Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown previously that N-glycosylation of Asn-144 and/or Asn-627 is important for functional expression of neutral endopeptidase-24.11 (NEP). All glycosylation sites of NEP are conserved within endothelin-converting enzyme-1 (ECE-1). In the present study we investigated the importance of proper glycosylation for the biologic function of ECE-1. We show that the double mutation of Asn-632 and Asn-651 leads to expression of an enzymatically inactive ECE-1 protein. In contrast, the single mutation of either Asn-632 or Asn-651 did not alter the enzymatic activity of ECE-1b.
J Cardiovasc Pharmacol 1998
PMID:Glycosylation of Asn-632 and Asn-651 is important for functional expression of endothelin-converting enzyme-1. 959 84

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.
J Cardiovasc Pharmacol 1998
PMID:Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells. 959 86

A number of studies using endothelin (ET) precursors, commonly termed big ETs, have revealed the presence of endothelin-converting enzyme (ECE) activity in various vascular and nonvascular preparations. Since then, more than one ECE has been cloned. It has also been observed that big ET-1 and big ET-3 are not converted by the same enzyme. The ECE responsible for big ET-3 conversion is rarely present because big ET-3 does not induce a contractile response in most isolated preparations tested. In this study we characterized ECE activities present in two human preparations, the umbilical artery and vein, testing the contractile activities of the three human Big ETs in the presence or absence of phosphoramidon, a dual ECE/neutral endopeptidase inhibitor. The results show that human big ET-1(1-38) is 6.3-fold more potent than big ET-2(1-38) in the human umbilical artery (an ETA preparation), whereas big ET-1 is equipotent to big ET-2 in the vein (which contains ETA and ETB receptors). Human big ET-3(1-41) is inactive on both vessels. Furthermore, phosphoramidon attenuated human big ET-1-induced contractions only in the umbilical artery and not in the vein. Such observations, in terms of substrate selectivity and phosphoramidon sensitivity, suggest the presence of distinct ECE activities in human vein and arteries.
J Cardiovasc Pharmacol 1998
PMID:Contractile activity of endothelins and their precursors in human umbilical artery and vein: identification of distinct endothelin-converting enzyme activities. 959

Endothelin-1 (ET-1) may be involved in the upregulation of cerebroarterial resistance under pathologic conditions, most notably in the development of vasospasm after subarachnoid hemorrhage. Therefore, blocking the contractile action of ET-1 by receptor antagonists may prove to be a new and worthwhile approach. However, decreasing synthesis and release of ET-1 by blocking the endothelin-converting enzyme (ECE) activity may also prove worthwhile. In this study we have therefore investigated the effect of several putative ECE inhibitors in isolated rat basilar artery by measuring isometric contraction after application of big ET-1, the precursor peptide which is not vasoactive in itself. In the presence of phosphoramidon (10(-4) M in segments with an intact endothelium or 5 x 10(-4) M in de-endothelialized segments), there was only a small shift to the right of the concentration-effect curve for big ET-1. Similarly, 10(-3) M thiorphan (a selective inhibitor of the neutral endopeptidase) did not affect big ET-1-induced contraction, both alone and in combination with phosphoramidon (10(-3) M). When the big ET-1 analogue [22Phe]big ET-1[19-37] was applied, an increase in resting tension occurred irrespective of whether or not the endothelium was present. Furthermore, in the presence of 10(-5) M [22Phe]big ET-1[19-37], contraction induced by big ET-1 was not affected in de-endothelialized segments but rather was enhanced in endothelium-intact segments. These results suggest the presence of functional ECE activity in the rat basilar artery wall. However, such activity could not be markedly inhibited with different putative enzyme inhibitors. Therefore, the chemical nature of the cerebroarterial ECE activity must be further elucidated before rational development of efficient ECE inhibitors for treatment of cerebral vasospasm becomes possible.
J Cardiovasc Pharmacol 1998
PMID:Evidence for functional endothelin-converting enzyme activity in isolated rat basilar artery: effect of inhibitors. 959 2

