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)

The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.
 ...
PMID:Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension. 784 19

Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.
 ...
PMID:Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes. 785 75

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99-126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28,603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys' diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 mumol/kg intravenous of SQ 28,603 increased from 665 +/- 64 to 1015 +/- 224 mu Eq/3 h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 mumol/kg, p.o., of SQ 28,603 from 700 +/- 332 mu Eq/3 h in normal monkey to 2437 +/- 841 mu Eq/3 h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys treated with vehicle or 10 mumol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99-126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28,603 and candoxatrilat (0.3 to 10 mumol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys receiving 5 mL/kg+0.2 mL/min saline. In addition, the highest dose of SQ 28,603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99-126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.
 ...
PMID:Sodium loads enhance the natriuretic responses to atrial natriuretic peptide and neutral endopeptidase inhibitors in conscious cynomolgus monkeys. 788 75

We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of alpha-rat atrial natriuretic peptide (alpha-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating alpha-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/min/kg) was equal to that of exogenously administered alpha-rANP (100 pmol/min/kg) in MI rats, whereas plasma alpha-rANP concentration under NEP inhibition was much lower than that after administration of alpha-rANP. The endogenous alpha-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to alpha-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous alpha-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating alpha-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.
 ...
PMID:Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure. 789 35

We examined adenosine 5'-triphosphate (ATP), pertussis toxin (PT) and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, modulation of atrial natriuretic peptide (ANP)-stimulated cell-membrane guanylate cyclase (ANP-s-GC) activity and ANP stimulation of whole-cell cGMP accumulation (ANP-s-cGMP) in an ANP-receptor-transduction cell model, the human renal cell line (SK-NEP-1). Acute and long-term effects of PMA on PKC isotype activity are different: Acute (20-min) PMA activation of PKC inhibits ANP-s-cGMP and ANP-s-GC; whereas, long-term (36-h) PMA treatment inhibits slightly less by only partially down-regulating PKC activity, the type-III PKC isotype being 36-h resistant. Long-term 10(-7)M PMA treatment of cells neither affected membrane basal GC activity nor ANP-s-GC activity but partially inhibited ATP enhancement of ANP-s-GC. This partial inhibition was completely reversed by the PKC inhibitor H7 and a PKC inhibitory antibody but only partially reversed by the antibody to the catalytic domain of PKC type III. The EC50 for ATP and its non-phosphorylating analog ATP gamma S in the presence of acute PMA inhibition of ANP-s-cGMP was similar (approximately 10(-9)). This enhancement of PMA inhibition was two orders of magnitude more sensitive (EC50 10(-7)M) than inhibition of ANP-s-cGMP that we previously reported for acute PMA treatment of whole SK-NEP-1 cells. The three- to four-fold ATP enhancement of cell membrane ANP-s-GC was not blocked by 12-hour preincubation of cells with 150 ng/mL PT but was completely blocked if 2-x-10(-7)M PMA was then added for 20 minutes, indicating that acute activation of PKC by PMA does not require a functional "G-type" protein. Acute PMA inhibition of ANP-s-cGMP was reversed by permeabilizing SK-NEP-1 cells to a specific PKC inhibitory peptide, further confirming that PMA inhibition was mediated through PKC activation. These data demonstrated that ANP-s-GC and ANP-s-cGMP were modified through non-phosphorylating interactions with ATP, by multiple PMA activatable PKC isoforms, and that neither were affected by PT-sensitive guanine-nucleotide-binding (G)-protein(s).
 ...
PMID:Adenosine 5'-triphosphate, phorbol ester, and pertussis toxin effects on atrial natriuretic peptide stimulation of guanylate cyclase in a human renal cell line. 790 11

CGS 26303 is a potent and structurally unique non-peptidic inhibitor of neutral endopeptidase (NEP) capable of protecting atrial natriuretic peptide (ANP) from enzymatic degradation. In addition, CGS 26303 displays modest endothelin-converting enzyme (ECE) inhibitory activity in vitro. Unlike CGS 24592, a potent but selective NEP inhibitor, CGS 26303 significantly blocks endothelin-1 production in rats after exogenous administration of big ET-1 and reduces the mean arterial pressure in spontaneously hypertensive rats during chronic administration. These results suggest that CGS 26303 represents a new class of therapeutic agents with potential benefits for the treatment of cardiovascular and renal disorders.
 ...
PMID:Pharmacological profile of a non-peptidic dual inhibitor of neutral endopeptidase 24.11 and endothelin-converting enzyme. 794 87

