Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endopeptidase 24.11 (EC 3.4.24.11) enzymatic activity was spectrofluorimetrically measured in human urine, using a synthetic peptidic substrate. Urinary endopeptidase 24.11 output (Uendo) was determined in 24-hour urine samples of 10 kidney transplant recipients during the first 2 weeks after surgery. In 9 patients, a large increase in Uendo levels was noted during the 1st and/or the 2nd postoperative days (mean +/- SEM of peak Uendo 624 +/- 122 micrograms/24 h, p = 0.0003 as compared to 239 +/- 20 micrograms/24 h in a healthy control population). This occurred whether patients received OKT3 (n = 6) or cyclosporine A (n = 3) as primary immunosuppression. Uendo returned to normal between the 3rd and the 5th postoperative day. We conclude that renal transplantation is associated with an early and marked release of endopeptidase 24.11 in urine. This could be due to the potentially toxic effects of ischemia and/or immunosuppressive drugs on the proximal tubular epithelium. The clinical usefulness of urinary endopeptidase 24.11 as a marker of tubular injury remains to be assessed.
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PMID:Pathological release of urinary endopeptidase 24.11 early after renal transplantation. 130 55

The purpose of this study was to examine whether neutral endopeptidase and angiotensin I-converting enzyme, two membrane-bound metalloenzymes that are widely distributed in the microcirculation, play a role in bradykinin-induced increase in vascular permeability in the hamster cheek pouch. Changes in vascular permeability were quantified by counting the number of leaky sites and by calculating the clearance of fluorescein isothiocyanate (FITC)-dextran (molecular mass, 70,000 d) during suffusion of the cheek pouch with bradykinin. Bradykinin produced a concentration- and time-dependent increase in the number of leaky sites and clearance of FITC-dextran. The selective, active site-directed neutral endopeptidase inhibitors phosphoramidon (1.0 microM) and thiorphan (10.0 microM) and the selective angiotensin I-converting enzyme inhibitor captopril (10.0 microM) each shifted the concentration-response curve to bradykinin significantly to the left. During suffusion with bradykinin (1.0 microM) and phosphoramidon, the number of leaky sites increased significantly from 17 +/- 2 to 27 +/- 4 sites per 0.11 cm2 (mean +/- SEM, p less than 0.05), and FITC-dextran clearance increased significantly from 1.0 +/- 0.2 to 2.1 +/- 0.3 ml/sex x 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of peptidases in bradykinin-induced increase in vascular permeability in vivo. 131 17

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10-200 mg), and the effect of an infusion of a pharmacological dose [45 micrograms (90 micrograms in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean +/- SEM 22.0 +/- 6.2 pmol/l) compared with healthy control subjects (1.3 +/- 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P less than 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P less than 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 +/- 74 pmol/l, which is a level of atrial natriuretic peptide which would have 'swamped' all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism. 132 May 40

In this study, we examined whether inhalation of hypertonic saline aerosols increases vascular permeability in the rat trachea, and we examined the role of neurogenic inflammation in this response. Stereological point counting was performed to measure the percent area occupied by Monastral blue-labeled blood vessels as a means of quantifying the increase in vascular permeability in tracheal whole mounts. Hypertonic saline aerosols (3.6-14.4% NaCl) increased vascular permeability in a dose-dependent fashion compared with 0.9% NaCl. Thus, the area density of Monastral blue-labeled vessels after inhalation of 3.6% NaCl was greater (21.2 +/- 3.5% mean +/- SEM, n = 5) than after 0.9% NaCl aerosol (3.3 +/- 0.9%, n = 5, P less than 0.5). The neutral endopeptidase inhibitor phosphoramidon (2.5 mg/kg, i.v.) significantly potentiated the increase of vascular permeability caused by 3.6% NaCl. Desensitization of sensory nerve endings by pretreatment with capsaicin markedly reduced the usual increase in vascular permeability caused by 3.6% NaCl, but the increase in vascular permeability induced by aerosolized substance P (10(-4) M) was unchanged. These findings suggest that hypertonic saline increases vascular permeability in the rat trachea by stimulating the release of neuropeptides from sensory nerves.
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PMID:Hypertonic saline increases vascular permeability in the rat trachea by producing neurogenic inflammation. 169 78