The purpose of this study was to identify endothelin-converting enzyme (ECE) inhibitors that also possess inhibitory activity for neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE). The ortho-substituted benzofused macrocyclic lactams, such as CGS 26670, are generally potent NEP inhibitors but poor ACE inhibitors. CGS 26670 inhibited ECE activity with an IC50 of 600 nM, whereas it inhibited NEP and ACE activities with IC50 values of 0.9 and > 10,000 nM, respectively. This compound also prevented the conversion of big endothelin-1 (big ET-1) to ET-1 by denuded porcine coronary arterial smooth muscle with an IC50 of 200 nM. The ACE inhibitory activity is greatly is greatly improved in metasubstituted benzofused macrocyclic lactams. For example, CGS 26582 inhibited ECE, NEP, and ACE activities with IC50 values of 620, 4, and 175 nM, respectively. When injected at 30 mg/kg i.v. in conscious rats, followed by a challenge with big ET-1 at 1 nmol/kg i.v., this compound suppressed by 44% the increase in mean arterial blood pressure owing to the generation of ET-1 by ECE. Because ECE, NEP, and ACE play regulatory roles in cardiovascular and renal function, triple inhibitors of these enzymes may represent a novel class of agents for treatment of cardiovascular and renal diseases.
J Cardiovasc Pharmacol 1998
PMID:Benzofused macrocyclic lactams as triple inhibitors of endothelin-converting enzyme, neutral endopeptidase 24.11, and angiotensin-converting enzyme. 959 4

We have previously detected in cardiac patients severalfold higher levels of endothelin (ET) in the pericardial fluid (PF) than in the plasma (PL). We postulated that this is due to different activities of neutral endopeptidase (NEP) in the two compartments. With approval of the ethical committee and informed consent by 32 patients (18 men, 14 women, aged 62 +/- 2 years; NYHA II-IV), PF was taken during cardiac surgery. PL samples were obtained on the day of surgery before premedication. ET was measured by radioimmunoassay after extraction (SepPakC18). NEP activity was measured by a microplate-based kinetic enzyme assay over 120 min. PF ET (78 +/- 11 pg/ml) was significantly (p < 0.05) higher than PL ET (3.38 +/- 0.48 pg/ml). The PF/PL ratio was 38 +/- 14, range 7-200. PF ET was inversely related to the NYHA state of the patients, whereas a similar relation was not found with PL ET. PL and PF ET levels did not correlate. In HPLC, the total immunoreactive ET activity co-eluted with the human ET standard. PF NEP activity (2.26 +/- 0.12 U/l) was lower (p < 0.05) than PL NEP (3.62 +/- 0.22 U/I). PL NEP was not different from that of healthy controls (3.28 +/- 0.22 U/L; n = 50). No correlation was found between NEP in either compartment and the NYHA state of the patients. ET concentration and NEP activity did not correlate in PF or PL. We conclude that ET is extremely high in the PF of cardiac patients and that this is not caused by altered NEP activity.
J Cardiovasc Pharmacol 1998
PMID:High pericardial fluid levels of endothelin are not caused by altered neutral endopeptidase activity in cardiac patients. 959 61

