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)

C-type natriuretic peptide (CNP) is a 22-amino-acid peptide, structurally related to but genetically distinct from atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whereas ANP and BNP are ligands for a guanylyl cyclase-coupled receptor, the NPR-A receptor, CNP is a specific ligand for the NPR-B receptor. In addition to clearance by the NPR-C receptor, CNP is subject to degradation by the ectoenzyme neutral endopeptidase 24.11 (NEP), which is widely distributed in the kidney, lung, heart, and endothelial cells. Although initially identified in porcine brain, CNP immunoreactivity has been found in human vascular endothelial cells, plasma, and kidney. CNP has potent systemic cardiovascular actions, which include reductions in cardiac filling pressures and output, secondary to vasorelaxation and decreases in venous return, but has minimal renal actions. Unlike ANP, CNP is a selective endothelium-independent venodilator. However, it is also a potent coronary vasodilator. Expression of the CNP gene by the endothelial cells, the presence of CNP receptors on vascular smooth muscle cells (VSMCs), and the antimitogenic effect of CNP on VSMCs suggest that CNP is produced by the endothelium and acts on adjacent VSMCs serving as an autocrine/paracrine endothelium-derived vasoregulatory system.
J Cardiovasc Pharmacol 1998
PMID:C-type natriuretic peptide: the endothelial component of the natriuretic peptide system. 988 43

Previous results from our laboratory have suggested that morphine can attenuate neutrophil activation in patients with acute myocardial infarction. To elucidate if morphine preconditioning (PC) has the same effects via activation of neutrophil endopeptidase 24.11 (NEP), we measured serum levels of intercellular adhesion molecule-1 (ICAM-1), gp100MEL14 and NEP in adult Wistar rats subjected to ten different protocols (n = 10 for each) at baseline, immediately after and 2 h after morphine PC. All groups were subjected to 30 min of occlusion and 2 h of reperfusion. Similarly, morphine-induced PC was elicited by 3-min drug infusions (100 micrograms/kg) interspersed with 5-min drug-free periods before the prolonged 30-min occlusion. Infarct size (IS), as a percentage of the area at risk (AAR), was determined by triphenyltetrazolium staining. Pretreatment with morphine increased NEP activities (9.86 +/- 1.98 vs. 5.12 +/- 1.10 nmol/mg protein in control group; p < 0.001). Naloxone (mu-opioid receptor antagonist) (4.82 +/- 1.02 nmol/mg protein) and phosphoramidon (NEP inhibitor) (4.66 +/- 1.00 nmol/mg protein) inhibited morphine-activated NEP, whereas glibenclamide (ATP-sensitive potassium channel antagonist) and chelerythrine (protein kinase C inhibitor) had no effects. The ICAM-1 and gp100MEL14 of the third sampling were lowest for those with morphine PC (280 +/- 30 ng/ml and 2.2 +/- 0.7 micrograms/ml; p < 0.001), but naloxone (372 +/- 38 ng/ml and 3.8 +/- 0.9 micrograms/ml) and phosphoramidon (382 +/- 40 ng/ml and 4.2 +/- 1.1 micrograms/ml) abolished the above phenomenon. IS/AAR were definitely lowest for those with morphine PC (24 +/- 7%; p < 0.05). Morphine preconditioning increases NEP activities to attenuate shedding of gp100MEL14 and to ICAM-1 and, thus, provides myocardial protection.
Cardiovasc Res 1998 Dec
PMID:Morphine preconditioning attenuates neutrophil activation in rat models of myocardial infarction. 1007 Apr 97

