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)

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

A novel small linear C-atrial natriuretic factor receptor ligand [C-ANF-(11-15)] and phosphoramidon (PHO) were used to determine the effects of C-ANF receptor blockade alone, or in combination with inhibition of neutral endopeptidase (NEP), on the pharmacokinetics and metabolism of ANF in the rat. C-ANF-(11-15) infusion decreased apparent volume of distribution (Vss) and metabolic clearance rate (MCR) of administered 125I-ANF-(1-28) to one-third of their control values, whereas PHO alone was without effect on these parameters. In combination with C-ANF-(11-15), however, PHO further decreased MCR of 125I-ANF-(1-28) and increased plasma half time by more than threefold. High-performance liquid chromatography analysis revealed that C-ANF-(11-15) inhibited the delayed appearance of free 125I and [125I]monoiodotyrosine but had no effect on the small proportion of NEP metabolites in plasma. The combination of C-ANF-(11-15) and PHO further delayed the appearance of small metabolites, abolished the appearance of NEP metabolites, and markedly prolonged the permanence of intact 125I-ANF-(1-28) in plasma. The results demonstrate that C-ANF receptor blockade by C-ANF-(11-15) impairs clearance and metabolism of ANF, an effect which is synergistically potentiated by concomitant inhibition of NEP. C-ANF-(11-15) alone or in combination with NEP inhibitors may be a potentially useful therapeutic tool in the treatment of cardiovascular and renal diseases.
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PMID:Clearance receptor and neutral endopeptidase-mediated metabolism of atrial natriuretic factor. 141 84

A bivariate assay has been developed to measure both ANF, and cleaved ANF (ANF(101-105/106-126)) the primary product of endopeptidase-24.11 action on rat ANF(101-126). The assay employed two different antisera directed to the carboxy-terminal and ring regions of ANF to enable discrimination and measurement of intact endogenous ANF(99-126) and infused cleaved ANF (rat ANF(101-105/106-126)) in sheep plasma extracts. The assay which was validated by HPLC analysis of plasma extracts, had sufficient accuracy and precision to measure the metabolic clearance rate and half-life of cleaved ANF when infused in normal sheep.
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PMID:Bivariate assay for cleaved atrial natriuretic factor (ANF(101-105/106-126)) in sheep plasma. 143 81

The effects of a neutral endopeptidase (NEP) inhibitor, SCH 39.370, and a clearance receptor ligand, C-atrial natriuretic factor-(4-23) [C-ANF-(4-23)] on the plasma concentration of atrial natriuretic peptide (ANP) and hemodynamics under basal conditions and during increased circulating ANP levels produced by acute volume loading in conscious rats were studied. Measurements of plasma immunoreactive N-terminal fragment of pro-ANP (IR-NT-ANP) concentrations were used to characterize the endogenous secretion of the biologically active peptide in response to drug infusions and volume expansion. Infusion of SCH 39.370 increased plasma IR-ANP levels dose-dependently in conscious normotensive Wistar rats; maximal increases of 17% (P less than 0.02) after the dose of 3 mg/kg, iv, and 67% (P less than 0.002) after the dose of 10 mg/kg, iv, SCH 39.370 were noted. Similarly, infusion of C-ANF-(4-23) alone (30 micrograms/kg, iv bolus, followed by infusion of 3 micrograms/kg.min for 30 min) increased plasma IR-ANP levels by 37% (P less than 0.001). Given in combination, SCH 39.370 and C-ANF-(4-23) produced a greater increase in plasma IR-ANP concentration (83%; P less than 0.001) than when either substance was infused alone. Neither SCH 39.370 nor C-ANF-(4-23), alone or in combination, had any effect on basal plasma IR-NT-ANP concentrations. The combination reduced mean arterial pressure (8 +/- 2 mm Hg; P less than 0.01) and right atrial pressure (0.67 +/- 0.20 mm Hg; P less than 0.01), while administration of SCH 39.370 or C-ANF-(4-23) alone had no effect on mean arterial pressure, heart rate, or right atrial pressure in conscious rats. Acute volume expansion with 0.9% saline (1.1 ml/100 g BW) resulted in an increase in right atrial pressure (2.7 +/- 0.2 mm Hg; P less than 0.001) as well as in plasma IR-ANP (55%; P less than 0.001) and IR-NT-ANP concentrations (24%; P less than 0.03). Volume expansion in rats pretreated with SCH 39.370 resulted in a greater increase in plasma IR-ANP concentrations than in control animals; the relative ANP increases corresponding to the 2.5-mm Hg increase in right atrial pressure were 1.48-, 1.69-, and 2.28-fold in control, 3 mg/kg SCH 39.370-treated, and 10 mg/kg SCH 39.370-treated groups, respectively. When the relation between changes from control in plasma IR-ANP and right atrial pressure in response to acute volume expansion was analyzed in the presence of C-ANF-(4-23), no difference was noted between control and treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Basal and volume expansion-stimulated plasma atrial natriuretic peptide concentrations and hemodynamics in conscious rats: effects of SCH 39.370, an endopeptidase inhibitor, and C-ANF-(4-23), a clearance receptor ligand. 153 Nov 29

