Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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. The ability of the putative chymase product of big endothelin-1 (big ET-1), ET-1(1 - 31), to constrict isolated endothelium-denuded preparations of human coronary and internal mammary artery was determined. 2. pD2 values in coronary and mammary artery respectively were 8.21+/-0.12 (n=14) and 8.55+/-0.11 (n=12) for ET-1, 6.74+/-0.11 (n=16) and 7.10+/-0.08 (n=16) for ET-1(1 - 31) and 6.92+/-0.10 (n=15) and 7.23+/-0.11 (n=12) for big ET-1. ET-1(1 - 31) was significantly less potent than ET-1 (P<0.001, Student's t-test) and equipotent with big ET-1. 3. Vasoconstrictor responses to 100 - 700 nM ET-1(1 - 31) were significantly (P<0.05, Student's paired t-test) attenuated by the ET(A) antagonist PD156707 (100 nM). 4. There was no effect of the ECE inhibitor PD159790 (30 microM), the ECE/NEP inhibitor phosphoramidon (100 microM) or the serine protease inhibitor chymostatin (100 microM) on ET-1(1 - 31) responses in either artery. 5. Radioimmunoassay detected significant levels of mature ET in the bathing medium of coronary (1.6+/-0.5 nM, n=14) and mammary (2.1+/-0.6 nM, n=14) arteries, suggesting that conversion of ET-1(1 - 31) to ET-1 contributed to the observed vasoconstriction. 6. ET-1(1 - 31) competed for specific [(125)I]-ET-1 binding to ET(A) and ET(B) receptors in human left ventricle with a pooled K(D) of 71.6+/-7.0 nM (n=3). 7. Therefore, in human arteries the novel peptide ET-1(1 - 31) mediated vasoconstriction via activation of the ET(A) receptor. The conversion of ET-1(1 - 31) to ET-1, by an as yet unidentified protease, must contribute wholly or partly to the observed constrictor response. Chymase generated ET-1(1 - 31) may therefore represent an alternative precursor for ET-1 production in the human vasculature.
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PMID:Vasoconstrictor activity of novel endothelin peptide, ET-1(1 - 31), in human mammary and coronary arteries in vitro. 1170 58

Endothelial cells are strategically located between the circulating blood and the vascular smooth muscle. These cells are involved in regulating the functions of vascular smooth muscle and circulating blood cells by releasing numerous vasoactive substances. Important endothelium-delivered vasodilators include prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarising factor. Nitric oxide is also important in inhibiting cellular growth and migration, and acts in concert with prostacyclin to exert potent antiatherogenic and thromboresistant effects by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors such as angiotensin II and endothelin-1, which exert prothrombotic inflammatory and growth-promoting properties. Cardiovascular risk factors give rise to cardiovascular disease by causing endothelial dysfunction. Consequently, modern therapeutic strategies focus on preserving or restoring endothelial integrity. Calcium antagonists counteract the effects of angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. In addition to their role in inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors raise the activity of bradykinin, thereby leading to an increase in nitric oxide release. In patients with cardiovascular risk, chronic ACE inhibition improves endothelial function. This may explain why patients treated with ACE inhibitors experience a greater cardiovascular benefit than is attributable to the decrease in blood pressure. Recently developed neutral endopeptidase inhibitors, particularly in combination with ACE inhibitors, induce potent antihypertensive effects. These effects are due partly to decreased breakdown of natriuretic peptides but also as a result of the inhibition of endothelin-1 production. Experimental studies suggest that endothelin-1 antagonists are effective in lowering blood pressure in hypertensives, and also exert beneficial clinical and haemodynamic effects in patients with congestive heart failure. Further clinical studies are under way to determine whether restoration of endothelial function has clinical benefits for patients with cardiovascular disease.
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PMID:Vascular protection: current possibilities and future perspectives. 1171 56

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

Angiotensin converting enzyme (ACE) inhibition is a well-established principle in the treatment of hypertension, and numerous large scale clinical studies have clearly demonstrated the beneficial effects of inhibiting the renin-angiotensin-aldosterone system (RAS) in hypertension. The clinical success 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, which is involved in the degradation of several regulatory peptides including the natriuretic peptides, and augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide. 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, and in turn decrease 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. Based on these considerations, numerous preclinical studies with vasopeptidase inhibitors have been performed and reveal promising results in experimental hypertension. Correspondingly, large-scale clinical studies in patients with hypertension are on the way, to transfer the principle of vasopeptidase inhibition from bench to bedside.
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PMID:Vasopeptidase inhibition: effective blood pressure control for vascular protection. 1179 Feb 96

