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)

The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure. 128 Jul 35

Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6+/-2.3 to 33.2+/-5.9 pmol/L, P<0.01; controls, 7.7+/-1. 2 to 10.6+/-2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650+/-370% versus 450+/-150%, P=0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9+/-2.0% versus 7.4+/-2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation.
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PMID:Enhanced natriuretic response to neutral endopeptidase inhibition in heart-transplant recipients. 1020 32

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor-alpha (TNF-alpha) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of beta-blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)-inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin-angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large-scale trials with ACE-inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non-peptide antagonists is ongoing. Endothelin-1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N-terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF-alpha has drawn attention. Experimental studies suggest that TNF-alpha is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF-alpha seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a 'neuroendocrine profile' which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to beta-blockers, ACE-inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.
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PMID:Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. 1172 73

Since the original discovery of atrial natriuretic peptide (ANP) nearly 20 years ago and the subsequent realisation of the existence of a family of natriuretic peptides, there has been considerable progress in the elucidation of the physiological and pathophysiological significance of these peptides. This review has examined two potentially important practical aspects arising from natriuretic peptide research - the significance of measurement of plasma levels of ANP and of brain natriuretic peptide BNP for cardiovascular disease and the therapeutic potential of targeting the natriuretic peptide system. Several situations where the measurement of plasma ANP and BNP may be of benefit in the overall assessment and prognosis of cardiac disease have been discussed. The measurement of plasma levels of these peptides appears to have limited value as a specific diagnostic tool and is unlikely to replace well-established procedures to assess cardiac function. Nevertheless, given the strong negative predictive value, the value of the measurement of plasma natriuretic peptides particularly BNPs, in people with suspected heart disease, rests on the evidence that a normal value indicates a low risk of cardiac impairment. Moreover, a consistently elevated plasma level of BNP after myocardial infarction is associated with a distinctly poor prognosis. In turn, this may help to select those with high plasma levels for subsequent detailed investigation of cardiac dysfunction. This may be an important option, especially where the facilities for the more invasive cardiological procedures are not available. Intriguingly, recent research also suggests the possibility that plasma levels of natriuretic peptides may have an important role in guiding more effective therapy for heart failure. The potent cardiovascular and renal effects of ANP and BNP provide an important therapeutic potential for hypertension and for conditions associated with volume overload. A number of approaches which have been used to enhance endogenous activity of these peptides have been highlighted. The use of the native peptides ANP and BNP may well be valuable in some circumstances, such as in critically ill individuals with congestive heart failure or renal failure. However, the limitations of the use of peptides, especially for long-term treatment, are obvious. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides by inhibition of breakdown by neutral endopeptidase. This research has led to the development of vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin-converting enzyme - to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity. The broad spectrum of action and the potentially important target-organ protection of these inhibitors offer potential benefits which may well go beyond existing treatment of hypertension and of conditions associated with overt volume overload.
J Renin Angiotensin Aldosterone Syst 2000 Dec
PMID:Practical implications of current natriuretic peptide research. 1196 16

Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (Vanlev, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease.
J Renin Angiotensin Aldosterone Syst 2002 Jun
PMID:Vasopeptidase inhibitors. 1222 48

Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.
J Renin Angiotensin Aldosterone Syst 2003 Sep
PMID:Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure. 1460 17

Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis. This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet. At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73 2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%. Six weeks feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O2- concentration and bioavailability of NO. In this study, a similar protective effect on endothelial function was shown by ACE-NEP inhibition as already seen with ACE inhibitors in an animal model of atherosclerosis.
J Renin Angiotensin Aldosterone Syst 2003 Sep
PMID:Effect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits. 1460 26

In the kidney, neutral endopeptidase (NEP) is implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as the atrial natriuretic peptide, bradykinin and angiotensin I. Due to its physiological importance in the modulation of pressor responses, the presence of NEP in mouse mesangial cells has been investigated, since these cells control glomerular function and are able to synthesise components of the renin-angiotensin system. A NEP-like activity (NEP-like) that cleaves the fluorogenic substrates Abz-BKQ-EDDnp and Abz-DRRL-EDDnp was purified from mesangial cell lysate by ion-exchange, followed by gel filtration chromatography. The enzyme was able to hydrolyse bradykinin at the G4-F5 peptide bond and was inhibited by thiorphan. A pH study established that enzyme activity was maximal at pH 7.5 and the determined K(m) was 4.86 M using Abz-DRRL-EDDnp as substrate. NEP-like was recognised by monoclonal anti-NEP and had a molecular mass of 95 kDa. The purified enzyme was sequenced and showed similarity with human, rat, mouse and rabbit NEPs. We isolated, for the first time, NEP-like from mesangial cells. This enzyme could have an important role in the renal physiology by its action upon different peptides that are able to alter renal haemodynamics.
J Renin Angiotensin Aldosterone Syst 2003 Dec
PMID:Neutral endopeptidase expression in mesangial cells. 1468 70

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.
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PMID:Targeting the renin-angiotensin system: what's new? 1563 41

Natriuretic peptides play an important role in sodium regulation and blood pressure (BP) control. We examined the effects of atrial natriuetic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on human isolated resistance arteries and the mechanisms involved in vasorelaxation. Human subcutaneous resistance arteries were mounted in an isometric myograph and contracted with phenylephrine. CNP, but not ANP or BNP, relaxed arteries in a concentration dependent manner. The action of CNP was unaffected by removal of the endothelium, inhibition of nitric oxide synthase by NG-monomethyl-Larginine or inhibition of soluble guanylate cyclase by 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one. Blockade of cyclic GMPdependent kinase by 8- bromoguanosine- 3, 5- cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) inhibited CNP relaxation. CNP relaxation was also inhibited by high potassium or iberiotoxin, indicating that it was due to opening of BKCa channels. Omapatrilat, a vasopeptidase inhibitor of neutral endopeptidase and angiotensin-converting enzyme, enhanced the effect of CNP and inhibited responses to Ang I. In summary, CNP, but not ANP or BNP, relaxes human resistance arteries by activating cyclic GMP-dependent kinase and BKCa. The effects of CNP are enhanced by vasopeptidase inhibition and this may contribute to the vasodilator effects of these agents in vivo. Since CNP is widely present in endothelium it may play a role in the regulation of peripheral resistance in man in physiological and pathological circumstances.
J Renin Angiotensin Aldosterone Syst 2006 Jun
PMID:CNP, but not ANP or BNP, relax human isolated subcutaneous resistance arteries by an action involving cyclic GMP and BKCa channels. 1708 62


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