To determine whether exogenously administered neutral endopeptidase (NEP; enkephalinase, EC 3.4.24.11) inhibits the substance P-induced increase in vascular permeability in the skin, we examined the effects of recombinant human NEP on plasma extravasation induced by intradermal injection of substance P in guinea pig skin. Injection of substance P (2.5 X 10(-8) M) induced significant plasma extravasation in the skin (53 +/- 4 mm2 of Evans blue extravasation; mean +/- 1 SEM). In vitro incubation of substance P with recombinant human NEP prior to injection prevented the substance P-induced plasma extravasation in the skin in a dose-dependent fashion. Intradermal preinjection of recombinant human NEP partially inhibited plasma extravasation induced by subsequent injection of substance P (52 +/- 9% of the control without NEP). The H1 and H2 histamine antagonists pyrilamine and cimetidine, and a muscarinic antagonist, atropine, had no effects on substance P-induced responses. Two products of substance P degradation by NEP containing the carboxy-terminal portion, substance P7-11 and substance P8-11, were also without effect. These findings suggest that recombinant human NEP can attenuate substance P-induced increases in vascular permeability in guinea pig skin and, therefore, may be useful in treating dermatologic disorders in which abnormal responses to substance P or other neuropeptides cleaved by NEP may occur.
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PMID:Recombinant neutral endopeptidase attenuates substance P-induced plasma extravasation in the guinea pig skin. 169 12

We used cultured rabbit tracheal epithelium to determine the effect of mammalian-derived tachykinin on airway ciliary activity and its modulation by neutral endopeptidase EC 3.4.24.11 (NEP). Neurokinin A (NKA) caused dose-dependent increases in ciliary beat frequency (CBF), as measured by a photoelectric method, with the maximal increase from the baseline 15.7 +/- 1.7% (mean +/- SEM, p less than 0.01), whereas substance P (SP) had no effect. The NKA-induced increase in CBF was not inhibited by phentolamine, propranolol, or atropine, but it was abolished by the tachykinin antagonist [D-Pro2, D-Trp7,9]SP. Pretreatment of tissue with thiorphan (10(-5) M), a NEP inhibitor, had little effect on CBF responses to NKA; however, it significantly potentiated the responses to SP (14.9 +/- 3.0%, p less than 0.01). Other peptidase inhibitors, including captopril, bestatin, and leupeptin, did not alter the tachykinin-induced CBF response, suggesting that angiotensin converting enzyme, aminopeptidases, and serine proteinases do not modulate ciliary activity in response to tachykinins. These results suggest that NKA increases CBF by acting directly on tachykinin receptors and that NEP may play a role in modulating the tachykinin-induced stimulatory effects on CBF.
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PMID:Neutral endopeptidase inhibitor potentiates the tachykinin-induced increase in ciliary beat frequency in rabbit trachea. 169 40

This study was designed to evaluate the role of endogenous enkephalinase in regulating bronchoconstrictor responses in guinea pigs. We evaluated the effects of phosphoramidon, an enkephalinase inhibitor, on the increases in lung resistance (RL) caused by exogenous substance P and inhaled capsaicin (an agent thought to provoke bronchoconstriction in guinea pigs by stimulating the release of tachykinins from afferent nerve endings). In 6 of 6 animals, phosphoramidon potentiated the substance P-induced increase in RL (RL increased 380 +/- 100% [mean +/- SEM] before phosphoramidon and 1,300 +/- 400% afterward, p less than 0.025). In 4 of 4 animals, the repeated administration of a single dose of substance P after saline did not result in potentiation of the increase in RL caused by substance P. Similarly, in 6 animals exposed to inhaled capsaicin, phosphoramidon significantly increased capsaicin responsiveness when compared to 6 capsaicin-exposed animals not treated with phosphoramidon. Phosphoramidon-induced augmentation of the airway responsiveness to substance P and to capsaicin was not simply the result of a nonspecific increase in airway smooth muscle responsiveness because phosphoramidon failed to potentiate the bronchoconstrictor response to inhaled acetylcholine. These results suggest the enkephalinase plays an important role in modulating in vivo bronchoconstrictor responses to substance P in guinea pigs. Therefore, alterations in enkephalinase activity could contribute to in vivo alterations in bronchoconstrictor responsiveness.
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PMID:Phosphoramidon potentiates the increase in lung resistance mediated by tachykinins in guinea pigs. 244 5