The endopeptidase called endothelin-converting enzyme-1 (ECE-1) is thought to play a physiological role in endothelin-1 (ET-1) biosynthesis. For human ECE-1, differential splicing of messenger RNA (mRNA) results in the synthesis of three isoforms, termed ECE-1a, ECE-1b, and ECE-1c. The isoform(s) responsible for the hydrolysis of the biosynthetic intermediate big ET-1 in endothelial cells have yet to be assigned. To investigate whether the expression of mRNAs for preproET-1 and ECE-1 are regulated in parallel, a variety of conditions were used to compare levels of ET-1 synthesis by bovine aortic endothelial cells (BAECs) with levels of mRNA for preproET-1, ECE-1a, ECE-1c, and the combined ECE-1 isoforms (ECE-1a/b/c). Stimulation of BAECs with tumor necrosis factor-alpha or transforming growth factor-beta increased ET-1 synthesis, and treatment of BAECs with 2-chloroadenosine or staurosporine caused concentration-dependent reductions in ET-1 synthesis. Estimates of mRNA levels by reverse transcription-polymerase chain reaction (RT-PCR) with linear cycling conditions showed changes in preproET-1 expression to correlate well with ET-1 secretion. In contrast, RT-PCR analysis of ECE-1 expression by using primer pairs to measure ECE-1a, ECE-1c, or all the ECE-1 isoforms simultaneously showed no correlation between their mRNA levels and those of preproET-1. This indicates that under the conditions investigated, expression of ECE-1 is not coordinated with ET-1 synthesis in BAECs.
J Cardiovasc Pharmacol 1999 Apr
PMID:The expression of endothelin-1 and endothelin-converting enzyme-1 (ECE-1) are independently regulated in bovine aortic endothelial cells. 1021 41

Vasopeptidase inhibitors are single molecules that inhibit neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) simultaneously. Omapatrilat, the first in this new class of cardiovascular agents, potentiates vasodilatory and cardioprotective peptides and represses angiotensin II. This study compared the effects of omapatrilat with those of a pure ACE inhibitor on cardiac geometry and survival in animals with heart failure. BIO TO-2 cardiomyopathic hamsters (CMHs) in the early stages of dilated heart failure were treated with vehicle or maximal ACE inhibitory doses of captopril (750 micromol/kg/day) or omapatrilat (200 micromol/kg/day). Prolonged vasopeptidase inhibition increased median survival time after the start of treatment by 99 and 31% compared with vehicle and captopril, respectively (median survival times: 146, 221, and 290 days with vehicle, captopril, and omapatrilat, respectively; p < 0.001 for all comparisons). In similar CMHs, captopril or omapatrilat administered for 2 months significantly (p < 0.05) decreased heart weight, pulmonary congestion (lung weight), and left ventricular (LV) chamber volume compared with vehicle. Omapatrilat significantly increased LV mass-to-volume ratio compared with vehicle and captopril. Omapatrilat, but not captopril, significantly increased urinary atrial natriuretic peptide excretion, indicating NEP inhibition. Thus vasopeptidase inhibition with omapatrilat was more effective than ACE inhibition with captopril in preventing changes in LV geometry and premature mortality in hamsters with dilated heart failure.
J Cardiovasc Pharmacol 1999 Dec
PMID:Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. 1059 20