After i.v. injection of 125I-labeled rat atrial natriuretic factor ([125I] ANF; 99-126) in tracer dose to mice, a saturable binding to lung membranes was evidenced using a filtration assay. Analysis of the membrane-bound radioactivity by high-pressure liquid chromatography indicated that it corresponded to the intact hormone in sinorphan-treated mice. [125I]rANF binding was inhibited completely by i.v. administration of rANF with an ED50 of 1.0 +/- 0.1 nmol/kg, a value obtained in sinorphan-treated mice. SC 416,542, an ANF analog with a four amino acid deletion in its ring, representing a selective ligand of ANF clearance receptors, was as potent as rANF in inhibiting the in vivo binding. By contrast, ANF fragments produced by enkephalinase (EC 3.4-24.11, membrane metalloendopeptidase) were less potent or even inactive in competing with [125I]rANF. It is concluded that [125I]rANF binding to lung membranes in vivo occurs to clearance receptors. [125I]rANF binding was enhanced by more than 2-fold in mice receiving enkephalinase inhibitors such as sinorphan and, although to a lesser extent, aminopeptidase inhibitors; on the other hand inhibitors of a variety of other peptidases were ineffective. These data confirm by a novel approach that enkephalinase plays a key role in the inactivation of circulating ANF. Hence, the in vivo binding test can be used to assess the activity of clearance receptor ligands and peptidase inhibitors, two classes of drugs affecting ANF metabolism, with potential clinical utility in cardiovascular and salt-retaining diseases.
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PMID:Binding of [125I]atrial natriuretic factor to mouse lung membranes in vivo: characterization and effects of peptidase inhibitors. 153 34

In the present study, we investigated the effects of calmodulin, adenosine 5'-triphosphate (ATP) and pertussis toxin (PT) on phorbol ester (PMA) (a protein kinase C activator) induced inhibition of ANF-stimulated cyclic GMP formation in cells from the human renal cell line, SK-NEP-1. PMA inhibited ANF-stimulated guanylate cyclase activity in particulate membranes by about 65%. Calmodulin reversed this inhibition in a dose dependent manner. ATP potentiated Mg++ but not Mn++ supported guanylate cyclase activity. In PMA treated membranes, ATP potentiating effects were abolished. PMA also inhibited ANF-stimulated cGMP accumulation, but pretreatment with PT prevented this PMA inhibition. PT did not affect basal or ANF-stimulated cGMP accumulation. In conclusion, these results demonstrated that PMA (activated protein kinase C) inhibited ANF stimulation of particulate guanylate cyclase in opposition to the activating effects of calmodulin or ATP in SK-NEP-1 cells. The protein kinase C inhibitory effects appeared to be mediated via a PT-sensitive G protein.
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PMID:The opposing effects of calmodulin, adenosine 5'-triphosphate, and pertussis toxin on phorbol ester induced inhibition of atrial natriuretic factor stimulated guanylate cyclase in SK-NEP-1 cells. 167 90

We examined calcium and calmodulin regulation of atrial natriuretic factor stimulation of particulate-membrane guanylate cyclase (ANF-s-GC) in SK-NEP-1 cells. W7 and trifluoropiperazine, but not W5, inhibited whole cellular ANF-stimulated cyclic GMP accumulation (ANF-s-cGMP). EGTA and LaCl3 decreased ANF-s-GC and calmodulin reversed this inhibition. A23187-induced inhibition of ANF-s-cGMP was only partly reversible by IBMX. H7 or staurosporine counteracted the inhibitory effect of A23187. Calcium inhibited basal and ANF-s-GC. These data suggest that at low concentrations of calcium, ANF-s-GC was calcium-calmodulin dependent but high concentrations of calcium inhibited ANF-s-GC through phosphodiesterase, through inhibition of GC, and probably through protein kinase C.
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PMID:Calcium and calmodulin regulate atrial natriuretic factor stimulation of cyclic GMP in a human renal cell line. 168 32

The pathophysiological role of atrial natriuretic factor in patients with chronic heart failure is still unclear. Plasma ANF levels are elevated in this condition, particularly in patients with severe left ventricular dysfunction and during acute exacerbations. Drug therapy, including diuretics, vasodilators and inotropes which reduce cardiac filling pressures also reduce plasma ANF levels. In the clinical setting the measurement of ANF levels may provide a useful means of assessing salt and water retention in patients with heart failure. Intravenous infusion of ANF to patients with heart failure causes a diuresis and natriuresis, a fall in filling pressures and possibly suppression of the renin-angiotensin aldosterone system. High bolus dosing with the peptide may reduce systemic vascular resistance resulting in hypotension, which markedly attenuates the renal effects. A new pharmacological approach in this area is the development of neutral endopeptidase inhibitors, which prolong the half-life of endogenous ANF and potentiate its effects. The therapeutic potential of ANF in heart failure has yet to be realised.
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PMID:Atrial natriuretic factor in chronic heart failure. 182 7

The sequence of ovine ANF is not known, yet sheep have been used extensively for ANF studies. We sequenced the circulating form of ovine ANF from coronary sinus plasma of sheep in paced heart failure. The main circulating form was identical to human ANF(99-126). Small amounts of ANF identical to human ANF(103-126) and ANF(101-126) peptides were also found. Incubation of labeled ANF in ovine serum suggested ANF(103-126) could be a degradation product of ANF(99-126). The endopeptidase-24.11 degradation product ANF(99-105/106-126) was not found in ovine plasma, in contrast to human plasma where it was a minor component. These results show that while the main circulating forms are similar in sheep and humans, there are differences in the minor peptides.
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PMID:Ovine atrial natriuretic factor: sequence of circulating forms and metabolism in plasma. 182 9

Our studies with the prototypical NEP inhibitor SCH 34826 indicate the potential role of this class of compounds in cardiovascular modulation. The data assembled to date indicate that NEP inhibition elicits significant ANF-like effects in animals and man. The early data generated to date on SCH 34826, when considered with those data generated on other NEP inhibitors, indicate that NEP inhibition may have therapeutic utility in some forms of hypertension and congestive heart failure.
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PMID:SCH 34826: an overview of its profile as a neutral endopeptidase inhibitor and ANF potentiator. 183 84


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