Placebo‐controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure

Northridge, David B.; Currie, Peter; Newby, David E.; McMurray, John J.V.; Ford, Michael T.; Boon, Nicholas A.; Dargie, Henry J.

doi:10.1016/s1388-9842(98)00003-8

Cited by 39 publications

(20 citation statements)

References 23 publications

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“…Candoxatril is the pro-drug of the active compound candoxatrilat and is a potent competitive and selective inhibitor of NEP-24.11; it was developed as a diuretic for clinical use [31][32][33]. Candoxatril does not affect the activity of carboxypeptidase A, leucine aminopeptidase (aminopeptidase M) or angiotensin-converting enzyme, which belong to the same zinc metalloprotease superfamily as NEP-24.11 [20], or that of the more closely NEP-related enzyme, endothelin-converting enzyme-1 [31].…”

Section: Discussionmentioning

confidence: 99%

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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Aims/hypothesis: The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear. Methods: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs. Results: During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t ½ 2.3±0.1 to 8.

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Section: Discussionmentioning

confidence: 99%

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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“…45 For example, in this study in heart failure, NEP inhibition did not change plasma ANP, yet in both experimental hypertension and essential hypertension, SCH42495 increased plasma ANP. 10,46 It has also been shown in human heart failure that one NEP inhibitor, candoxatril, increased exercise duration, 47 whereas another, ecadotril, had no effect on symptoms. 48 The relative degree of ACE versus NEP inhibition also varies between vasopeptidase inhibitors; in the rat, omapatrilat has similar potency to inhibit renal NEP and ACE, 11 whereas S21402 has greater efficacy to inhibit renal NEP compared with ACE.…”

Section: Burrell Et Al Vasopeptidase Inhibition With S21402mentioning

confidence: 99%

Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

et al. 2000

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Abstract-S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensinconverting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg ⅐ kg), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (PϽ0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (PϽ0.01). Both S21402 and captopril increased plasma renin activity (PϽ0.01), all treatment lowered plasma aldosterone (PϽ0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (PϽ0.01), SCH42495 inhibited NEP (PϽ0.01), and captopril inhibited ACE (PϽ0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (PϽ0.01), SCH42495 reduced right ventricular mass (PϽ0.01), and S21402 decreased left (PϽ0.05) and right ventricular mass (PϽ0.01), atrial mass (PϽ0.05), and lung mass (PϽ0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure. Key Words: vasopeptidase inhibitors Ⅲ neutral endopeptidase Ⅲ heart failure Ⅲ myocardial infarction Ⅲ natriuretic peptides Ⅲ cardiac remodeling C ongestive heart failure (CHF) is a progressive disease characterized by neurohormonal activation, salt and water retention, and cardiac remodeling. Inhibitors of angiotensin converting-enzyme (ACE), which prevent the formation of the constrictor, antinatriuretic, and trophic hormone angiotensin (Ang) II, attenuate ventricular remodeling, improve cardiac function and survival, and are standard treatment for CHF. 1 Atrial natriuretic peptide (ANP) is elevated in proportion to the degree of left ventricular dysfunction 2 and acts as an endogenous antagonist of the renin-angiotensin system (RAS) to cause natriuresis and diuresis, and vasodilation and suppression of the sympathetic nervous system. 3 An increase in endogenous levels of ANP by inhibition of its enzymatic degradation by neutral endopeptidase 24.11 (NEP) is a potential therapeutic strategy in heart failure. 4 Selective NEP inhibition has met with limited success as hyporesponsiveness to the biological actions of ANP occurs with increasing severity of heart failure, whereas the addition of an ACE inhibitor restores some benefits of NEP inhibition, including natriuresis. 5,6 Several compounds that simultaneously inhibit NEP and ACE, or vasopeptidase inhibitor...

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“…Candoxatrilat is the active product of the orally active Candoxatril, which has been used in numerous studies in humans 15,16 ; a lower dose of Candoxatrilat (3 mg/kg) was reported to inhibit renal NEP binding in rats for up to 24 hours. 17 …”

Section: Nep Inhibitor Treatment In Conscious Ratsmentioning

confidence: 99%

Restorative Effect of Atrial Natriuretic Peptide or Chronic Neutral Endopeptidase Inhibition on Blunted Cardiopulmonary Vagal Reflexes in Aged Rats

et al. 2008

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Abstract-Arterial baroreflex function diminishes with age, but whether cardiopulmonary vagal reflexes are similarly altered with physiological aging has not been fully elucidated. In this study, predominantly cardiac high pressure mechanoreceptor-activated (ramp baroreflex) and cardiopulmonary chemoreceptor-activated (von Bezold-Jarisch reflex) vagal reflexes in conscious, instrumented rats were impaired by 30% to 40% (PϽ0.05) in 24-month-old (nϭ12) compared with 6-month-old rats (nϭ12). To determine whether this is a restorable deficit, the influence of atrial natriuretic peptide (ANP), either by infusion or blockade of its breakdown, was studied. ANP infusion was previously shown to enhance Bezold-Jarisch reflex and ramp baroreflex bradycardia in young adult rats. The present study confirmed that vagal reflex augmentation by ANP (50 pmol/kg per minute) also occurs in old rats (increased by 60Ϯ18% (Bezold-Jarisch reflex) and 91Ϯ15% (ramp baroreflex; PϽ0.05). Direct vagal stimulation in anesthetized animals showed that the target for ANP was not the cardiac vagus itself in old rats (nϭ7), although in young rats only, we confirmed the published finding that ANP enhances vagal bradycardia (by 58Ϯ14%, nϭ7). Neutral endopeptidase 24.11 degrades ANP and several other peptides. The neutral endopeptidase inhibitor candoxatrilat (5 mg/kg per day IV for 7 to 9 days) restored vagal reflex bradycardia in old rats (nϭ6) to levels similar to those in young neutral endopeptidase inhibitor-treated rats (nϭ6). Impaired cardiopulmonary vagal reflex control of heart rate is thus a feature of normal aging, and this deficit may be ameliorated by either ANP infusion or chronic neutral endopeptidase inhibition. Key Words: aged Ⅲ autonomic Ⅲ cardiac Ⅲ ischemia Ⅲ sensory afferent D iminished arterial baroreflex control of heart rate (HR) is a well-documented feature of aging (see reviews 1,2 ), but surprisingly few studies have examined the effect of aging on reflexes originating in the heart. It is generally accepted that low-pressure cardiopulmonary reflexes are less effective with advancing age and that this may play a role in the decreased ability of the elderly to regulate blood volume and maintain blood pressure during gravity challenges. 3,4 Whether other cardiocardiac vagal reflexes such as the cardiopulmonary chemoreflex (von Bezold-Jarisch [BJR]) or those activated by high-pressure ventricular stretch receptors (ramp baroreflex) are also compromised with age is not clear. The BJR is thought to be cardioprotective (promoting reflex bradycardia, hypotension, and vasodilatation) and is activated by 5-HT 3 receptors on ventricular vagal afferents. 5 Davidow and colleagues concluded that the BJR in conscious 14-and 24-month-old rats was reduced compared with 6-month-old rats, 6 whereas Sakima and colleagues 7 reported that the BJR was not diminished in older (16-to 20-month-old) rats.The potential for cardioprotection by enhancing parasympathetic activity has long been recognized and this avenue is underexploited by current ther...

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Placebo‐controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure

Cited by 39 publications

References 23 publications

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

Restorative Effect of Atrial Natriuretic Peptide or Chronic Neutral Endopeptidase Inhibition on Blunted Cardiopulmonary Vagal Reflexes in Aged Rats

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