EC:3.4.24.11 - FACTA Search

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)

The natriuretic peptide family consists of three members: atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Atrial and brain natriuretic peptides possess similar effects, causing natriuresis, vasodilation, and suppression of the renin-angiotensin-aldosterone system. C-type natriuretic peptide has been suggested to exert its predominant effect on the vasculature, eliciting vasodilation and inhibiting the proliferation of vascular smooth muscle cells. Numerous studies have broadened our current knowledge of the regulation of natriuretic peptide gene expression, biosynthesis, and secretion, as well as structure of specific receptors. This has led to a better understanding of the renal, cardiovascular, and endocrine actions of natriuretic peptides in both normal and pathophysiological states, including hypertensive disease. Development of nonpeptide neutral endopeptidase inhibitors and antagonists for natriuretic peptide receptors may reveal the range of potential therapeutic application of atrial and other natriuretic peptides in hypertension.
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PMID:The natriuretic peptides in hypertension. 749 58

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.
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PMID:Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. 749 88

To explore the mechanisms of the renal effects of neutral endopeptidase (NEP) inhibition, the effects of an NEP inhibitor, candoxatril (UK 79,300; UK), in Dahl salt-sensitive (SS) and salt-resistant (SR) rats were examined. UK dose-dependently decreased blood pressure (BP) in SS rats (20 mg/kg: 174 +/- 5 vs. 155 +/- 8 mm Hg, p < 0.01) but not in SR rats. Urinary sodium excretion (UNaV) of both rat strains receiving high-salt diets was increased to a greater extent than that of rats receiving low-salt diets. Basal plasma atrial natriuretic peptide (ANP) level in hypertensive SS rats was higher than in SR rats (192 +/- 18 vs. 118 +/- 24 pg/ml, p < 0.05). UK increased ANP levels in the plasma and urine two- and 11-fold, respectively. UK-induced increases in UNaV, urinary cyclic GMP, and plasma ANP concentrations were significantly augmented by coadministration of a clearance receptor agonist, C-ANF(4-23) or brain natriuretic peptide (BNP). Thus, the effects of NEP inhibition appear to be potentiated by the reduced receptor-mediated metabolism of ANP. This may explain the greater response to the NEP inhibitor in Dahl rats with hypertension or high-salt feeding.
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PMID:Mechanisms of the natriuretic effects of neutral endopeptidase inhibition in Dahl salt-sensitive and salt-resistant rats. 751 59

1. We have previously shown that atrial natriuretic peptide causes bronchodilatation and reduces bronchial reactivity when administered intravenously or by inhalation to asthmatic patients. We wished to determine the direct effect of exogenously applied atrial natriuretic peptide on isolated airway and the role of proteases important in atrial natriuretic peptide degradation in other organ systems. 2. The ability of atrial natriuretic peptide (alpha-human atrial natriuretic peptide 28-amino acid) to relax precontracted tissues and to protect against methacholine-induced contraction was studied in human and bovine tissue. The role of neutral endopeptidase-24.11 and other proteases in regulating the effect of atrial natriuretic peptide on bronchial smooth muscle was also examined by studying the influence of phosphoramidon, a protease inhibitor, whose actions include the inhibition of neutral endopeptidase-24.11, and the protease inhibitors leupeptin, aprotinin and soybean trypsin inhibitor on the airway response to atrial natriuretic peptide. 3. In human and bovine tissue atrial natriuretic peptide (10(-6) mol/l) caused a slight relaxation of methacholine-contracted tissue [mean (SEM) percentage inhibition of contraction of 13.2 (3.02)% and 9.41 (2.63)% respectively] and evoked a significant rightward shift of the cumulative concentration-response curve to methacholine [pD2 5.15 (0.23) and 4.85 (0.1) compared with control values of 6.14 (0.1) and 5.85 (0.16), respectively]. 4. Phosphoramidon potentiated atrial natriuretic peptide-induced relaxation of methacholine-induced tone and the ability of atrial natriuretic peptide to protect against methacholine-induced contraction. The combination of leupeptine, aprotinin and soybean trypsin inhibitor did not significantly alter the bronchial response to atrial natriuretic peptide in either human or bovine tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of the effect of atrial natriuretic peptide in human and bovine bronchi by phosphoramidon. 751 55

We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were > 500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted < 60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 microgram/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 muEq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 muEq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacologic profile of CGS 24128, a potent, long-acting inhibitor of neutral endopeptidase 24.11. 751 77

The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.
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PMID:Acute renal effects of neutral endopeptidase inhibition in humans. 751 5

We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide in chronically hypertensive dogs. 755 24

