Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The term vasopeptidase means any peptidase able to generate or to inactivate a vasoactive peptide. This term got a more definitive meaning when a new class of drugs, the vasopeptidase inhibitors, was introduced. These drugs are especially represented by the inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE is now primarily considered a kininase rather than an angiotensinase and ACE-inhibitors have been used successfully in the treatment of many cardiovascular diseases, including hypertension and heart failure. Preliminary results suggest that the use of NEP inhibitors could also contribute to improve prognosis of cardiovascular diseases. Vasopeptidase inhibitors simultaneously inhibiting both NEP and ACE have shown to be more effective than currently available ACE inhibitors. (Omapatrilat is at present the most clinically advanced in these drugs). However, many side-effects of vasopeptidase inhibitors have been reported, but the most dangerous is angioedema which is potentially life threatening. Since this complication is mediated by bradykinin, and both inhibition of ACE and NEP can produce bradykinin increasing, it has been suggested that the incidence of angioedema due to vasopeptidase inhibitors could be higher compared with that related to ACE-inhibitors. The FDA raised concern about this adverse effect, and the manufacturer decided to withdraw the application temporarily. In order to identify patients at risk of angioedema we have recently shown that low plasma levels of aminopeptidase P, another enzyme which cabolises bradykinin, could indicate a predisposition for development of angioedema in some patients treated with vasoinhibitor drugs.
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PMID:[Vasopeptidases and their inhibitors]. 1240 10

The angiotensin converting enzyme (ACE), endothelin (ET) converting enzyme (ECE) and neutral endopeptidase (NEP) are all zinc-metallopeptidases expressed in almost all the organs, such as heart, vessels and kidneys. While ACE and ECE are respectively involved in the transformation of angiotensin I and Big-ET into angiotensin II and ET-1 respectively, which possess vasoconstrictor and mitogenic properties, NEP is involved in the degradation of atrial natriuric factor (ANF), which possesses vasorelaxant, diuretic/natriuretic and antihypertrophic properties. These three systems are activated in heart failure and modulate the progression of heart failure. This article will discuss preliminary date concerning simultaneous inhibition of ACE, ECE and/or NEP and their therapeutic potential interest in the treatment of heart failure.
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PMID:Emerging concepts of neurohumoral modulation in the treatment of congestive heart failure. 1240 98

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

Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.
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PMID:Vasopeptidase inhibitors: potential role in the treatment of heart failure. 1263 92

Sampatrilat is a novel vasopeptidase inhibitor that may offer a greater benefit than traditional angiotensin-converting enzyme (ACE) inhibitors in the treatment of chronic heart failure (CHF). The present study was undertaken to determine whether sampatrilat improves hemodynamic function and cardiac remodeling through a direct action on the failing heart in rats with CHF following left coronary artery ligation (CAL). Sampatrilat (30 mg/kg a day) was administered orally to the animals from the 1st to 6th week after the operation. Sampatrilat reduced the mortality of the rats with CAL (20 versus 57% for untreated rats). Treatment with sampatrilat for 5 weeks suppressed tissue ACE and neutral endopeptidase (NEP) activities. Sampatrilat did not affect the arterial blood pressure, whereas it attenuated the CAL-induced increases in the left ventricular end-diastolic pressure, heart weight, and collagen content of the viable left ventricle. To assess the direct effects of sampatrilat on collagen synthesis, we measured the incorporation of [(3)H]proline into cultured cardiac fibroblasts. Sampatrilat at concentrations that inhibited NEP activity in vitro augmented the atrial natriuretic peptide-induced decrease in [(3)H]proline incorporation by the cells. In addition, sampatrilat prevented the angiotensin I-induced increase in [(3)H]proline incorporation, whereas captopril did not. The results suggest that long-term treatment with sampatrilat regresses cardiac remodeling in rats with CAL, which is associated with improvement of hemodynamic function. The mechanism by which sampatrilat improved cardiac remodeling may be attributable to the direct inhibition of cardiac fibrosis, possibly acting through the cardiac natriuretic peptide system.
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PMID:Beneficial effects of sampatrilat, a novel vasopeptidase inhibitor, on cardiac remodeling and function of rats with chronic heart failure following left coronary artery ligation. 1264 57