Endothelin-converting enzyme-1 (ECE-1) is a membrane-bound zinc metallopeptidase that is homologous to neprilysin in amino acid sequence. A major in vivo function of ECE-1 is the generation of endothelin-1, a potent vasoconstrictor, from big endothelin-1. ECE-1 is also potentially involved in the processing or degradation of other peptide hormones. In this study we have used substrates based on the sequence of the COOH-terminal half of big endothelin-1 to examine the subsite specificity of recombinant ECE-1. The big endothelin-1 [16-38] peptides were systematically varied at either position 21 (P(1)) or position 22 (P'(1)) and used in steady-state kinetic analyses of ECE-1. The results indicate that the S(1) pocket of ECE-1 is relatively nonselective, but that the S'(1) subsite of ECE-1 has a preference for large hydrophobic side chains. The peptidyl carboxydipeptidase activity of ECE-1 was also characterized, revealing that substrates with COOH-terminal carboxylates are highly preferred over the cognate amides and esters. A site-directed mutagenesis study was carried out to identify the active-site amino acid residues specifically involved in binding to the COOH-terminal carboxylate of substrates. The data indicate that Arg(133) of ECE-1, which corresponds to Arg(102) of neprilysin that has been identified as an active-site residue of neprilysin involved in binding to the free carboxylate of some substrate peptides, may not play the same role. However, the low activity observed for an ECE-1 Arg(726) mutant is consistent with a role for this arginine residue in the binding of substrates, a role which has been ascribed to arginine residues in both thermolysin (Arg(203)) and neprilysin (Arg(717)).
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PMID:Mapping the active site of endothelin-converting enzyme-1 through subsite specificity and mutagenesis studies: a comparison with neprilysin. 1183 55

We investigated the hemodynamic, renal, and hormonal responses to neutral endopeptidase (NEP) inhibition during a 6-h, double-blind, randomized, placebo-controlled study in seven chronic, stable heart transplant patients. Baseline characteristics were similar during both experiments, and no significant changes were observed after placebo. NEP inhibition increased circulating endothelin-1 (from 2.01 +/- 0.1 to 2.90 +/- 0.2 pmol/l; P < 0.01), atrial natriuretic peptide (ANP; from 21.5 +/- 2.7 to 29.6 +/- 3.7 pmol/l; P < 0.01), and the ANP second messenger cGMP. Noteworthy, systemic blood pressure did not increase. Renal plasma flow and glomerular filtration rate remained unmodified after NEP inhibition. Filtration fraction (33 +/- 13%), diuresis (196 +/- 62%), and natriuresis (315 +/- 105%) increased significantly in relation to ANP and cGMP. A strong inverse relationship was observed between excreted cGMP and sodium reabsorption (r = -0.71, P < 0.0001). Thus, despite significantly increasing endothelin-1, NEP inhibition did not adversely influence systemic or renal hemodynamics in transplant patients. ANP, possibly through a tubular action, enhances the natriuresis observed after NEP inhibition.
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PMID:Hormonal, renal, hemodynamic responses to acute neutral endopeptidase inhibition in heart transplant patients. 1213 66

PgPepO is a homologue of endothelin-converting enzyme-1 (ECE-1), with which it shares 31% identity. PgPepO was isolated from the periodontal pathogen Porphyromonas gingivalis. Recent studies have suggested a link between periodontal and cardiovascular disease, and several groups have suggested that bacterial and viral infections may contribute to the latter. P. gingivalis possesses the ability to invade, and multiply within, aortic endothelial cells and has been localized to atherosclerotic plaques. PgPepO was expressed and purified to homogeneity and we have begun detailed functional analysis, in terms of substrate preference and inhibitor specificity, in order to provide active-site comparisons with other members of the neprilysin (NEP)/ECE family. PgPepO possesses similar substrate specificity to ECE-1 and has been shown to cleave big endothelin-1 (big ET-1), big ET-2 and big ET-3, converting the substrates into their respective mature endothelin peptides. Substance P, angiotensin I, angiotensin II and neurotensin are all cleaved at multiple sites by PgPepO and the kinetics of these reactions have been compared. The potent vasoconstrictor urotensin II is not hydrolysed by PgPepO. Cleavage of bradykinin by PgPepO occurs at the Pro(7)-Phe(8) bond and is inhibited by the NEP and ECE-1 inhibitor phosphoramidon in a pH-dependent fashion (IC(50) =10 microM at pH 7.0) but not by thiorphan, an NEP-specific inhibitor. PgPepO activity is completely inhibited by EDTA. Characterization of this enzyme is important in elucidating possible links between periodontal pathogens and cardiovascular disorders such as atherosclerosis, and provides an opportunity to gain structural information on a bacterial protein with striking similarity to human ECE-1.
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PMID:Characterization of PgPepO, a bacterial homologue of endothelin-converting enzyme-1. 1219 62