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), are two mechanistically similar enzymes involved in the metabolism of several vasoactive peptides. Selective inhibitors of ACE are effective antihypertensive agents in high-renin, renovascular rats and normal-renin, spontaneously hypertensive rats (SHR), but are not effective in the low-renin, deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In contrast, NEP inhibitors are only effective in the low-renin model of hypertension. Treatment with a combination of selective inhibitors or with a dual inhibitor of both enzymes produces an antihypertensive response regardless of basal plasma renin activity. In this study, we compared the activities of MDL 100,173, a novel subnanomolar inhibitor of both ACE and NEP, with those of equimolar doses of captopril, a selective ACE inhibitor, following intravenous administration in these three rat models of hypertension. Treatment with MDL 100,173 significantly lowered blood pressure compared to vehicle treatment in all three models, whereas captopril treatment lowered blood pressure in the renovascular and SHR models only. Administration of MDL 100,173 also significantly elevated diuresis and natriuresis compared to either vehicle or captopril treatment in the SHR and DOCA-salt rats. Urinary excretion of atrial natriuretic peptide (ANP) was increased by MDL 100,173 treatment in all three models of hypertension. Treatment with captopril did not alter urine, sodium, or ANP excretion in any of the models. However, plasma-renin activity was elevated by both MDL 100,173 and captopril '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''
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PMID:Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase in rats with hypertension. 756 49

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs. Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100 micrograms/kg/min and 10 micrograms/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone. Coadministration of both compounds increased urinary excretion of volume and sodium, cGMP and ANP. We found also increased plasma cGMP, plasma ANP and decreased plasma renin activity. No effects were observed with respect to blood pressure, left ventricular pressure or heart rate during the infusion period of 2 h. We conclude from these investigations, that blocking both degrading pathways of ANP with the ANP-C receptor ligand AP 811 and the neutral endopeptidase inhibitor (S)-thiorphan is more effective than inhibition of either system alone. Such a combination might therefore be a useful therapeutic tool in cardiovascular diseases.
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PMID:Interaction of a neutral endopeptidase inhibitor with an ANP-C receptor ligand in anesthetized dogs. 758 Dec 58

1. This study examined the activity and mechanisms of action of urodilatin in bovine bronchi. For comparison, the ability of urodilatin to evoke bronchodilatation or protect against subsequent challenge was compared to that of the closely related peptide alpha-human atrial natriuretic peptide (ANP). 2. Urodilatin reversed methacholine-evoked contraction in a concentration-dependent manner in bovine bronchi. In the absence of any attempt to prevent degradation by neutral endopeptidases, urodilatin was more potent than ANP in this tissue. 3. The bronchodilator properties of urodilatin were significantly augmented by the neutral endopeptidase inhibitor, phosphoramidon (3.68 x 10(-5) M). This provides evidence for at least partial degradation of urodilatin by neutral endopeptidases. With phosphoramidon present, urodilatin and ANP were equipotent. 4. In the presence of phosphoramidon (3.68 x 10(-5) M), pre-incubation with urodilatin (10(-6) M) had a protective effect against subsequent methacholine-induced contraction. This action of urodilatin was quantitatively similar to that of ANP in the presence of this endopeptidase inhibitor. 5. The actions of urodilatin appear to involve ATP-sensitive K+ channels since tolbutamide (10(-6) - 10(-5) M) significantly attenuated the relaxations induced by this peptide. 6. Small conductance Ca(2+)-activated K+ channels seem likewise to be implicated in the actions of urodilatin since blockade of these channels with apamin (10(-7) - 10(-6) M) resulted in a marked attenuation of urodilatin-evoked responses. 7. The presence of charybdotoxin (10-9 M-10-M) had no significant effect on subsequent responses tourodilatin suggesting that large conductance Ca2+-activated K+ channels are not involved in the relaxations evoked by this peptide.8. In the presence of phosphoramidon (3.68 x 10-5 M), urodilatin (10-6 M) evoked elevation of cyclic GMP levels within bovine bronchial tissue. Levels of cyclic GMP increased significantly within 5-10 s in response to this peptide and preceded the initiation of relaxant responses. Maximum increases in cyclic GMP levels were reached within 5 min; the time required for maximal relaxation evoked by this peptide.9. In conclusion, urodilatin, like ANP reversed and protected against, subsequent methacholine-induced bronchoconstriction; an action enhanced by the presence of phosphoramidon (3.68 x 1O-5 M).Associated with these actions of urodilatin was a rise in cyclic GMP levels as well as the opening of ATP-sensitive K+ and small conductance Ca2+-activated K+ channels.
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PMID:Bronchodilator and pre-protective effects of urodilatin in bovine bronchi in vitro: comparison with atrial natriuretic peptide. 760 43

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