    PFEFFER, JM
    PFEFFER, MA
    BRAUNWALD, E
    [J]. CIRCULATION RESEARCH, 1985, 57 (01) : 84 - 95