Prostaglandins are known to participate in the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin type 1 (AT1)-receptor antagonism. Because angiotensin-(1-7) [Ang-(1-7)] is markedly elevated after prolonged ACE-inhibitor treatment, we determined whether the antihypertensive effects of Ang-(1-7) were mediated by release of prostaglandins. Male spontaneously hypertensive rats (SHRs, 10 weeks) were treated for 9 days with either lisinopril (20 mg/kg) or losartan (10 mg/kg) or a combination of both drugs. Rats were implanted with catheters in the carotid artery and jugular vein to record blood pressure and to infuse drug solutions, respectively. Neutralization of circulating Ang-(1-7) by monoclonal antibody resulted in a dose-dependent increase in blood pressure in SHRs treated with either lisinopril or losartan. Administration of CGS 24592 to block Ang-(1-7) formation also resulted in an increase in blood pressure that was comparable to antibody infusion. However, Ang-(1-7) blockade evoked a greater elevation in blood pressure in the lisinopril and lisinopril/losartan-treated rats in comparison to those treated with losartan alone. Acute treatment with the cyclooxygenase (COX) inhibitor indomethacin increased blood pressure to a similar extent to that of CGS 24592, as well as blocked the increase in pressure with the neprilysin inhibitor in the lisinopril/losartan group. In the losartan-treated animals, however, indomethacin increased blood pressure by a larger extent than that of the Ang-(1-7) antibody or CGS 24592, and CGS 24592 did not abolish the subsequent pressor response to indomethacin in these animals. In contrast to the antibody or neprilysin inhibitor, administration of the Ang-(1-7) antagonist D-[Ala7]-Ang-(1-7) increased blood pressure to a similar extent in lisinopril or losartan treatments. Moreover, D-[Ala7]-Ang-(1-7) increased blood pressure to a comparable extent as indomethacin and blocked any further increase with the COX inhibitor in the losartan-treated SHRs. High-resolution emulsion autoradiography revealed 125I-[Sarcosine1, Threonine8]-Ang II (Sarthran) binding in the mesenteric artery and thoracic aorta in the presence of both LOS and the AT2 antagonist PD123319. The non-AT1/non-AT2 Sarthran binding was displaced by Ang-(1-7), DALA, or Ang II. These studies suggest that vasodilatory eicosanoids mediate the antihypertensive effects of endogenous Ang-(1-7) in both LIS and LIS/LOS therapies. Furthermore, in the presence of AT1-receptor blockade, Ang II may interact with a DALA-sensitive site to promote eicosanoid release.
J Cardiovasc Pharmacol 2000 Jul
PMID:Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system. 1089 68

CGS 26303 has previously been shown to inhibit human endothelin converting enzyme-1 (ECE-1) with an IC50 of 410 nM and to be efficacious in several animal disease models. However, it is a more potent inhibitor of neutral endopeptidase 24.11 (NEP) with an IC50 of 1 nM. The aim of this study was to optimize CGS 26303 for greater potency and selectivity towards ECE-1 inhibition. The in vivo activity of the compounds was assessed by inhibition of the big endothelin-1 (ET-1)-induced pressor response in anesthetized rats at 90 min after treatment with a dose of 10 mg/kg, i.v. Under these conditions, CGS 26303 inhibited the pressor response to big ET-1 by 50%. Replacement of the biphenyl and tetrazol groups in CGS 26303 with a dibenzofuran and carboxylic acid, respectively, yielded CGS 35066, a potent ECE-1 inhibitor having an IC50 of 22 nM. In contrast, these substitutions markedly weakened the NEP inhibitory activity of the compound to an IC50 of 2.3 microM. CGS 35066 also exhibited a potent and sustained ECE-1 inhibitory activity in vivo, blocking the pressor response to big ET-1 by 84%. Its orally active prodrug, CGS 35339, was obtained by introducing two phenyl groups at the phosphonic acid substituent in CGS 35066. Therefore, CGS 35066 and CGS 35339 represent novel compounds for assessing the pathogenic role of ET-1 overproduction in various disease states.
J Cardiovasc Pharmacol 2000 Nov
PMID:Design and synthesis of a potent and selective endothelin-converting enzyme inhibitor, CGS 35066. 1107 30

