Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension

O’Connell, Janice; Jardine, Alan G.; Davidson, Gillian; Connell, John

doi:10.1097/00004872-199203000-00011

Cited by 62 publications

(33 citation statements)

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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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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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“…10,17 However, a reduction in blood pressure has not been clearly demonstrated in normotensive subjects, 10,18,20,21 and two studies have even reported an increase in blood pressure 22,23 despite the potent vasodilator actions of the natriuretic peptides. 12,13,16 Also, several studies on hypertensive patients 19,[32][33][34][35] have not demonstrated a reduction in blood pressure. Interestingly, and perhaps relevant to our own findings, a recent study in patients with chronic heart failure showed that candoxatril increases systemic vasoconstriction and decreases cardiac index.…”

Section: Discussionmentioning

confidence: 99%

“…Although NEP inhibitors have been reported to lower blood pressure in patients with essential hypertension, 24 -31 this finding has not been universal. 19,[32][33][34][35] Thus, the therapeutic value of NEP inhibitors in hypertension remains uncertain. In patients with heart failure, these agents do not reduce afterload although they do reduce pulmonary capillary wedge pressure, presumably because of natriuresis.…”

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confidence: 99%

Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

et al. 1998

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Background-Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone. Methods and Results-Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12Ϯ2%; Pϭ0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (Pϭ0.6) after pretreatment with both placebo (13Ϯ1%, Pϭ0.006) and enalapril (17Ϯ6%, Pϭ0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ET A antagonist BQ-123 (100 nmol/min), and both combined.

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“…In addition, acute administration of various NEP inhibitors has been shown to increase plasma ANP in various animal models of hypertension when the ANP was already elevated, e.g., in NaCI-sensitive spontaneously hypertensive rats (22) and in DOCAlsalt hypertensive rats (23), whereas NEP inhibitors failed to modify plasma ANP in intact normotensive rats (3), dogs (24), and humans (25). In hypertensive patients, NEP inhibition raised ANP levels (26) and a small decrease in blood pressure was observed (15,27,28).…”

Section: Discussionmentioning

confidence: 99%

Neutral Endopeptidase Inhibition Potentiates the Effects of Natriuretic Peptides in Renin Transgenic Rats.

1996

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The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)).These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure. (Hypertens Res 1996;19: 229-238) Key Words: neutral endopeptidase 24.11, (S)-thiorphan, ecadotril, TGR(m(Ren2)27), ANP, BNP, CNPThe natriuretic peptides are a family of related polypeptide hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These natriuretic peptides have a common structural motif consisting of a loop of 17 amino acids formed by intramolecular disulfide bonds. Only 6 of the 17 amino acids in this ring differ among the three peptides isolated from the pig, whereas the N-and C-terminals vary both in amino acid composition and length (1,2). Neutral m...

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Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension

Cited by 62 publications

References 0 publications

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

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

Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

Neutral Endopeptidase Inhibition Potentiates the Effects of Natriuretic Peptides in Renin Transgenic Rats.

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