Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.11 (CD10)
9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We compared the cardiovascular and renal actions of the neutral endopeptidase (NEP) inhibitor, SQ 28,603, in normal rats and in rats with healed myocardial infarcts. The infarcted rats were studied in the conscious state 8 weeks after ligation of the left main coronary artery and 4 h after placement of cardiovascular and renal catheters. Infarct size was 39 +/- 1.2% of left ventricle circumference; right ventricle and lung weight to body weight ratios were twice those of normal rats. These postmortem values were shown to be associated with elevated left ventricular end diastolic pressure and high plasma atrial natriuretic peptide (ANP) concentration in separate groups of rats. SQ 28,603 at 100 mumol/kg intravenously (i.v.) caused urine volume and sodium excretion to increase by 79 +/- 11 microliters/min and 8.2 +/- 1.4 microEq/min, respectively, 20 min after injection in infarcted rats; these changes were significantly greater than those in normal rats (12 +/- 5 microliters/min and 1.6 microEq/min, respectively). Thoracic venous pressure decreased by 1.9 +/- 0.4 mm Hg 80 min after SQ 28,603 in infarcted rats and by only 0.1 +/- 0.1 mm Hg in normal rats (p less than 0.05 vs. infarcted rats). SQ 28,603 had no effects on mean arterial pressure (MAP), cardiac output (CO), or glomerular filtration rate (GFR). The observation that NEP inhibition has more pronounced effects in animals with high ambient ANP level than in those with normal ANP is consistent with previous studies in a variety of animal models and supports the concept that NEP inhibition potentiates endogenous ANP.
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PMID:Heart failure augments the cardiovascular and renal effects of neutral endopeptidase inhibition in rats. 172 Aug 29

An endopeptidase has been purified to homogeneity from a crude cell extract of Lactococcus lactis subsp. cremoris Wg2 by a procedure that includes diethyl-aminoethane-Sephacel chromatography, phenyl-Sepharose chromatography, hydroxylapatite chromatography, and fast protein liquid chromatography over an anion-exchange column and a hydrophobic-interaction column. Gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a molecular mass of the purified enzyme of 70,000 Da. The endopeptidase can degrade several oligopeptides into various tetra-, tri-, and dipeptides. The endopeptidase has no aminopeptidase, carboxypeptidase, dipeptidase, or tripeptidase activity. It is optimally active at pH 6.0 to 6.5 and in the temperature range of 30 to 38 degrees C. The enzyme is inactivated by the chemical agents 1,10-phenanthroline, ethylenedinitrilotetraacetate, beta-mercaptoethanol, and phenylmethylsulfonyl fluoride and is inhibited by Cu2+ and Zn2+. The ethylenedinitrilotetraacetate- or 1,10-phenanthroline-treated enzyme can be reactivated by Co2+. Immunoblotting with specific antibodies raised against the purified endopeptidase indicated that the enzyme is also present in other Lactococcus spp., as well as in Lactobacillus spp. and Streptococcus salivarius subsp. thermophilus.
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PMID:Purification and characterization of an endopeptidase from Lactococcus lactis subsp. cremoris Wg2. 178 32

The effects of a clearance receptor ligand Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Cys-NH2 with a disulfide bridge between the two cycteines [C-ANF(4-23)] and the potent neutral endopeptidase (NEP) inhibitor SQ 28,603 on mean arterial pressure (MAP), plasma atrial natriuretic factor (ANF) concentration and renal excretion of sodium and cyclic GMP were determined in conscious deoxycorticosterone acetate/salt hypertensive rats and normotensive rats. In the hypertensive rats, i.v. infusion of C-ANF(4-23) produced depressor responses of approximately 25 mm Hg, but did not significantly affect plasma ANF concentration or stimulate cyclic GMP excretion. In contrast, SQ 28,603 (300 mumol/kg i.v.) significantly reduced MAP and increased excretion of sodium and cyclic GMP. When C-ANF(4-23) was administered in combination with SQ 28,603, the depressor activity was additive and plasma ANF concentrations were significantly increased. The excretion of cyclic GMP was slightly enhanced, but, was not significantly different from the effects of SQ 28,603 alone. Neither SQ 28,603 nor C-ANF(4-23) affected MAP or plasma ANF in the normotensive rats. Finally, the in vitro hydrolysis of C-ANF(4-23) by NEP was prevented by SQ 28,603, indicating that inhibition of NEP may protect peptides recognized by the clearance receptors as well as the biological receptors for ANF. Therefore, the additive effects of C-ANF(4-23) and SQ 28,603 may be due to blockade of separate pathways which inactivate ANF or to the inhibition of C-ANF(4-23) degradation by NEP.
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PMID:Possible regulation of atrial natriuretic factor by neutral endopeptidase 24.11 and clearance receptors. 182 31

Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.
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PMID:EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide. 182 51

To explore whether pathophysiological plasma levels of atrial natriuretic peptide (ANP) actually involve sodium excretion in spontaneously hypertensive rats (SHR), we examined the in vivo and ex vivo effects of ANP and an endopeptidase inhibitor, thiorphan, on urinary sodium excretion and the elimination rate of ANP. We found the following: 1) The basal plasma ANP level was higher in 16-week-old SHR than in Wistar-Kyoto (WKY) rats (109 +/- 10 [SEM] versus 63 +/- 4 pg/ml, p less than 0.001). Thiorphan (30 mg/kg i.v.) significantly increased plasma ANP by 60% in both SHR and WKY rats. However, increases in urinary sodium excretion (+290% versus +130%, p less than 0.05) and cyclic GMP (+160% versus +60%, p less than 0.05) were greater in SHR than in WKY rats. Urinary excretion of ANP was markedly increased by thiorphan, and its increase was greater in SHR than in WKY rats. 2) The thiorphan-induced natriuresis was substantially attenuated by antiserum for ANP but not by a bradykinin receptor antagonist. 3) Isolated SHR kidneys excreted 50% less sodium than WKY rat kidneys at perfusion pressures of 100 and 160 mm Hg (p less than 0.05). Urinary sodium excretion was increased at the perfusate ANP level of 100 pg/ml, a concentration similar to the SHR plasma ANP (+70% at 160 mm Hg). 4) After bolus administration of ANP to the isolated kidney, the ANP concentration of the recirculating perfusate decreased rapidly in a log-linear fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of endogenous atrial natriuretic peptide in regulating sodium excretion in spontaneously hypertensive rats. Effects of neutral endopeptidase inhibition. 182 56

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.
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PMID:Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension. 183 59

Endogenous atrial natriuretic factor (ANF) serves a functional role to maintain sodium homeostasis and inhibit activation of the renin-angiotensin-aldosterone system in acute congestive heart failure despite arterial hypotension. However, as heart failure progresses, maximal synthesis and release of ANF from both the atrial and ventricular myocardium may occur resulting in relative ANF deficiency. This relative deficiency of ANF results in a progressive inability to excrete sodium and antagonize the renin-angiotensin-aldosterone system. Consequently, agents that increase circulating ANF and (or) enhance its local action have potential therapeutic efficacy. Recent studies suggest that inhibitors of neutral endopeptidase 24.11, which block ANF degradation, potentiate the natriuretic action of endogenous ANF independent of systemic or renal hemodynamics. This action does not parallel increases in plasma ANF and is associated with marked increases in urinary ANF and cyclic guanosine monophosphate consistent with enhanced local action of the peptide. In addition, agents that selectively bind to biologically inactive ANF clearance receptors increase endogenous plasma ANF and promote increases in renal sodium excretion. These studies suggest a therapeutic role for neutral endopeptidase inhibition and clearance receptor blockade, while advancing our understanding of the pathophysiology of ANF in congestive heart failure.
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PMID:Pathophysiology of congestive heart failure: role of atrial natriuretic factor and therapeutic implications. 183 25

Inhibition of the enzyme neutral metalloendopeptidase potentiates responses to atrial natriuretic factor and elicits reductions of blood pressure in desoxycorticosterone acetate sodium hypertensive rats. The present study evaluated the role of atrial natriuretic factor and bradykinin in the antihypertensive response to neutral metalloendopeptidase inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which neutral metalloendopeptidase inhibition interferes with atrial natriuretic factor metabolism was explored. The antihypertensive response to the neutral metalloendopeptidase inhibitor SCH 34826 was abruptly reversed by i.v. injection of a polyclonal antiserum to atrial natriuretic factor. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist Thi5,8-D-Phe7 bradykinin. The renal response to atrial natriuretic factor, SCH 34826, and phosphoramidon was inhibited by the bradykinin antagonist. The NEP inhibitor SCH 39370 significantly delayed the disappearance of TCA precipitable radioactivity from plasma following i.v. bolus dosing with 125I-labelled ANF 99-126. The effects were enhanced in the presence of the C receptor ligand. The results indicate that atrial natriuretic factor, but not bradykinin, plays an important role in the antihypertensive response to SCH 34826. Bradykinin plays a permissive role in the diuretic responses to atrial natriuretic factor and inhibitors of neutral metalloendopeptidase. Lastly, neutral metalloendopeptidase inhibition significantly alters the clearance and metabolism of tracer quantities of atrial natriuretic factor.
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PMID:Neutral metalloendopeptidase inhibitors as ANF potentiators: sites and mechanisms of action. 183 29

