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)

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.
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PMID:Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. 1108 29

S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg. kg(-1). d(-1)), an ACE inhibitor (captopril, 50 mg. kg(-1). d(-1)), a NEP inhibitor (SCH42495, 60 mg. kg(-1). d(-1)), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (P<0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (P<0.01). Both S21402 and captopril increased plasma renin activity (P<0.01), all treatment lowered plasma aldosterone (P<0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (P<0.01), SCH42495 inhibited NEP (P<0.01), and captopril inhibited ACE (P<0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (P<0.01), SCH42495 reduced right ventricular mass (P<0.01), and S21402 decreased left (P<0.05) and right ventricular mass (P<0.01), atrial mass (P<0.05), and lung mass (P<0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure.
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PMID:Beneficial renal and cardiac effects of vasopeptidase inhibition with S21402 in heart failure. 1111 33

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT(1)) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3+/-0.5 versus 6.9+/-0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P<0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats (P<0.01) compared with control rats, whereas heart rates were not different. Heart weight- and kidney weight-to-body weight ratios were higher in GK rats (P<0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition (P<0.05), whereas the sodium nitroprusside-induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K(+) channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P<0.05). The serum level of 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT(1) receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT(1) receptor expression, medullary and cortical angiotensin type 2 (AT(2)) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT(1), AT(2), ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT(1) receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT(1) receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure-independent mechanisms.
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PMID:Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. 1123 Mar 14

Vasopeptidase inhibitors, a new class of cardiovascular compounds, inhibit both neutral endopeptidase, an enzyme that helps in the breakdown of vasodilator substances, and ACE. Simultaneous inhibition of neutral endopeptidase and ACE enhances peptides with vasodilatory properties, such as atrial natriuretic peptide, brain natriuretic peptide, and C type natriuretic peptide, and inhibits the production of the vasoconstrictor angiotensin II. The properties of these natriuretic peptides and their function in the regulation of the cardiovascular system are reviewed. Clinical results with vasopeptidase inhibitors and other therapeutic modalities based on the natriuretic peptide system in the treatment of hypertension and heart failure are also reviewed. Omapatrilat, an agent that has been recently evaluated, is an effective agent in lowering diastolic and particularly systolic blood pressures in a broad range of populations and may have beneficial effects beyond blood pressure control. The mechanism of action of omapatrilat and clinical results with this compound are discussed. (c)2000 by Le Jacq Communications, Inc.
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PMID:Vasopeptidase Inhibition: A New Approach to the Management of Cardiovascular Disease. 1141 31

There is now substantial evidence supporting a role of the natriuretic peptides as a major defence mechanism against excess salt and water retention and high blood pressure. Because of this there has been considerable interest in the therapeutic potential of the natriuretic peptide system. Several approaches have been explored including the use of native peptides, the development of natriuretic peptides mimetics and targetting of endogenous clearance of natriuretic peptides. While ANP and BNP administration may be valuable in some circumstances, however, the limitations of the use of peptides especially for long-term treatment are well apparent. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides through inhibition of breakdown by neutral endopeptidase. This research has now led to the vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin converting enzyme. These agents clearly provide a novel approach to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity and may lead to an important advance in the treatment of hypertension and of conditions associated with overt salt and water overload.
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PMID:Atrial natriuretic peptide mimetics and vasopeptidase inhibitors. 1147 32

Natriuretic peptides play an important role in water and salt homeostasis and in the regulation of the cardiovascular system. In recent years, exogenous administration of natriuretic peptides has primarily been used to improve our understanding of the role of natriuretic peptides. Also, it became evident that natriuretic peptides may be used therapeutically. Because of their peptide character, they cannot be administered orally and, therefore, may be used for short-term intravenous therapy only. In recent years, inhibitors of neutral endopeptidase, which degrades natriuretic peptides to inactive metabolites, have been investigated. This review focuses on the potential benefits of increasing natriuretic peptide levels, either through exogenous administration or inhibiting the degradation of endogenous natriuretic peptides.
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PMID:Therapeutic benefits of increasing natriuretic peptide levels. 1147 41

Mild heart failure is characterized by increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11, which degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, urinary ANP excretion, and glomerular filtration rate (P<0.05 for OMA versus ACE inhibition). Plasma renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.
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PMID:Endogenous natriuretic peptides participate in renal and humoral actions of acute vasopeptidase inhibition in experimental mild heart failure. 1150 74

Two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are found principally in the heart. In preliminary experiments with mouse kidney cells or slices, we found mouse BNP1-45 much more potent than ANP1-28 in causing elevations of cGMP (>50-fold). The guanylyl cyclase-A (GC-A) receptor has been suggested to represent the primary means by which both peptides signal. In cultured cells overexpressing GC-A, BNP and ANP were almost equivalent in potency, suggesting that a receptor unique for BNP exists in the kidney. However, in mice lacking the GC-A gene, neither BNP nor ANP significantly elevated cGMP in kidney slices. Phosphoramidon, a neutral endopeptidase inhibitor, shifted the apparent potency of ANP to values equivalent to that of BNP, suggesting these kidney cell/slices rapidly degrade ANP but not BNP. Mass spectroscopic analysis confirmed that ANP is rapidly cleaved at the first cysteine of the disulfide ring, whereas BNP is particularly stable to such cleavage. Other tissues (heart, aorta) failed to significantly degrade ANP or BNP, and therefore the kidney-specific degradation of ANP provides a mechanism for preferential regulation of kidney function by BNP independent of peripheral ANP concentration.
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PMID:Apparent B-type natriuretic peptide selectivity in the kidney due to differential processing. 1155 80

The drug treatment of heart failure, once simple, has become complex. Apart from a loop diuretic and digoxin, most patients should now be receiving an angiotensin-converting enzyme inhibitor (or angiotensin II receptor blocker), a beta-blocker and spironolactone. Newer drugs, such as endothelin-receptor antagonists and combined blockers of converting-enzyme and neutral endopeptidase, might soon become available. When to introduce these drugs and what dose is optimal for any individual, are questions that currently vex clinicians. We proposed that plasma levels of the cardiac hormone brain natriuretic peptide (BNP, or better, its 1-76 amino-acid N-terminal fragment, N-BNP), would provide an objective index for guiding drug treatment in patients with established, stable cardiac failure. In a pilot study, 69 patients were randomized to drug treatment based on clinical criteria, or based on plasma levels of N-BNP. After a median follow-up of 9.6 months, those in the N-BNP group had fewer clinical end-points than those in the group managed by clinical criteria alone (19 vs 54; P= 0.02). These preliminary data encourage the concept that the increasingly complex pharmacotherapy for heart failure, both chronic (as in this trial) and acute, might best be guided by an objective measure such as plasma levels of BNP or N-BNP.
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PMID:Brain natriuretic peptide-guided therapy for heart failure. 1158 3

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


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