Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Candoxatrilat is a potent and selective inhibitor of neutral endopeptidase (EC 3.4.24.11), the enzyme responsible for the degradation of atrial natriuretic factor (ANF). In these studies, the renal effects of candoxatrilat were investigated in euvolemic and hypervolemic anaesthetised rats. In euvolemic rats, candoxatrilat (675 micrograms/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cyclic GMP excretion. However, in hypervolemic rats, the natriuretic and diuretic responses to volume expansion were markedly potentiated by the candoxatrilat infusion, with a concomitant increase in urinary cyclic GMP. Acute volume expansion was characterised by natriuresis, diuresis and increased levels of plasma ANF and cyclic GMP (1.5-fold and 2-fold increases respectively, when compared to euvolemic rats). The results presented suggest that plasma ANF levels and volume status modulate responses to neutral endopeptidase inhibition. The development of the neutral endopeptidase inhibitor, candoxatrilat, provides the opportunity to exploit endogenous ANF effectively in disease states with elevated ANF.
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PMID:Renal effects of neutral endopeptidase inhibition in euvolemic and hypervolemic rats. 822 41

We have characterized the endothelin-converting enzyme (ECE)-like activity involved in big endothelin (ET)-1-induced contraction in rabbit saphenous artery (RSA). Big ET-1 30 nM caused a contraction that was independent of the vascular endothelium. Phosphoramidon and the neutral endopeptidase (NEP) inhibitors thiorphan and candoxatrilat blocked the vasoconstriction caused by big ET-1 in endothelium-denuded RSA. Candoxatrilat (IC50 17 nM) and thiorphan (IC50 2.5 nM), were 5- to 30-fold more potent than phosphoramidon (IC50 83 nM). Other protease inhibitors were inactive. In cultured endothelial cells the ET-1 release was inhibited only by phosphoramidon (IC50 16 microM) but at a concentration 200-fold that required an endothelium-denuded RSA. In conclusion, we can speculate that the big ET-1 contraction in RSA is mediated by an ECE, probably present on smooth muscle cells, which is susceptible to NEP inhibitors and is different from the ECE on endothelial cells.
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PMID:Characterization of big endothelin-1-induced contraction in rabbit saphenous artery. 858 74

We investigated the effects of inhibiting endogenous atrial natriuretic factor (ANF) metabolism on renal hemodynamics, sodium excretion and neurohormones in 12 patients with New York Heart Association functional class II congestive heart failure (CHF) due to left ventricular systolic dysfunction. In a randomized, placebo-controlled, double-blinded fashion, 8 patients received a single oral dose of candoxatril, an inhibitor of renal neutral endopeptidase, and 4 patients received placebo. Candoxatril treatment increased plasma ANF by 70 +/- 71 pg/ml (p < 0.015 vs. placebo) and plasma cGMP by 7.9 +/- 2.7 pmol/ml (p < 0.001 vs. placebo), with maximal effects at 3.5 h. Urinary cGMP more than doubled (p = 0.025 vs. placebo). Candoxatril increased urinary sodium by 2.7 +/- 2.0 mEq/h (p < 0.05 vs. placebo) and significantly elevated filtration fraction with no significant effect on glomerular filtration rate, renal plasma flow or lithium clearance. A significant reduction in aldosterone concentration with a similar trend in plasma renin activity was noted in candoxatril-treated patients. Thus in patients with moderate heart failure, renal neutral endopeptidase inhibition increases urinary sodium excretion. The lack of an effect on renal hemodynamics suggests that this natriuresis results from ANF-mediated inhibition of tubular sodium reabsorption. These findings justify additional investigation into potential clinical benefit of endopeptidase inhibition in patients with CHF.
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PMID:Effects of renal neutral endopeptidase inhibition on sodium excretion, renal hemodynamics and neurohormonal activation in patients with congestive heart failure. 863 Oct 44

1. The present studies compare the early renal response to (a) an endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) (b) an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) and (c) the combination of endopeptidase-24.11 and ACE inhibition in the rat A-V fistula model of chronic volume overload. 2. Candoxatrilat (3 and 10 mg kg-1) i.v. produced a prompt 3 fold increase in urinary sodium and cyclic GMP excretion without affecting significantly blood pressure or glomerular filtration rate (GFR). 3. Lisinopril (0.03 mg kg-1) alone inhibited the pressor response to angiotensin I but had no significant effect on urinary sodium excretion or blood pressure. 4. Lisinopril (0.03 mg kg-1) attenuated significantly the early natriuretic response to candoxatrilat (3 mg kg-1) and the associated rise in urinary cyclic GMP, but sodium excretion eventually reached levels associated with acute E-24.11 inhibition. 5. Doses of the dual E-24.11/ACE inhibitor, sampatrilat, that inhibited the pressor response to angiotensin I reduced mean arterial blood pressure and produced a delayed natriuresis and rise in urinary cyclic GMP excretion when compared to candoxatrilat alone. 6. Concurrent administration of an ACE inhibitor reduces the early renal response to E-24.11 inhibition in the A-V fistula rat, an effect attributable to the hypotensive action of this combination.
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PMID:Renal effects of concurrent E-24.11 and ACE inhibition in the aorto-venocaval fistula rat. 892 44

