Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure. 785 75

The presence of neutral endopeptidase 24.11 was demonstrated in human umbilical vein endothelial cells by immunostaining. Enzymatic activity of neutral endopeptidase was determined as 0.167 +/- 0.02 mU/mg protein in the membrane fraction of human umbilical vein endothelial cells, using the fluorogenic peptide substrate, dansyl-D-Ala-Gly-Phe(pNO2)-Gly. No activity was found in the cytosolic fraction of endothelial cells. The role of this peptidase in the degradation of the endogenous vasodilator bradykinin was investigated by incubating human umbilical vein endothelial cell monolayers with bradykinin (10(-8) mol/l). The inhibitor of neutral endopeptidase, phosphoramidon (10(-8) mol/l), decreased the degradation of bradykinin in the supernatant of endothelial cells; the half-life of bradykinin was then increased from 29 +/- 1 to 46 +/- 2 minutes. The angiotensin-converting enzyme inhibitor, lisinopril (10(-8) mol/l), increased the half-life of bradykinin to 244 +/- 20 minutes; the combination of both inhibitors increased the half-life of bradykinin to 381 +/- 51 minutes. Inhibitors of aminopeptidase (amastatin) and carboxypeptidase (2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid) caused no significant effect. The effect of phosphoramidon was small in comparison with that of lisinopril, but was pronounced in combination with lisinopril. Neutral endopeptidase activity is localized in the membranes of human endothelial cells and seems to be involved in the degradation of bradykinin by the vascular endothelium, particularly during angiotensin converting enzyme inhibition.
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PMID:Degradation of bradykinin by neutral endopeptidase (EC 3.4.24.11) in cultured human endothelial cells. 839 30

Neutral endopeptidase (NEP; also known as neprilysin and enkephalinase; EC 3.4.24.11) is a cell-surface metallopeptidase that is present in many mammalian tissues. It is particularly abundant on the brush-border membranes of the kidney proximal tubule. In this paper, the presence of NEP in purified glomeruli from dog kidney was assessed by measuring phosphoramidon- and thiorphan-sensitive [D-Ala2,Leu5]enkephalin-degrading activity. Using this assay, the Km and kcat. of the glomerular enzyme were found to be identical to those of the tubular enzyme. By Western blotting the apparent M(r) of the glomerular enzyme was found to be 104,000, compared with 94,000 for the tubular enzyme. This might be due to a different glycosylation pattern, since endoglycosidase F treatment of NEP obtained from both tissues yielded deglycosylated enzymes with similar electrophoretic mobilities. The glomerular enzyme also appears to be membrane-bound, since it was retained in the detergent-rich phase after phase separation with Triton X-114. Autoradiography experiments performed with RB104, a new highly selective and potent NEP inhibitor, showed that NEP was expressed in both glomeruli and proximal tubules. The presence in glomeruli of NEP and some other brush-border peptidases (dipeptidyl-dipeptidase IV, aminopeptidase N and angiotensin I-converting enzyme) suggests that cell-surface peptidases might play an important role as regulators of plasma-derived peptides in this part of the nephron.
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PMID:Characterization of neutral endopeptidase 24.11 in dog glomeruli. 848 5

The circulation is controlled by overlapping haemodynamic, structural and neurohumoral mechanisms. Many hormonal vasoactive substances, mostly derived from endothelial cells, are also growth regulators. Although neurohormonal systems are involved in normal physiological compensatory responses they often become maladaptive in conditions such as congestive heart failure. The success of blocking the renin angiotensin system by angiotensin converting enzyme (ACE) inhibitors has led to efforts to block other hormonal systems. Neutral endopeptidase (NEP), the major enzymatic pathway for degradation of natriuretic peptides, has a similar catalytic site to ACE. This has led to compounds that simultaneously inhibit both enzymes. Such dual ACE/NEP inhibitors show promise in experimental hypertension and heart failure. Similar dual NEP/ECE (endothelin converting enzyme) inhibitors are becoming available. The hormone vasopressin has dual actions on the vasculature and the kidney via specific membrane receptors. Specific orally active vasopressin receptor antagonists have been developed and their therapeutic potential in hypertension, heart failure and oedematous states are being explored.
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PMID:New hormonal blockade strategies in cardiovascular disease. 954 Jan 35

The pathogenesis of hypertension in diabetes type 1 and type 2 is different. Diabetic nephropathy is regarded as the most essential factor contributing to the development of hypertension in patients with diabetes mellitus type 1. Obesity, insulin resistance and hyperinsulinaemia are responsible for hypertension in diabetes mellitus type 2. In both types of diabetes, hypertension is involved in fast progress of diabetic renal disease. Antihypertensive treatment in diabetic patients should include: non-pharmacological interventions, drug-therapy, regular blood pressure monitoring, educational efforts. ACE-inhibitors, calcium antagonists, diuretics, beta-blockers, angiotensin II receptor antagonists and alpha 1-blockers are used as antihypertensive agents in diabetic patients. Neutral endopeptidase inhibitors are the new, promising therapeutic option.
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PMID:[Hypertension in patients with diabetes mellitus--selected pathogenetic and therapeutic aspects]. 1147 57

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
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PMID:Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? 1159 26

The human cardiovascular system is regulated by haemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure. The clinical success of blocking the renin-angiotensin system by angiotensin converting enzyme (ACE)-inhibitors and the sympathetic nerve system by beta-blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems. Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side-effect profile however, is questionable in this new class of agents.
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PMID:Vasopeptidase inhibitors: will they have a role in clinical practice? 1467 37

Diabetic neuropathy is a debilitating disorder that occurs in more than 50 percent of patients with diabetes. Evidence suggests that there are at least five major pathways involved in the development of diabetic neuropathy: metabolic, vascular, immunologic, neurohormonal growth factor deficiency, and extracellular matrix remodeling. In light of the complicated etiologies, an effective treatment for diabetic neuropathy has not yet been identified. Hyperglycemia increases tissue angiotensin II, which induces oxidative stress, endothelial damage and other pathologies including vasoconstriction, thrombosis, inflammation and vascular remodeling. Angiotensin converting enzyme inhibition and/or blocking of the angiotensin II receptor are recognized as first line treatment for nephropathy and cardiovascular disease in diabetes patients. A new class of drug in late stages of development is vasopeptidase inhibitors. This drug inhibits both angiotensin converting enzyme activity and neutral endopeptidase. Neutral endopeptidase is a protease that degrades a number of biologically active peptides including vasoactive peptides. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. Pre-clinical studies suggest that these drugs may be useful in treating diabetic complications involving vascular tissue. The purpose of this review is to evaluate the use of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy.
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PMID:The potential role of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy. 1822 Jul 15


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