Endopeptidase 24.11, a widely distributed membrane-bound peptidase is found in low levels in the serum of normal individuals. Although increased levels of the enzyme have been found in sera of patients with sarcoidosis and adult respiratory distress syndrome, the cellular origin of circulating endopeptidase 24.11 remains unknown. As the brush border of the proximal tubular epithelial cells have the highest endopeptidase specific activity, we investigated the possible contribution of the kidney to the release of endopeptidase 24.11 in the systemic circulation. Therefore, we measured serum levels of the enzyme in patients with end-stage renal failure (ESRF) treated by haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Increased serum levels of endopeptidase 24.11 were observed both in HD patients (mean +/- SEM: 74.6 +/- 20.9 ng/ml) and in CAPD patients (mean +/- SEM: 45.1 +/- 8.1 ng/ml) as compared to normal individuals (mean +/- SEM: 13.6 +/- 1.4 ng/ml). Endopeptidase levels remain stable during haemodialysis sessions on two different dialysis membranes. Finally, serum levels of the enzyme in anephric patients tend to be lower than in ESRF patients, suggesting that the kidney may contribute to the generation of the circulating form of endopeptidase 24.11.
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PMID:Increased serum levels of endopeptidase 24.11 ('enkephalinase') in patients with end-stage renal failure. 254 94

Enkephalins are short lived peptides which are rapidly cleaved by 2 membrane peptidases: an enkephalinase and a carboxypeptidase. Enkephalin-like immuno-reactivity has been demonstrated in the smooth muscle and in the myenteric plexus of the human lower esophageal sphincter (LES). Opioid receptors have been found in the gastrointestinal tract and recently an enkephalin analog has been shown to inhibit LES relaxation and modify the peristaltic progression of the esophageal contractions. Acetorphan is an enkephalinase inhibitor which prevents, at least to some extent, the hydrolysis of endogenous enkephalins. Thus, the present work was designed to study the effect of acetorphan on esophageal motility. Ten healthy volunteers (mean age: 23 years) were studied. On 2 separate days, each subject received in random order acetorphan (2.5 mg/kg intravenously at a constant rate in 20 min) or placebo. Esophageal manometry was performed with a Dentsleeve. Wet swallows (5 ml) were performed at 1 min intervals during 80 min and results were pooled in 10 min periods. Acetorphan inhibited significantly (p less than 0.02) LES relaxation 20 min after the beginning of the infusion and throughout the study. The maximal effect occurred 50 min after the beginning of acetorphan infusion and LES relaxation (m +/- SEM) was reduced from 92 +/- 2.6 to 79.5 +/- 2.9 p. 100 (p less than 0.01). Duration, amplitude, and velocity of esophageal contractions were not modified. Acetorphan an enkephalinase inhibitor, is able to reproduce the effect of IV exogenous enkephalins on LES relaxation in man. This result suggest that endogenous enkephalins might play a role in the normal control of the LES relaxation.
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PMID:Effects of an enkephalinase inhibitor on esophageal motility in man. 322 Feb 32

We are interested in the mechanisms of ozone-induced lung effects after short-term exposure and the relationship with subsequent pulmonary inflammation and disease. Our hypothesis is that ozone, as a powerful oxidant, will diminish the activity of neutral endopeptidase (NEP) in the airways of humans with resulting increased concentrations of neuropeptides such as substance P (SP). We have exposed seven (two women, five men) healthy, nonsmoking individuals (22 to 30 yr of age) to filtered air and ozone (0.25 ppm) for 1 h in an environmental chamber during heavy exercise. Bronchoscopy with airway lavage (AL) and bronchoalveolar lavage (BAL) was performed immediately after ozone exposure. The lavage samples were analyzed by enzyme immunoassay for SP and 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) (a marker for oxidative free radical reaction) and by radioimmunoassay for complement fragments. FEV1 had declined 12.4 +/- 1.9% (mean +/- SEM) as a result of ozone exposure. The AL concentration for SP and 8-epi-PGF2 alpha and BAL concentration of C3a after ozone exposure were significantly higher than after the filtered air exposure (P < 0.05). There was a significant correlation between SP and 8-epi-PGF2 alpha concentrations in the AL fluid (r2 = 0.89 and P < 0.05). There were no changes in C5a in either compartment or any of the mediators in the plasma samples. These results extend previous results from animal studies suggesting that ozone's mechanism of action is through an oxidative reaction resulting in a decreased activity of NEP in the airways with a subsequent increase in the concentration and activity of SP.
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PMID:Ozone-induced increases in substance P and 8-epi-prostaglandin F2 alpha in the airways of human subjects. 769 98


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