1. Candoxatrilat, an active neutral endopeptidase inhibitor, was released rapidly from the inactive prodrug candoxatril in vivo in mouse, rat, rabbit, dog and man. 2. Oral doses of [14C]-candoxatril were cleared rapidly, mostly by ester hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [14C]-candoxatrilat showed that the active drug was virtually completely renally cleared. Neither candoxatril nor candoxatrilat underwent chiral inversion in man. 3. Systemic availability of candoxatrilat from the oral prodrug was estimated to be 88, 53, 42, 17 and 32% in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rapid to enable pharmacokinetic parameter calculation in mouse and rabbit; for man, the apparent oral clearance was 57.9 ml/min/kg and the elimination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mouse, rat, rabbit, dog and man respectively. Renal clearance values were 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and these approximate to the respective glomerular filtration rates. Allometric scaling with respect to bodyweight across the species allowed reasonable prediction of the above two clearance parameters in man.
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PMID:Formation and pharmacokinetics of the active drug candoxatrilat in mouse, rat, rabbit, dog and man following administration of the prodrug candoxatril. 936 44

Candoxatril is an inhibitor of neutral endopeptidase, a membrane-bound enzyme that degrades atrial natriuretic peptide. The effects of candoxatril on hemodynamic parameters and cardiovascular hypertrophy were evaluated in the rat model of myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in rats and they were treated either with candoxatril (10mg/kg per day) or a vehicle for up to 4 weeks. Systolic blood pressure and body weight did not change for up to 4 weeks between the 2 groups. At the end of treatment, hemodynamic parameters were measured, and then plasma, heart, lungs and kidneys were collected. Kidney neutral endopeptidase, as measured by the quantitative autoradiographic method, was significantly inhibited in candoxatril-treated rats compared with that in controls (66.6+/-3.2% of control, p<0.001). On the contrary, there were no significant differences in right atrial pressure, left ventricular end-diastolic pressure, systemic pressure, and plasma level of atrial natriuretic peptide between the 2 groups. There were also no significant differences in cardiac weight and lung weight. These data indicate that inhibition of neutral endopeptidase by candoxatril at a dose of 10 mg/kg per day did not oppose cardiac hypertrophy in the rat model of myocardial infarction in spite of significant neutral endopeptidase inhibition.
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PMID:Effect of chronic neutral endopeptidase inhibition on cardiac hypertrophy after experimental myocardial infarction. 976 7

Inhibition of neutral endopeptidase (NEP) in the kidney was studied ex vivo after oral administration of candoxatril (UK79300), an NEP inhibitor, to rats to study the time course and dose response by quantitative in vitro autoradiography by using the NEP inhibitor 125I-SCH47896 as a radioligand. In control rats, high NEP binding was demonstrated in the deep proximal tubule. After oral administration of candoxatril (10 mg/kg), kidney NEP binding was rapidly decreased and recovered gradually over a period of 24 h. The inhibition was maximal at 1 h (13.3 +/- 2.5% of control). Increasing doses of candoxatril administered to rats produced progressive inhibition of NEP binding in the kidney. A dose of 100 mg/kg inhibited kidney NEP binding to 2.6 +/- 0.2% of the control value at 1 h after administration. Candoxatrilat (UK73967), an active metabolite of candoxatril, given intravenously inhibited kidney NEP binding also in a time- and dose-dependent manner. This inhibition of NEP activity at the tissue level may be important in the actions of NEP inhibitors.
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PMID:Inhibition of kidney neutral endopeptidase after administration of the neutral endopeptidase inhibitor candoxatril: quantitation by autoradiography. 982 42

Candoxatril, a prodrug for candoxatrilat, a selective inhibitor of neutral endopeptidase, was administered orally to groups of 24 female rats at doses of 0, 120, 400 or 1200 mg/kg/day from gestation day 6 to lactation day 21 to assess effects on pre- and postnatal development of F1 offspring. All dams were allowed to litter and to raise their F1 offspring until lactation day 21. The F1 offspring were examined for postnatal developmental indices, reflex behaviors and memory. A functional observational battery (FOB) was also conducted. A marked increase in spontaneous activity of the dams was observed in all candoxatril-treated groups. Maternal body weight gain was decreased in the 400 and 1200 mg/kg/day groups during the treatment periods. No significant differences were found for reproductive parameters. The male and female pups in the 1200 mg/kg/day group had significantly lower body weights beginning on postnatal days 21 and 14, respectively, through to the end of the study. There were no drug-related effects on pre- and postnatal developmental indices, FOB, sensory function tests or memory test. The no observed adverse effect levels were 120 and 400 mg/kg/day for the F0 dams and F1 offspring, respectively.
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PMID:Reproductive study. II: Prenatal and postnatal development study with candoxatril in Sprague-Dawley rats. 989 6

