Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure

Marie, Christine; Mossiat, Claude; Lecomte, Jeanne‐Marie; Bralet, J

doi:10.1159/000028212

Cited by 15 publications

(25 citation statements)

References 25 publications

(25 reference statements)

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“…The present study demonstrates that early or late treatment with these agents significantly attenuated the increase in cardiac mass in rats with ACF. A similar trend was reported by Marie et al (17) in rats with CHF due to coronary artery ligation. In a similar model of CHF, Maki and co-workers (16) reported that treatment with sampatrilat, another VPI, improved and actually prevented cardiac remodeling at least by direct inhibition of cardiac fibrosis.…”

Section: Discussionsupporting

confidence: 89%

“…These dual inhibitory actions offer potential hemodynamic and neurohormonal advantages over the inhibition of each enzyme alone. Recent results in heart failure suggest beneficial hemodynamic and renal effects mediated by the synergistic ACE and NEP inhibition offered by this drug in both experimental (5,17,33) and clinical (15,18,19,27) CHF. These effects include increased cardiac output and attenuated cardiac hypertrophy in both mild and severe experimental heart failure induced by pacing (33) or coronary ligation (5,17).…”

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confidence: 99%

“…Recent results in heart failure suggest beneficial hemodynamic and renal effects mediated by the synergistic ACE and NEP inhibition offered by this drug in both experimental (5,17,33) and clinical (15,18,19,27) CHF. These effects include increased cardiac output and attenuated cardiac hypertrophy in both mild and severe experimental heart failure induced by pacing (33) or coronary ligation (5,17). The Inhibition of Metalloproteinaze in a Randomized Exercise and Symptoms Study in Heart Failure study reported a greater improvement in New York Heart Association (NYHA) class and reduction in combined mortality/hospitalization end points for patients with systolic heart failure receiving OMP compared with ACE inhibitor alone (27).…”

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confidence: 99%

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Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Abassi

Yahia²,

Zeid³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure. Am J Physiol Heart Circ Physiol 288: H722-H728, 2005. First published October 21, 2004 doi:10.1152/ ajpheart.00737.2004 is a novel mixed inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme that metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both an excessive effect of angiotensin II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal and cardiac effects of OMP in rats with compensated [urinary sodium excretion (U NaV) Ͼ 1,200 eq/day] and decompensated (U NaV Ͻ 100 eq/day) CHF, induced by a surgical aortocaval fistula (ACF). Bolus injection of OMP (10 mg/kg) to sham controls produced significant diuretic and natriuretic responses [U NaV increased from 0.67 Ϯ 0.19 to 3.27 Ϯ 1.35 eq/min, P Ͻ 0.05; fractional sodium excretion (FE Na) increased from 0.23 Ϯ 0.06 to 0.95 Ϯ 0.34%, P Ͻ 0.01] despite a significant decline in blood pressure (BP). Rats with compensated CHF displayed blunted diuresis and natriuresis to this dose of OMP but a significant decrease in BP. However, in rats with decompensated CHF, OMP induced significant natriuresis (FE Na increased from 0.18 Ϯ 0.15 to 0.82 Ϯ 0.26%, P Ͻ 0.05) despite a further decrease in BP (from 90 Ϯ 9 to 71 Ϯ 6 mmHg, P Ͻ 0.01). Two weeks after ACF, the heart/body weight ratio was significantly greater in rats with CHF than controls (0.51 Ϯ 0.026 vs. 0.30 Ϯ 0.004%, P Ͻ 0.0001), and U NaV was significantly lower. Immediate or late (1 or 6 days after ACF) OMP treatment in the drinking water (140 mg/l) reduced cardiac hypertrophy to 0.41-0.43% (P Ͻ 0.01) and induced natriuresis. These results suggest that OMP improves both sodium balance and cardiac remodeling and might be advantageous to ACE inhibitors for the treatment of decompensated CHF. cardiac hypertrophy; renal function; rat; angiotensin-converting enzyme inhibitor; neutral endopeptide inhibitor

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

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confidence: 99%

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Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Abassi

Yahia²,

Zeid³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…One of these reports is on the effects of 4 weeks of treatment with TM1, a prodrug of the NEP inhibitor SQ28603, 27 and the other 2 reports describe the effects of 4 weeks of treatment with alatriopril or aladotril, mixed inhibitors of NEP and ACE. 28,29 Treatment with TM1 reduced the development of right ventricular and atrial hypertrophy but had no effect on the left ventricle and septum weights. 27 Alatriopril showed a greater potency than captopril in reducing cardiac hypertrophy, suggesting that enhancement of ANP levels via NEP inhibition magnifies the capacity of ACE inhibition to prevent cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 97%

