Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
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PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.
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PMID:Vasopeptidase inhibition: a new concept in blood pressure management. 1034 Aug 42

Vascular resistance in the mammalian pulmonary circulation is affected by many endogenous agents that influence vascular smooth muscle, right ventricular myocardium, endothelial function, collagen and elastin deposition, and fluid balance. When the balance of these agents is disturbed, e.g. by airway hypoxia from high altitude or pulmonary obstructive disorders, pulmonary hypertension ensues, as characterized by elevated pulmonary artery pressure (P(PA)). Among neuropeptides with local pulmonary artery pressor effects are endothelin-1 (ET-1), angiotensin II (AII), and substance P, and among mitigating peptides are calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), atrial natriuretic peptide (ANP), vasoactive intestinal peptide (VIP) and ET-3. Moreover, somatostatin28 (SOM28) exacerbates, whereas SOM14 decreases P(PA) in hypoxic rats, with lowering and increasing of lung CGRP levels, respectively. Pressure can also be modulated by increasing or decreasing plasma volume (VIP and ANP, respectively), or by induction or suppression of vascular tissue remodeling (ET-1 and CGRP, respectively). Peptide bioavailability and potency can be regulated through hypoxic up- and down- regulation of synthesis or release, activation by converting enzymes (ACE for AII and ECE for ET-1), inactivation by neutral endopeptidase and proteases, or by interaction with nitric oxide (NO). Moreover, altered receptor density and affinity can account for changed peptide efficacy. For example, upregulation of ET(A) receptors and ET-1 synthesis occurs in the hypoxic lung concomitantly with reduced CGRP release. Also, receptor activity modifying protein 2 (RAMP2) has been shown to confer ADM affinity to the pulmonary calcitonin-receptor-like receptor (CRLR). We recently detected the mRNA encoding for RAMP2, CRLR, and the CGRP receptor RDC-1 in rat lung. The search for an effective, lung selective treatment of pulmonary hypertension will likely benefit from exploring the imbalance and restoring the balance between these native modulators of intrapulmonary pressure. For example, blocking of the ET-1 receptor ET(A) and vasodilation by supplemental CGRP delivered i. v. or via airway gene transfer, have proven to be useful experimentally.
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PMID:The role of endogenous lung neuropeptides in regulation of the pulmonary circulation. 1119 57

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
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PMID:Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure. 1156 14

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

Omapatrilat is the most clinically advanced of a new class of drugs, vasopeptidase inhibitors, which are being studied for the treatment of patients with cardiovascular disease. Omapatrilat inhibits the enzymatic activities of angiotensin-converting enzyme and neutral endopeptidase. The end result is blockade of angiotensin-II formation and inhibition of the catabolism of vasodilatory hormones, such as the natriuretic peptides, bradykinin, and adrenomedullin. Some of the ultimate pharmacologic effects include vasodilation, natriuresis, and diuresis, which may be beneficial in the management of various cardiovascular diseases, such as hypertension and heart failure. The pharmacokinetics of omapatrilat are compatible with once-daily dosing and a duration of antihypertensive efficacy of more than 24 hours. Omapatrilat decreases blood pressure in both high-renin and low-renin states, which suggests antihypertensive efficacy that is independent of the status of the renin-angiotensin system. Furthermore, the antihypertensive effect of omapatrilat is indiscriminate of age or race. Omapatrilat has consistently shown efficacy in decreasing both systolic and diastolic blood pressure to a similar or greater extent than either lisinopril or amlodipine; however, systolic pressure is more responsive to omapatrilat treatment than diastolic pressure. Although the role of omapatrilat in heart failure is still evolving, preliminary results are promising: hemodynamic improvements and clinical benefits of omapatrilat are similar or greater to those achieved with an angiotensin-converting enzyme inhibitor. Future studies (specifically the OVERTURE Study) will be of pivotal importance in establishing the role of omapatrilat in the treatment of patients with heart failure. The side-effect and drug-interaction profiles of omapatrilat are largely incomplete, but suggest excellent tolerability and a side-effect profile that is similar to placebo. Omapatrilat could be a revolutionary addition to the management of cardiovascular disease, and its clinical development will be followed closely by many who are curious if larger clinical trials will echo the impressive preliminary data that have been seen thus far.
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PMID:Omapatrilat: a unique new agent for the treatment of cardiovascular disease. 1172 68