These studies examined the interactions of neutral endopeptidase (NEP), endothelin-1 (ET-1), and nitric oxide (NO) in deoxycorticosterone acetate (DOCA)-induced hypertension. Male Sprague-Dawley rats (n = 35) were uninephrectomized (UNx) or uninephrectomized and treated with DOCA (25 mg pellet implanted subcutaneously). Candoxatril (30 mg/kg day(-1)), a NEP inhibitor, was given orally for 3 weeks in UNx or DOCA rats. Sham nephrectomized rats (SHAM) served as controls. Except SHAM, all other groups received 1% NaCl in drinking water ad libitum. Measurements were taken of systolic blood pressure (SBP), left ventricle (LV), and aortic weight (AW), plasma ET-1, and urinary excretion of nitrite and Na+. Whole body vascular hypertrophy and morphometric analysis of histological sections of the heart were also determined. In DOCA rats, SBP increased from 113 +/- 5 to 170 +/- 5 mmHg without significant changes in body weight (BW). Candoxatril reduced the increase in SBP to 135 +/- 9 mmHg (P < 0.05), abolished the increased LV wall thickness (P < 0.05), and increased the reduced LV lumen diameter (P < 0.05) in DOCA-salt rats. Candoxatril also reduced plasma ET-1 by 88 +/- 9% and 89 +/- 17% (P < 0.05) in UNx and DOCA rats, respectively, and elicited increases in urinary excretion of nitrite. These effects were accompanied by a marked increase in urinary excretion of Na+ (U(Na)V) (P < 0.05) and a blunting of the proteinuria (32 +/- 5%; P < 0.05) in DOCA rats. We conclude that endopeptidase inhibition in DOCA-salt hypertension reduced the increase in blood pressure and the attendant tissue hypertrophy and renal injury. These effects suggest a correlation between endopeptidase-related reduction in ET-1 production and protection in DOCA-salt hypertension.
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PMID:Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection. 1294 Apr 71

Glucagon has a short plasma t(1/2) in vivo, with renal extraction playing a major role in its elimination. Glucagon is degraded by neutral endopeptidase (NEP) 24.11 in vitro, but the physiological relevance of NEP 24.11 in glucagon metabolism is unknown. Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs. Candoxatril increased endogenous glucagon concentrations, from 6.3 +/- 2.5 to 20.7 +/- 6.3 pmol/l [COOH-terminal (C)-RIA, P < 0.05]. During glucagon infusion, candoxatril increased the t(1/2) determined by C-RIA (from 3.0 +/- 0.5 to 17.0 +/- 2.5 min, P < 0.005) and midregion (M)-RIA (2.8 +/- 0.5 to 17.0 +/- 3.0 min, P < 0.01) and reduced metabolic clearance rates (MCR; 19.1 +/- 3.2 to 9.4 +/- 2.0 ml.kg(-1).min(-1), P < 0.02, C-RIA; 19.2 +/- 4.8 to 9.0 +/- 2.3 ml.kg(-1).min(-1), P < 0.05, M-RIA). However, neither t(1/2) nor MCR determined by NH2-terminal (N)-RIA were significantly affected (t(1/2), 2.7 +/- 0.4 to 4.5 +/- 1.6 min; MCR, 30.3 +/- 6.4 to 28.5 +/- 9.0 ml.kg(-1).min(-1)), suggesting that candoxatril had no effect on NH2-terminal degradation but leads to the accumulation of NH2-terminally truncated forms of glucagon. Determination of arteriovenous glucagon concentration differences revealed that renal glucagon extraction was reduced (but not eliminated) by candoxatril (from 40.4 +/- 3.8 to 18.6 +/- 4.1%, P < 0.02, C-RIA; 29.2 +/- 3.1 to 14.7 +/- 2.2%, P < 0.02, M-RIA; 26.5 +/- 4.0 to 19.7 +/- 3.5%, P < 0.06, N-RIA). Femoral extraction was reduced by candoxatril when determined by C-RIA (from 22.7 +/- 2.4 to 8.0 +/- 5.1%, P < 0.05) but was not changed significantly when determined using M- or N-RIAs (10.0 +/- 2.8 to 4.7 +/- 3.7%, M-RIA; 10.5 +/- 2.5 to 7.8 +/- 4.2%, N-RIA). This study provides evidence that NEP 24.11 is an important mediator of the degradation of both endogenous and exogenous glucagon in vivo.
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PMID:Neutral endopeptidase 24.11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. 1512 40


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