“…28 Aladotril decreased LVEDP to approximately the same extent as captopril and reduced cardiac hypertrophy without any hypotensive effect. 29 In the present study, we examined the effects of only one dose of candoxatril. In our preliminary experiment using quantitative in vitro autoradiography, a single gavage of candoxatril at a dose of 10 mg/kg inhibited kidney NEP binding to 13% of that of the controls at 1 h, and this inhibition was significant for up to 24 h. As demonstrated in the present study by quantitative in vitro autoradiography, NEP binding was significantly inhibited compared with that of the controls, even after the chronic 4-week treatment period.…”

Section: Discussionmentioning

confidence: 99%

Effect of Chronic Neutral Endopeptidase Inhibition on Cardiac Hypertrophy after Experimental Myocardial Infarction

et al. 1998

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ongestive heart failure carries a grave prognosis, with a mortality rate of over 50% within 5 years of diagnosis. 1,2 The progressive nature of the disease is due in part to a series of neurohumoral homeostatic responses that initially maintain cardiac output and tissue perfusion but ultimately prove deleterious by increasing cardiac work and further reducing cardiac function. 3,4 These responses include enhancement of sympathetic tone, alteration in regional vascular resistance, activation of the renin-angiotensin-aldosterone system, and sodium retention.Atrial natriuretic peptide (ANP) is a peptide hormone of cardiac origin with multiple biologic effects including diuresis, natriuresis, vasodilatation, and inhibition of renin and aldosterone secretion. 5,6 Based on these properties, some studies have suggested a therapeutic role for ANP in congestive heart failure. 7,8 However, the therapeutic potential of ANP is limited by its peptidic nature and rapid elimination from circulation. Long-term therapy requires either an orally active analogue or an inhibitor of ANP metabolism. Neutral endopeptidase (NEP) is a major ANP-degrading enzyme, 9-11 and a new therapeutic approach has been developed by inhibiting the enzyme and potentiating the effects of endogenous ANP. 12-15 Beneficial acute hemodynamic and renal effects of (±)-candoxatrilat (UK69578), an NEP inhibitor, have been reported in patients with congestive heart failure. 12,13 Furthermore, reports about the effects of NEP inhibitors on cardiovascular remodeling have been published recently. 16,17 In patients with myocardial infarction, progressive left ventricular dilatation begins soon after myocardial infarction 18 and left ventricular volume is the most powerful predictor of prognosis. 19,20 In the rat model of chronic heart failure with coronary ligation, a time-dependent increase in ventricular volume was attenuated by chronic therapy with captopril, an angiotensin converting enzyme (ACE) inhibitor 21 and, moreover, therapy with captopril had a pronounced effect on survival. 22 The aim of this study was to examine whether chronic treatment with the NEP inhibitor candoxatril (UK79300) would modify cardiac hypertrophy in the rat model of myocardial infarction. Candoxatril is an orally active indanyl ester prodrug of the compound candoxatrilat (UK73967), the active isomer of the racemic mixture known as (±)-candoxatrilat (UK69578). 12,13 MethodsAdult male Sprague-Dawley rats (Biological Research Laboratories, Austin Hospital, Victoria, Australia) weighing about 300 g were used for this study. These animal studies conformed to the guiding principles of the NHMRC/CSIRO code of conduct and were approved by Effect of Chronic Neutral Endopeptidase Inhibition on Cardiac Hypertrophy after Experimental Myocardial InfarctionJpn Circ J 1998; 62: 680 -686 Kazunori Yoshida, MD; Minoru Yasujima, MD*; David J. Casley**; Colin I. Johnston, MD**Candoxatril is an inhibitor of neutral endopeptidase, a membrane-bound enzyme that degrades atrial natriuretic peptide. The ef...

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Discovery of Peptide Drugs as Enzyme Inhibitors and Activators

Nguyen

Kiso

2015

Peptide Chemistry and Drug Design

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Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure

Cited by 15 publications

References 25 publications

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Effect of Chronic Neutral Endopeptidase Inhibition on Cardiac Hypertrophy after Experimental Myocardial Infarction

Discovery of Peptide Drugs as Enzyme Inhibitors and Activators

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