Whole body clearance of atrial natriuretic factor is due to both receptor uptake and enzymatic degradation initiated by neutral endopeptidase 24.11. The effects of neutral endopeptidase inhibition have been studied in seven sodium-replete sheep using SCH 39370, a specific and potent inhibitor of neutral endopeptidase, in the presence or absence of exogenous hormone [rat ANF-(101-126), 2.4 pmol/kg/min for 2 hours]. SCH 39370 alone (2.5 mg/kg bolus) increased plasma atrial natriuretic factor and plasma cyclic GMP levels, lowered arterial pressure for periods beyond changes in plasma atrial natriuretic factor or cyclic GMP, and suppressed both plasma aldosterone and cortisol levels when compared with vehicle injections. The effects of SCH 39370 were similar to or exceeded those of atrial natriuretic factor infusions, which induced significantly greater increases in plasma atrial natriuretic factor (p = 0.01). Neither agent alone was natriuretic. When SCH 39370 and atrial natriuretic factor were given together, plasma cyclic GMP but not atrial natriuretic factor levels were increased (p = 0.013) compared with atrial natriuretic factor infusion alone, and the half-life was prolonged (p = 0.002) in the presence of SCH 39370. The hypotensive response was greater than that induced by atrial natriuretic factor alone (p = 0.03) but not different from SCH 39370 alone. Inhibitory effects of SCH 39370 on aldosterone levels were similar in the presence of absence of exogenous atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and hormonal effects of neutral endopeptidase inhibitor SCH 39370 in sheep. 185 Jul 15

A metallo-endopeptidase, which appears to be an integral membrane protein of rat kidney, was purified to homogeneity by a series of standard chromatographic procedures. This enzyme significantly hydrolyzed human parathyroid hormone [hPTH(1-84)] and a synthetic substrate Suc-Leu-Leu-Val-Tyr-Mec (Suc = succinyl, Mec = 4-methyl-coumarinyl-7-amide). The purified enzyme had apparent molecular masses of 250 kDa on gel filtration, and 88 kDa and 245 kDa on sodium dodecyl sulfate/polyacrylamide gel electrophoresis under reducing and non-reducing conditions, respectively. Its pH optimum for activity was 8.0-8.5 and its isoelectric point was pH 4.9. Its activity was inhibited by EDTA, EGTA and o-phenanthroline, but not by phosphoramidon. The metal-depleted enzyme was reactivated by the addition of metal ions. The enzyme was also inhibited by chymostatin and eglin C, and by thiol compounds. Of the synthetic substrates examined, the enzyme hydrolyzed only Suc-Leu-Leu-Val-Tyr-Mec, one of the synthetic substrates for alpha-chymotrypsin. It did not hydrolyze synthetic substrates with less than four amino acid residues with tyrosine in the P1 position. The enzyme hydrolyzed hPTH and reduced hen egg lysozyme but did not hydrolyze azocasein or [3H]methyl-casein. NH2-terminal amino acid sequence analyses of the degradation products of hPTH(1-84) and reduced hen egg lysozyme by the purified enzyme revealed that the enzyme preferentially cleaved these peptides at peptide bonds flanked by hydrophilic amino acid residues. Amino acid analyses showed that the main degradation products of PTH were hPTH(17-29), hPTH(30-38) and hPTH(74-84). The ability of the enzyme to hydrolyze peptide bonds flanked by hydrophilic amino acid residues and its inability to degrade azocasein distinguish it from several other kidney endopeptidases reported, such as endopeptidase 24.11 and meprin.
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PMID:A membrane-bound metallo-endopeptidase from rat kidney hydrolyzing parathyroid hormone. Purification and characterization. 188 19


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