The purpose of this study was to examine the pharmacologic properties of CGS 35066, a novel aminophosphonate inhibitor of endothelin-converting enzyme-1 (ECE-1). CGS 35066 inhibited the activity of human ECE-1 and rat kidney neutral endopeptidase 24.11 (NEP) in vitro with IC50 values of 22 +/- 0.9 nM and 2.3 +/- 0.03 microM, respectively. The in vivo effects of CGS 35066 were characterized in conscious, catheterized rats. At 30 and 120 min after treatment with vehicle, big endothelin-1 (big ET-1, 0.3 nmol/kg i.v.) produced increases in mean arterial pressure (MAP) of 982 +/- 31 and 992 +/- 43 mmHg x min (area under the curve), respectively. Doses of 0.3, 1.0, 3.0 and 10.0 mg/kg i.v., of CGS 35066 blocked these pressor responses by 61 +/- 7, 78 +/- 4, 93 +/- 4 and 98 +/- 2% at 30 min (p < 0.05 compared with vehicle controls, all doses), and by 29 +/- 7, 63 +/- 5, 63 +/- 5 and 84 +/- 10% at 120 min (p < 0.05, all doses). In contrast, the pressor effect (58 +/- 6 mmHg) of angiotensin-I (300 ng/kg i.v.) was unaffected by the ECE-1 inhibitor (10 mg/kg i.v.) indicating the absence of activity against angiotensin-converting enzyme. In rats infused with atrial natriuretic peptide (ANP), CGS 35066, at 1 mg/kg, had no effect on plasma irANP; however, irANP levels were doubled at a dose of 30 mg/kg. These results demonstrate that CGS 35066 is the most potent and selective ECE inhibitor identified to date.
J Cardiovasc Pharmacol 2000 Nov
PMID:Pharmacological properties of CGS 35066, a potent and selective endothelin-converting enzyme inhibitor, in conscious rats. 1107 31

The effects of CGS 26303, a dual inhibitor of endothelin-converting enzyme (ECE) and neutral endopeptidase 24.11, and its prodrug, CGS 26393, on bovine cerebrovascular endothelial cells stimulated with hemolysate were investigated. Upon incubation with hemolysate for 48 h, cell density was significantly decreased, with concomitant increases in endothelin-1 (ET-1) (42 vs 11 pg/ml) and big ET-1 (79 vs 27 pg/ml) levels in culture medium when compared with controls. Simultaneous addition of CGS 26303 (10 and 100 microM) and hemolysate protected against cell loss and decreased cellular vacuolization caused by hemolysate. The levels of ET-1 and big ET-1 in the culture medium were decreased dose-dependently. More drastically, pretreatment with 100 microM CGS 26303 for 30 min decreased the production of ET-1 and big ET-1 by 94% and 87%, respectively, when compared with the untreated control. However, treatment with CGS 26393 was much less effective. These results suggest that suppression of ET-1 production by ECE inhibitors may prove to be efficacious for the treatment of hemolysate-induced cytotoxicity on cerebral endothelial cells.
J Cardiovasc Pharmacol 2000 Nov
PMID:Effects of endothelin-converting enzyme inhibitors on hemolysate-induced morphological changes and production of endothelin-1 in bovine cerebrovascular endothelial cells. 1107 66

The gene expression and levels of endothelins (ETs) are increased in various animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodynamic and haematological disturbances, organ injury and circulatory failure in ENDO. Previous studies using ET(A)- and/or ET(B)-receptor antagonists exacerbated the effects of LPS in anaesthetized and conscious rats. We investigated the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mixed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-induced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injection, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. In addition, progressive liver dysfunction, characterized by increases in plasma bilirubin and alanine transferase, became even more apparent (higher than in those injected with LPS). Plasma creatinine and blood urea were similar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-induced deleterious effects.
J Cardiovasc Pharmacol 2000 Nov
PMID:Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats. 1107 21

In experimental animals, kinins protect the myocardium from ischemia-reperfusion injuries and reduce left ventricular hypertrophy and progression of heart failure. This suggests that in humans, also, the presence of an intact kinin system is critical for the prevention of heart failure. In addition to the kinin-generating system, the concentration of kinins, and consequently the extent of their actions, is regulated by their degradation. In the vascular bed of the human heart, bradykinin (BK) is degraded by angiotensin-converting enzyme (ACE). In contrast, in the interstitium of the human heart, BK is degraded by neutral endopeptidase (NEP). For potentiating the beneficial effects of BK, one strategy is elevation of the BK concentration by inhibition of BK-degrading enzymes. An even more effective form of pharmacological control of BK elevation than inhibition of ACE alone might be the combined inhibition of ACE and NEP.
Trends Cardiovasc Med 2000 Jan
PMID:Kinin-degrading pathways in the human heart. 1115 Jul 28


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