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)

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide which is processed from an adrenomedullin precursor. PAMP is rapidly cleaved by human neutral endopeptidase (NEP), a protease which plays a key role in the degradation of human atrial natriuretic peptide (ANP). A double reciprocal plot indicated that Km of NEP as a substrate of PAMP was 6.1 microM and V(max) was 3.1 mmol/min/mg of NEP. EDTA, phosphoramidon and thiorphan inhibit the proteolysis of PAMP by NEP. NEP cleaves at least 6 peptide bonds in human PAMP; Arg2-Leu3, Glu8-Phe9, Lys12-Trp13, Lys15-Trp16, Trp16-Ala17 and Ala17-Leu18. The present data suggest that NEP may be involved in the circulation control by degrading PAMP as well as ANP.
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PMID:Proadrenomedullin N-terminal 20 peptide is rapidly cleaved by neutral endopeptidase. 868 31

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
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PMID:Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure. 1156 14

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.
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PMID:Combined endopeptidase inhibition and adrenomedullin in sheep with experimental heart failure. 1179 85

Adrenomedullin (ADM), a multifunction peptide with important roles in regulating cardiovascular homeostasis, has the vasodilatory properties and is of particular interest in the pathophysiology of sepsis. ADM levels in plasma and tissues are regulated by the proteolysis of neutral endopeptidase (NEP), the major enzyme of ADM degradation. We observed the NEP activity in the plasma, the activity and distribution of NEP and its mRNA expression in the tissues of rats in septic shock to study the possible role of NEP in elevating tissue ADM concentration during sepsis. ADM level increases progressively during sepsis except in the jejunum. Rats in early phase of shock (ES) showed diverse changes in tissue NEP activity. Plasma NEP activity, tissue NEP activity and its protein and mRNA expression in the left ventricle, aorta, jejunum and lung in the late phase of shock (LS) rats were lower than those in ES and the control, but no statistical change of NEP activity in the kidney was observed. The level of ADM was inversely correlated with NEP activity in the plasma, ventricle and aorta and positively correlated with NEP activity in the jejunum. Thus, in sepsis, the local concentration and action of ADM in tissues may be differentially regulated by NEP.
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PMID:Relationship between contents of adrenomedullin and distributions of neutral endopeptidase in blood and tissues of rats in septic shock. 1500 37

The objective of this study was to determine whether adrenomedullin, a vasodilator peptide, modulates the process of cell death in cardiomyocytes and whether its effect would be enhanced by the endopeptidase inhibitor omapatrilat, which reduces adrenomedullin degradation. Further, we sought to determine whether the effect of adrenomedullin involved an action to preserve mitochondrial transmembrane potential (DeltaPsi(m)). Cardiomyocytes in culture were treated with agents that interrupted the mitochondrial electron transport chain, inhibiting glycolysis and oxidative phosphorylation. Cell death was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and DeltaPsi(m) was assessed by fluorescent microscopy. Cytochrome c loss from mitochondria and appearance in cytosol was determined by Western blotting. Potassium cyanide (KCN) plus deoxyglucose or antimycin A, for 24 h, produced significant (p<0.01) concentration-dependent reductions in cell viability or increases in cell death. Adrenomedullin reduced cell death produced in this manner and the effect of adrenomedullin was enhanced by treatment with omapatrilat. In contrast, there was no additional reduction in cell death by lisinopril treatment. Omapatrilat plus adrenomedullin reduced the KCN plus deoxyglucose-induced increase in cytosolic cytochrome c. A likely mechanism centers on the ability of adrenomedullin plus omapatrilat to prevent the decline in mitochondrial DeltaPsi(m) produced by KCN plus deoxyglucose treatment. In summary, adrenomedullin plus omapatrilat limited the decline in mitochondrial DeltaPsi(m) that accompanies interruption of mitochondrial metabolism and limited the extent of cell death in cardiomyocytes treated with KCN plus deoxyglucose or antimycin. Adrenomedullin plus the endopeptidase inhibitor omapatrilat may be a useful strategy to protect cardiomyocytes from cell death, in conditions associated with impairment of mitochondrial function.
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PMID:Omapatrilat enhances adrenomedullin's reduction of cardiomyocyte cell death. 1734 42

Adrenomedullin (AM) may play a role in the pathophysiology of heart failure. Plasma levels of AM are raised in cardiovascular disease in proportion to severity of cardiac dysfunction, and plasma AM levels measured in acute myocardial infarction and heart failure are a useful prognostic indicator of outcome. AM administration in both experimental and human heart failure induces a beneficial spectrum of biological action including reduced arterial and atrial pressures, improved cardiac output, inhibition of plasma aldosterone and preservation or augmentation of urinary sodium excretion. Combining AM administration with either angiotensin-converting enzyme inhibition or neutral endopeptidase inhibition results in augmentation of the hemodynamic and renal effects of the individual treatments. Manipulating the AM system may prove beneficial as an adjunctive therapeutic strategy in cardiac disease.
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PMID:Adrenomedullin in heart failure: potential therapeutic implications. 1980 68