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 pharmacotherapy of heart failure has become complex. Angiotensin-converting enzyme inhibitors (or angiotensin II receptor blockers), beta-blockers, spironolactone, diuretics and digoxin can be prescribed concurrently. Endothelin antagonists and combined inhibitors of converting enzyme and neutral endopeptidase are under investigation. Optimal dosing will become increasingly difficult to judge. Plasma brain natriuretic peptide (BNP) indicates the severity of left ventricular dysfunction. The C-terminal bioactive peptide and N-terminal BNP (N-BNP) circulate at concentrations related to cardiac status. We proposed that plasma levels of N-BNP would provide an index to guide drug treatment in established heart failure. Sixty-nine patients were randomized to treatment adjusted according to clinical criteria or plasma N-BNP. Hormone-guided therapy resulted in fewer clinical end points than did clinical management. This encourages further exploration of hormone guidance of anti-heart failure therapy, which could be extended to patients with preserved ejection fraction, in addition to those with established systolic dysfunction.
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PMID:BNP in hormone-guided treatment of heart failure. 1194 58

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.
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PMID:Practical implications of current natriuretic peptide research. 1196 16

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.
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PMID:Comparison of the effects of omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure. 1220 9

The identification of natriuretic peptides as key regulators of natriuresis and vasodilatation, and the appreciation that their secretion is under the control of cardiac hemodynamic and neurohumoral factors, has caused wide interest. The natriuretic peptides are structurally similar, but genetically distinct peptides that have diverse actions on cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin, while cardiac natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide receptor (NPR-A) which, via 3' 5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodialation, renin inhibition, and antimitogenic properties. CNP lacks natriuretic action but possesses vasodilating and growth inhibiting effects via the guanyl cyclase linked natriuretic peptide-B (NPR-B) receptor. All three peptides are cleared by natriuretic peptide-C receptor (NPR-C) and degraded by neutral endopeptidase, both of which are widely expressed in kidney, lung, and vascular wall. Recently, a fourth member of the natriuretic peptide, dendroaspsis natriuretic peptide (DNP) has been reported to be present in human plasma and atrial myocardium.
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PMID:Brain natriuretic peptide: role in cardiovascular and volume homeostasis. 1222 50

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.
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PMID:Vasopeptidase inhibitors. 1222 48

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 micromol/kg over 10 minutes) reduced peak left ventricular pressure (171+/-6 versus 130+/-6 mm Hg immediately after infusion, P<0.01) through arterial vasodilation (arterial elastance, 9.8+/-0.8 to 5.8+/-1.6 mm Hg/mL, P<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1+/-6.8 to 46.0+/-6.9 mL, P<0.01). At 60 minutes, preload decreased further (40.5+/-5.9 mL, P<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2+/-9.6 versus 72.3+/-15 pg/mL, P<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.
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PMID:Hemodynamic and humoral effects of vasopeptidase inhibition in canine hypertension. 1236 58

The natriuretic peptide and renin-angiotensin systems are physiological counterparts with opposite roles in the regulation of electrolyte balance and blood pressure. In both systems, membrane-bound, zinc-dependent peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II, and neutral endopeptidase (NEP) degrades the natriuretic peptides. Simultaneous inhibition NEP and ACE by a single molecule (a vasopeptidase inhibitor) is a new therapeutic approach in hypertension. Wider applications for vasopeptidase inhibitors being studied include their role as cardioprotective agents in heart failure, as renoprotective agents in chronic renal failure and diabetic nephropathy, and as vasculoprotective agents in endothelial dysfunction and athersclerosis.
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PMID:Inhibition of peptidases in the control of blood pressure. 1246 66

Heart failure is characterized by sodium and fluid retention, sympathetic overactivity, parasympathetic withdrawal, vasoconstrictor activation and cytokine elevation. New therapies for heart failure attempt to control neurohormonal activation and limit progressive left ventricular dysfunction. Nesiritide (human B-type natriuretic peptide) is a recently approved new vasodilator that has been given to almost 1,000 patients in numerous clinical investigations; it belongs to a new class of heart failure drugs known as natriuretic peptides. Nesiritide decreases pulmonary capillary wedge pressure, systemic vascular resistance, mean right atrial pressure and pulmonary artery pressure, while improving cardiac index, stroke volume and heart failure symptoms. Many endothelin receptor antagonists are in various stages of development. Early clinical studies have demonstrated beneficial cardiovascular hemodynamic effects. Other new drugs for heart failure also include calcium sensitizers, neutral endopeptidase and vasopeptidase inhibitors, aldosterone receptor antagonists, vasopressin antagonists and cytokine inhibitors. All are being actively investigated and many show significant promise as beneficial therapies in the treatment of heart failure.
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PMID:New therapies for the treatment of congestive heart failure. 1253 83

Pharmacological and validated treatment of chronic heart failure (HF) includes successively angiotensin converting enzyme inhibitors (ACEi), beta-blockers and antialdosterone, which is associated with diuretics. The effectiveness of this manner in which to block more and more hormonal systems demonstrate the validity of the "hormonal" paradigm to explain heart failure. Therefore broader educational means are required to increase the prescription of these drugs for HF. Several questions about these drugs remain unresolved: HF with preserved systolic function and elderly patients, class effect, and the role of antagonists of angiotensin II receptors (as an alternative or associated with ACEi). Other short- and mid-term pharmacological perspectives target target hormonal systems and cytokines: endothelin-receptor antagonists, inhibition of natriuretic peptide degradation (via neutral endopeptidase), and newer drugs acting against TNF such as etanercept. Moreover, recent knowledge about molecular mechanisms of myocardium remodeling allows new drug strategies with target more specifically remodeling such as metalloproteinases. Finally, these perspectives should be largely modified by on-going research in the field of genomics.
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PMID:[Drug prospects in the treatment of heart insufficiency]. 1255 90

The enormous benefits of inhibition of ACE demonstrate that manipulation of the metabolism of peptide hormones is a valuable therapeutic strategy for cardiovascular disease. Recent attempts to expand these benefits have combined ACE inhibition with inhibition of other peptidases such as neutral endopeptidase (NEP) in a single molecule, a strategy known as vasopeptidase inhibition. NEP metabolizes natriuretic peptides, and NEP inhibition offers the prospect of combining the benefits of increased natriuretic peptide levels with those of ACE inhibition. However, peptidases such as ACE and NEP have many different substrates, and there are complex interactions between ACE inhibition and NEP inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and kallidin, and NEP also converts angiotensin (Ang) I to Ang-(1-7) and metabolizes Ang II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates the ACE inhibitor-induced increase in kinin levels, increases Ang II levels, reduces Ang-(1-7) levels, and may increase endothelin levels. These additional consequences of combined ACE/NEP inhibition increase the risk of angioedema and may counteract any benefit of ACE inhibition that depends on reduced Ang II levels and increased Ang-(1-7) levels. Further considerations are that the ratio of ACE and NEP inhibition is fixed for vasopeptidase inhibitors, and there is uncertainty how these drugs should be compared with ACE inhibitors. Vasopeptidase inhibitors will therefore require careful evaluation before they are introduced to patient care.
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PMID:Vasopeptidase inhibition: a double-edged sword? 1262 31


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