The purpose of these studies was to compare the effects of CGS 30440 (CGS), a dual angiotensin-converting enzyme inhibitor (ACEI)/neutral endopeptidase inhibitor (NEPI) to benazepril (BZ), an ACEI, in a model of five-sixths nephrectomy. The doses of BZ and CGS 30440 tested were 6.5 micromol/kg/day and 2.2 micromol/kg/day. Drugs or vehicle (V) were administered subcutaneously for 6 weeks with dosing initiated 1 week after renal mass reduction. At 6 weeks of receiving drug (7 weeks after five-sixths nephrectomy), CGS/6.5 and BZ/6.5 and CGS/2.2 maintained systolic blood pressures (SBP) at presurgical values. BZ/2.2 did not reduce SBP and was similar to the V group. Urinary protein excretion increased >10-fold in the V-treated group. BZ, at either dose, reduced the proteinuria slightly. CGS/6.5 and CGS/2.2 caused significant (p < 0.05) reductions in proteinuria. Creatinine clearance (Cr(cl)), was reduced by 82% in V, 65 and 61% in the CGS/6.5 and CGS/2.2 groups, and by 69 and 74% in the BZ/6.5 and BZ/2.2 groups, respectively. Both CGS treatments improved the fractional excretion of Na+ (%FE(Na)) significantly from the BZ and V groups. The %FE(Na) for BZ at either dose did not differ from that of V. Elevated urinary cyclic guanosine monophosphate (cGMP), an indicator suggesting increased intrarenal levels of atrial natriuretic peptide (ANP), was observed only in the CGS groups. Histologic examination indicated that BZ/6.5 reduced glomerular sclerosis and the extent of tubular dilation, whereas BZ/2.2 had little effect. CGS, especially at the high dose, virtually normalized the glomerular and tubular pathology. Compared with BZ, CGS 30440 treatment further diminished tubular dilation and proteinaceous cast formation. These tubular effects are consistent with some of the renal actions of ANP. The results from these studies indicate that CGS 30440, a combined ACEI/NEPI, conferred a greater renal protective effect than did ACE inhibition alone.
J Cardiovasc Pharmacol 1998 Jul
PMID:Protective effects of CGS 30440, a combined angiotensin-converting enzyme inhibitor and neutral endopeptidase inhibitor, in a model of chronic renal failure. 967 26

Inhibition of neutral endopeptidase (NEP) in the kidney was studied ex vivo after oral administration of candoxatril (UK79300), an NEP inhibitor, to rats to study the time course and dose response by quantitative in vitro autoradiography by using the NEP inhibitor 125I-SCH47896 as a radioligand. In control rats, high NEP binding was demonstrated in the deep proximal tubule. After oral administration of candoxatril (10 mg/kg), kidney NEP binding was rapidly decreased and recovered gradually over a period of 24 h. The inhibition was maximal at 1 h (13.3 +/- 2.5% of control). Increasing doses of candoxatril administered to rats produced progressive inhibition of NEP binding in the kidney. A dose of 100 mg/kg inhibited kidney NEP binding to 2.6 +/- 0.2% of the control value at 1 h after administration. Candoxatrilat (UK73967), an active metabolite of candoxatril, given intravenously inhibited kidney NEP binding also in a time- and dose-dependent manner. This inhibition of NEP activity at the tissue level may be important in the actions of NEP inhibitors.
J Cardiovasc Pharmacol 1998 Nov
PMID:Inhibition of kidney neutral endopeptidase after administration of the neutral endopeptidase inhibitor candoxatril: quantitation by autoradiography. 982 42

Because chronic hypoxia increases the production of oxygen radicals, we hypothesized that antioxidants attenuate chronic hypoxic pulmonary hypertension. In part 1, we examined the temporal progress in chronic hypoxic pulmonary hypertension in 46 Wistar rats exposed to hypoxia from 0-3 weeks. In part 2, we tested whether antioxidants attenuated chronic hypoxic pulmonary hypertension in 82 rats divided into 10 groups: control, fullerenol-1, U-83836E, dimethylthiourea-1, dimethylthiourea-2, hypoxia, hypoxia + fullerenol-1, hypoxia + U83836E, hypoxia + dimethylthiourea-1, and hypoxia + dimethylthiourea-2. Control animals breathed room air and were injected intraperitoneally with saline for 2 weeks. Fullerenol-1, U-83836E, and dimethylthiourea are antioxidants and were administered intraperitoneally for 2 weeks, except that dimethylthiourea was given either on days 3, 5, and 7 (dimethylthiourea-1), or on days 8, 10, and 12 (dimethylthiourea-2). Hypoxic animals were placed into a hypobaric chamber with a barometric pressure of 380 Torr for 2 weeks. Hypoxia + antioxidant groups were administered antioxidants during hypoxic exposure. We observed a gradual increase in pulmonary artery pressure, the weight ratio of right ventricle to left ventricle plus septum, and hematocrit during the 3 weeks of chronic hypoxia. These hypoxia-induced alterations were significantly attenuated by U-83836E and dimethylthiourea, but not by fullerenol-1. Neither the temporal alterations nor the antioxidant effects can be explained by the change in either tracheal neutral endopeptidase activity or the lung or plasma substance P level, perhaps because of the time lag in sampling. These results indicate that oxygen radicals play an important role in the development of chronic hypoxic pulmonary hypertension.
J Cardiovasc Pharmacol 1998 Nov
PMID:Antioxidants attenuate chronic hypoxic pulmonary hypertension. 982 44

