Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure.

Cavero, Patricia G.; Margulies, Kenneth B.; Winaver, Joseph; Seymour, A A; Delaney, Norma G.; Burnett, John C.

doi:10.1161/01.cir.82.1.196

Cited by 100 publications

(40 citation statements)

References 25 publications

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“…Such a modulatory role of high circulating ANF levels in heart failure is suggested by a number of studies, using different experimental approaches such as autoimmune animals (17), monoclonal antibodies (18), exogenous ANF infusion (19), and inhibition of ANF metabolism (20).…”

Section: Introductionmentioning

confidence: 99%

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

Volpe¹,

Tritto²,

Luca³

et al. 1991

J. Clin. Invest.

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To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg. min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 143±2 to 19.5±3 and 26±4 pg/ml, at 60 and 120 min, respectively, P < 0.001), but not in HF (from 42.9±9 to 45.9±9 and 43.9±8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P < 0.001) by SL in N but not in HF. Urinary sodium excretion (UNSY) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did noi change in N and increased in HF (P < 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg min) that increased ANF levels from 37.1±10 to 146±22 pg/ml. In this group, SL raised both LVEDV (P < 0.01) and ANF (P < 0.05), whereas FVR did not rise. In addition, the UN.V increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence ofan adequate increase ofANF levels may contribute to the abnormal responses of HF patients to saline load. (J.

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Section: Introductionmentioning

confidence: 99%

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

Volpe¹,

Tritto²,

Luca³

et al. 1991

J. Clin. Invest.

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“…tissue uptake, and protease degradation. NEP In previous studies, the renal response to NEPI, in dogs ently been shown to be present within the lung with and without chronic CHF, was characterized by a signifingly, pathophysiologic conditions that cause elecant diuresis and natriuresis without increases in GFR or RBF sma ANF also produce elevated levels of NEP (22,23 (46). One must however be cautious in interpreting this increase in urinary ANF despite the increases in both urinary cGMP and sodium, as this assay technique may detect open-ringed peptide.…”

Section: Resultsmentioning

confidence: 99%

“…Experiments were conducted in two groups of anesthetized dogs (n = 6 pergroup) weighing 19-24 kg, with experimental acute CHF induced by rapid right ventricular pacing. This model is characterized by alterations in cardiorenal function and circulating hormones as observed in humans with acute biventricular heart failure (4,23,24).…”

Section: Methodsmentioning

confidence: 99%

“…A second objective of the study was to assess the contribution of enzymatic degradation of the atrial peptide to the urinary and pulmonary clearance of ANF in CHF by using a specific inhibitor of neutral endopeptidase 24.1 1 (NEPI) (22,23). A third objective ofthese investigations was to define the cardiovascular and renal effects of NEPI in the presence of acute CHF.…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary and urinary clearance of atrial natriuretic factor in acute congestive heart failure in dogs.

et al. 1991

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Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115±268 to 498±173 ml/ min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0±7.8 to 34.9±12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, a significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14±0.02 to 0.02±0.01 ml/min, P < 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF. (J. Clin. Invest.

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“…In some reports, effects of NEP inhibition were in parallel with the elevation of plasma ANP level, 12,15 while in other reports, NEP inhibitors exerted effects without any change in the plasma ANP level 30,31 or their effects did not parallel increases in plasma ANP. 32 In the present experiment, candoxatril was administered to the rats by dissolving it in drinking water. This method might have caused the difference in the relationship among plasma ANP level, kidney NEP binding and cardiovascular actions, because in most studies, NEP inhibitors were administered using a bolus method.…”

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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Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure.

Cited by 100 publications

References 25 publications

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

Pulmonary and urinary clearance of atrial natriuretic factor in acute congestive heart failure in dogs.

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

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