Angiotensin-converting enzyme (ACE) inhibition is a well-established principle in the treatment of endothelial dysfunction. Numerous preclinical and clinical studies have clearly demonstrated the beneficial effects of inhibiting the renin-angiotensin-aldosterone system (RAS) in states of impaired endothelial function. The successful use of ACE inhibitors encouraged attempts to inhibit other key enzymes in the regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase that is involved in the degradation of several regulatory peptides, including the natriuretic peptides, and, thus, NEP inhibition augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide (ANP). By inhibiting the RAS and potentiating the natriuretic peptide system at the same time, combined NEP/ACE inhibitors, the so-called vasopeptidase inhibitors, reduce vasoconstriction and enhance vasodilatation, thereby decreasing peripheral vascular resistance and blood pressure. Within the vessel wall this may lead to a reduction of vasoconstrictor and proliferative mediators, such as angiotensin II and endothelin-1, and may increase local levels of bradykinin as well as natriuretic peptides. Even though first results of both preclinical and clinical studies indicate that combined inhibition of ACE and NEP by vasopeptidase inhibitors represents a promising strategy in the treatment of hypertension and heart failure, angioedema occurs more frequently on vasopeptidase inhibition as compared to ACE inhibition. To establish vasopeptidase inhibition as a novel option in the treatment of cardiovascular disease, further validation of efficacy and safety of this promising therapeutic principle is mandatory.
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PMID:Vasopeptidase inhibition: a new treatment approach for endothelial dysfunction. 1269 9

The heart produces two related hormones, atrial (ANP) and B-type natriuretic peptides (BNP). Both are synthesized in the atria and ventricles as polypeptides, which upon release are split into ANP and BNP and the N-terminal fragments N-ANP and N-BNP (together named natriuretic peptides, NPs). The most important function of ANP and BNP is protection against volume-overload, by increasing natriuresis and diuresis amongst other things. Both peptides can be considered the natural antagonist of the renin-angiotensin system. Clearance occurs through a specific receptor and through enzymatic break-down by neutral endopeptidase (NEP). All 4 NPs circulate in plasma. Elevated concentrations of NPs are found when the filling pressures of the heart are elevated, as in acute coronary syndromes and congestive heart failure. Measurement of NPs is a useful tool in the differential diagnosis of cardiac versus non-cardiac dyspnoe (high negative predictive value), in the identification of heart failure patients most at risk and in optimising therapy in heart failure. In right ventricular overload caused by (corrected) congenital heart diseases and acute lung embolism, NP concentrations are also elevated, as they are in renal failure and in hypertension associated with left ventricular hypertrophy. Infusions of ANP and BNP lead to increased natriuresis and diuresis. Pharmacologically, increases in ANP and BNP can be accomplished with NEP-inhibitors or beta-blockers. Measurement of NP(s) will become as important for estimation of heart function as creatinine is for estimation of renal function.
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PMID:[Atrial and B-type natriuretic peptides: from the research lab to clinical practice]. 1273 63

Many different diseases may lead to heart failure. Nevertheless, the symptoms and pathophysiological changes in heart failure are uniform as are the basic principles of treatment. Although significant progress has been achieved in understanding the biology of heart failure and the therapeutic options, the quality of life of heart failure patients and their survival are often poor. Since cardiac transplantation as a final therapeutic option is limited by the availability of donor organs, new strategies and technologies need to be explored to treat the failing heart effectively. Approaches to improve the medical therapy of heart failure mainly focus on strategies to escape the vicious circle of decreased contractility and neurohumoral activation. Substances with promising experimental and clinical results include neutral endopeptidase inhibitors, endothelin antagonists or cytokine inhibitors, e.g. TNF antagonists. Mechanical and electrical devices are under development such as left ventricular assist devices (LVADs), biventricular pacemakers and artificial hearts, which may become valuable alternative therapies. Gene therapy approaches aim to improve the vascularization of the heart, the Ca-homeostasis of the myocytes or the survival of cardiac cells in disease. Finally, cellular cardiomyoplasty is a relatively novel approach to replace or support the cardiomyocytes of the diseased heart by implanting new ones. Which cell type under which conditions will turn out to be the most suitable is still unknown and subject to debate. Ongoing clinical studies will only help to demonstrate the safety and feasibility of this technique but not determine its long-term efficacy. It is highly desirable that one of these new therapeutic strategies or a combination of them will have a significant impact on the future management of heart failure. Currently, our main clinical focus must be to treat as many patients as possible with drugs that are known to improve symptoms and survival, like ACE inhibitors, beta-blockers, cardiac glycosides, diuretics and spironolactone.
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PMID:[Therapeutic perspectives in heart failure]]. 1280 18


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