Angiotensin-converting enzyme (ACE) inhibition as well as neutral endopeptidase (NEP) inhibition was demonstrated to influence hemodynamics in various cardiac disease states. However, specific effects of chronic combined ACE and NEP inhibition on left ventricular (LV) and myocyte geometry and function remain unclear. In this study, a dual-acting metalloprotease inhibitor (DMPI), which possesses both ACE and NEP inhibitory activity, was used in a rapid-pacing model of LV dysfunction. LV and myocyte geometry and function were examined in control dogs (n = 6), in dogs with pacing-induced LV dysfunction (216 +/- 2 beats/min, 28 days, n = 7), and in dogs with DMPI treatment during rapid pacing (10 mg/kg p.o., b.i.d., n = 6). With chronic rapid pacing, LV end-diastolic volume increased (84 +/- 4 vs. 49 +/- 3 ml), and LV ejection fraction decreased (38 +/- 3% vs. 68 +/- 3%) compared with control (p < 0.05). DMPI concomitantly administered during long-term rapid pacing did not change LV ejection fraction (35 +/- 3%), but LV end-diastolic volume was reduced (70 +/- 5 vs. 84 +/- 4 ml; p < 0.05) when compared with rapid pacing only. With long-term rapid pacing, myocyte cross-sectional area was decreased (278 +/- 5 vs. 325 +/- 5 microm2), and resting length increased (178 +/- 2 vs. 152 +/- 1 microm) when compared with control (p < 0.05). With DMPI concomitantly administered during rapid pacing, myocyte cross-sectional area (251 +/- 5 microm2) and resting length (159 +/- 4 microm) were reduced when compared with rapid pacing only (p < 0.05). Myocyte velocity of shortening decreased from control values with long-term rapid pacing (39.3 +/- 3.9 vs. 73.2 +/- 5.9 microm/s; p < 0.05) but improved with DMPI treatment during rapid pacing when compared with rapid pacing only (58.9 +/- 6.7 microm/s; p < 0.05). Myocyte velocity of shortening with beta-adrenergic-receptor stimulation (25 nM isoproterenol) was reduced from controls with rapid pacing (125 +/- 12 vs. 214 +/- 30 microm/s; p < 0.05) but was improved with DMPI treatment during rapid pacing when compared with rapid pacing only (178 +/- 12 microm/s; p < 0.05). In a model of rapid pacing-induced LV failure, concomitant DMPI treatment significantly reduced the degree of LV dilation with no apparent effect on LV pump function. At the level of the LV myocyte, long-term DMPI treatment with rapid pacing improved myocyte performance and beta-adrenergic response. Thus the improvement in isolated myocyte contractile function was not translated into improved global LV-pump performance. The mechanisms by which improved myocyte contractility was not translated into a beneficial effect on LV-pump function with DMPI treatment during rapid pacing remain speculative, but likely include significant changes in LV remodeling and loading conditions.
J Cardiovasc Pharmacol 1998 Dec
PMID:Chronic dual inhibition of angiotensin-converting enzyme and neutral endopeptidase during the development of left ventricular dysfunction in dogs. 986 95


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