Some studies have indicated that plasma calcitonin gene-related peptide (CGRP) increases in congestive heart failure (CHF). In vitro, neutral endopeptidase (NEP) cleaves CGRP. We studied CGRP-like immunoreactivity (CGRP-ir) in rat plasma in a coronary artery-ligation model of CHF with and without NEP inhibition. Rats with CHF (n = 6) and sham-operated controls (n = 6) were administered vehicle and, separately, SCH 34826, a NEP inhibitor, subcutaneously 90 mg/kg. Plasma sample was taken 60 minutes later. Seventeen untreated coronary-ligated rats with various degrees of CHF were studied separately. Systolic arterial pressure (SAP) was measured while conscious. All rats were killed by exsanguination, and heart and lungs were removed and weighed. In CHF rats, plasma atrial natriuretic peptide after vehicle (basal ANP) was 7.6-fold, but basal CGRP-ir was similar compared to controls. After SCH 34826, plasma CGRP-ir decreased marginally in CHF rats (57-> 51 ng/l, p = 0.011), and ANP increased 1.8-fold (418-> 730 ng/l, p = 0.001). In controls, these changes by SCH 34826 were small. Basal ANP correlated strongly with relative weight of heart (HE; R = 0.93, p < 0.001) and lungs (LU; R = 0.96, p < 0.001). There was no correlation between basal CGRP-ir, basal plasma renin activity (PRA), HE and LU. In the untreated coronary-ligated rats, plasma CGRP-ir did not correlate with HE, LU, SAP, plasma ANP or PRA, but plasma ANP correlated with HE (R = 0.62, p = 0.011) and LU (R = 0.70, p = 0.002). We conclude that, in rat plasma, CGRP-ir is not elevated either by NEP inhibition, or in post-infarction CHF.
 ...
PMID:Calcitonin gene-related peptide is not elevated in rat plasma by heart failure or by neutral endopeptidase inhibition. 803 65

A novel fluorogenic peptide, dansyl-Gly-(p-NO2) Phe-beta Ala (DGNPA), was synthesized as a selective substrate for neutral endopeptidase 24.11, an enzyme involved in enkephalin and atrial natriuretic peptide degradation and a marker of differentiation (CD10) on the surface of lymphohematopoietic cells. Cleavage of the substrate Gly-(p-NO2)Phe amide bond leads to an increase in fluorescence related to the disappearance of the intramolecular quenching of the dansyl fluorescence by the nitrophenyl residue. This new fluorogenic substrate is an improvement over the commercially available dansyl-D-Ala-Gly-(p-NO2)Phe-Gly, as the Gly4 residue of the latter has been replaced by a beta-alanine, therefore eliminating a residual sensitivity of the peptide toward angiotensin converting enzyme. Moreover, deletion of the D-Ala2 residue was shown to increase the quenching efficiency, thus raising the sensitivity of the assay, which was further improved by stopping the reaction with dioxane. The present substrate has improved affinity (Km = 37 microM, V = 0.72 mumol min-1 mg protein-1), selectivity, and sensitivity over its precursor and was used in automated assays using 96-well microplates and a fluorescence plate reader.
 ...
PMID:Dns-Gly-(p-NO2)Phe-beta Ala, a specific fluorogenic substrate for neutral endopeptidase 24.11. 805 59

To study the possible physiological role of atrial natriuretic peptide (ANP) in the regulation of intraocular pressure (IOP) the effects of an increase of endogenous ANP within the physiological range induced by the neutral endopeptidase 24.11 (NEP) inhibitor candoxatril were examined. In a single masked placebo controlled trial, seven patients were studied with normal IOP (six male, one female; average age 50 (range 37-62 years). Intraocular pressure in each eye was measured after 2 weeks of placebo, after 4 weeks of candoxatril 200 mg twice daily, and during the first 3 days of placebo washout. With 4 weeks of candoxatril, endogenous plasma ANP levels increased from 4.2 (SEM 1.5) to 6.0 (1.5) pmol/l (p < 0.04) and there was a significant decrease in mean arterial pressure from 119 (4) to 110 (3) mm Hg (p < 0.02; 12 hours after treatment). There was a significant reduction in IOP after 4 weeks' treatment with candoxatril (right eye 2.1 (0.8) mm Hg, p < 0.05 paired t test, left eye 2.8 (0.8) mm Hg, p < 0.02). The mean fall in IOP was 11% (4%) in the right eye and 16% (3%) in the left eye and the fall in IOP was greater the higher the initial IOP. The reduction in IOP with chronic NEP inhibition was positively correlated with the increase in ANP levels but not with changes in blood pressure. These findings suggest that ANP may play a physiological role in the regulation of IOP. As the fall in IOP was greater in subjects with higher initial IOP, NEP inhibitors may be of therapeutic value in the management of glaucoma.
 ...
PMID:Evidence for a new role of natriuretic peptides: control of intraocular pressure. 806 Sep 26

1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495. 2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage. 3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n = 8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level. 4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control hypoxic groups at day 10. 5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.
 ...
PMID:Effects of the neutral endopeptidase inhibitor, SCH 42495, on the cardiovascular remodelling secondary to chronic hypoxia in rats. 806 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>