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.
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PMID:Combined endopeptidase inhibition and adrenomedullin in sheep with experimental heart failure. 1179 85

Omapatrilat was designed to inhibit simultaneously angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The ubiquitous involvement of the renin-angiotensin-aldosterone system, originally conceived as an axis of sodium and fluid metabolism in inflammation, thrombosis and cardiac and smooth muscle hypertrophy, is a major factor in disease progression for conditions as diverse as hypertension, heart failure, coronary artery disease and diabetes. Interruption of angiotensin II generation and bradykinin degradation by ACE inhibition is a major therapeutic advance in the management of these diseases. NEP metabolizes both bradykinin and the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, c-type natriuretic peptide and adrenomedullin). These peptides counter the adverse effects of angiotensin II by their vasodilator, natriuretic, diuretic and autonomic neural actions; by their antitrophic effects; and by suppressing plasma renin activity. These two systems can be considered key components of a cardiorenal axis that maintains blood pressure and cardiopulmonary blood volume within a stable range. This balance is compromised in the setting of heart failure and primary hypertension. The combination of ACE and NEP inhibition should augment the beneficial hemodynamic and tissue effects of bradykinin and the natriuretic peptides. Vasopeptidase inhibition, therefore, is a novel approach to cardiovascular therapy, with implications for hypertension, heart failure, renal function and ischemic heart disease.
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PMID:Vasopeptidase inhibition: a novel approach to cardiovascular therapy. 1187 87

Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation. The consequence of such dual inhibition is a synergistic reduction of vasoconstriction and enhancement of vasodilation, thereby serving to more effectively reduce blood pressure. Furthermore, inhibition of the renin-angiotensin-aldosterone system (RAAS) prevents physiologic compensatory responses in vivo seen with NEP inhibition alone. Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models. Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function. Human studies have documented the efficacy of omapatrilat in the treatment of both hypertension and, to a lesser extent, heart failure. Safety concerns (specifically angioedema) are currently being addressed before the widespread utilization of this promising new agent.
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PMID:Vasopeptidase inhibitors, neutral endopeptidase inhibitors, and dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 1197 22

Human adrenomedullin (hAM) is a 52-amino-acid regulatory peptide containing a six-membered ring structure and an amidated C-terminus, features that are essential for its biological activity. Here, we describe a simple and effective protocol for producing large quantities of highly pure, functional recombinant hAM. A peptide precursor (hAM-Gly) was expressed in Escherichia coli as a fusion protein with thioredoxin and collected as inclusion bodies. The fusion protein was then digested with BLase, a glutamate-specific endopeptidase, to prepare hAM-Gly. The essential ring structure formed spontaneously, while the terminal amide was generated by conversion of the added glycine residue using peptidylglycine alpha-amidating enzyme. The low solubility of hAM-Gly enabled the use of a selective precipitation/extraction method to generate a product that was 80-90% pure, which was sufficient to proceed with the alpha-amidating enzyme reaction. The resultant hAM was then purified further by column chromatography. The final yield was about 82 mg/L of bacterial culture, and the purity, determined by reverse phase HPLC, was >99.5%. The recombinant hAM was biologically active, eliciting concentration-dependent increases in cAMP in CHO-K1 cells expressing a specific hAM receptor and hypotensive responses when intravenously injected into rats. This new approach to the synthesis of hAM is simpler and more cost-effective for large-scale production than chemical synthesis. It therefore represents a new powerful tool that has the potential to facilitate analysis of the structure and function of hAM, as well as the development of new therapeutic protocols for the treatment of ailments such as hypertension.
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PMID:Large-scale production of functional human adrenomedullin: expression, cleavage, amidation, and purification. 1218 25


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