Endothelins (ETs) are potent vasoconstrictors and have been implicated in the pathogenesis of various cardiovascular and renal diseases. In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic agent, which is mainly degraded by neutral endopeptidase 24.11 (NEP) in vivo. Thus, compounds that can suppress the biosynthesis of ETs by inhibiting endothelin converting enzymes (ECEs), which catalyse the final step of post-translational processing of the vasoconstrictors, while simultaneously potentiating the levels of ANP by inhibiting NEP may have novel therapeutic utility. Through targeted screening of our compound library and subsequent optimization, CGS 34226 was identified as a potent, dual inhibitor of ECE-1 and NEP, inhibiting the enzymes with respective IC(50) values of 11 and 4.6 nM. In vivo, CGS 34226 suppressed the big endothelin-1 (big ET-1)-induced pressor response dose-dependently. At 15 and 90 min after an intravenous dose of 30 mg/kg in anaesthetized rats, this compound inhibited the big ET-1-induced effect by 79% and 65% respectively. In addition, CGS 34226 increased plasma ANP immunoreactivity by 120% up to 4 h after an intravenous dose of 10 mg/kg in conscious rats infused with ANP at a rate of 450 ng/kg per min, intravenously. These results show that CGS 34226 is a potent dual inhibitor of ECE-1 and NEP in vitro and in vivo and that the compound may represent a novel agent for the treatment of cardiovascular and renal dysfunction.
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PMID:CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11. 1219 64

CGS 34226 is a thiol-containing, potent dual inhibitor of endothelin converting enzyme-1 (ECE-1) and neutral endopeptidase 24.11 (NEP) with IC(50) values of 11 and 5 nM respectively. The purpose of the present study was to characterize the inhibitory effects of CGS 34225, an orally active prodrug of CGS 34226, on ECE-1 and NEP in vivo. The effects on ECE-1 and NEP were assessed by determining the inhibition of big endothelin-1 (big ET-1)-induced increases in mean arterial pressure (MAP) and increases in plasma atrial natriuretic peptide (ANP) concentrations respectively, in conscious rats. Thirty and 120 min after the administration of vehicle, big ET-1 (0.3 nmol/kg, intravenously; i.v.) produced pressor responses of approximately 800 mmHg.min (area under the curve for change in MAPxtime). Treatment with CGS 34225 at 1 mgEq/kg, per os (p.o.), decreased the pressor effect of big ET-1 by 39 and 53% at 30 and 120 min respectively (P<0.05, both times). Increasing the dose of CGS 34255 to 30 mgEq/kg, p.o., resulted in greater inhibition, 84 and 92% (P<0.05) at 30 and 120 min respectively. Furthermore, at this higher dose, the inhibitory effect on ECE-1 was long-lasting, averaging 86, 75 and 30% (P<0.05, all times) at 4, 8 and 24 h respectively. In rats treated with vehicle, the infusion of ANP at 450 ng/kg per min i.v. resulted in plasma ANP concentrations of 3.9-4.8 ng/ml that remained relatively constant for 4 h. Treatment with CGS 34225 at 10 mgEq/kg, p.o., increased the ANP level to 7.7+/-1.0 and 10.6+/-1.8 ng/ml at 1 and 4 h after dosing (P<0.05, both times). These data demonstrate that CGS 34225 is a potent, orally active and long-acting inhibitor of ECE-1 and NEP in vivo. It is anticipated that compounds with this dual function may be useful in the treatment of cardiovascular diseases where the ET system plays a pathogenic role and the potentiation of ANP elicits therapeutic benefits.
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PMID:Effects of the ECE/NEP inhibitor CGS 34225 on the big ET-1-induced pressor response and plasma atrial natriuretic peptide concentration in conscious rats. 1219 65

Maturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ET(A) and ET(B)) to produce its effects. In the guinea pig, the systemic administration of ET-1 produces a bronchoconstrictor response that is mediated indirectly via the release of thromboxane A(2) through ET(B) receptor activation. A new potent metabolite of big ET-1, ET-1 (1-31), has been reported to act as an ET(A) receptor selective agonist. In this study we investigated the effects of ET-1 (1-31), compared with ET-1, on the release of eicosanoids in the isolated and perfused guinea pig lung. We also clarified the implication of ET receptors in these effects using selective ET(A) or ET(B) receptor antagonists, BQ-123 and BQ-788 respectively. Finally, using the neutral endopeptidase 24.11 (NEP 24.11) inhibitor, thiorphan, we determined the involvement of this enzyme on ET-1 (1-31) effects. Infusion of ET-1 (1-31) (50 nM) stimulates a marked release of thromboxane A(2) and prostacyclin equivalent to that observed with a ten times lower concentration of ET-1 (5 nM). BQ-788 (5 nM and 10 nM), but not BQ-123 (1 microM), decreases the release of thromboxane A(2) and prostacyclin triggered by both agonists. Interestingly, thiorphan (25 microM) abolishes the eicosanoid-releasing properties of big ET-1 (100 nM) and ET-1 (1-31). This study demonstrates that ET-1 (1-31) is less potent than ET-1 in stimulating the release of eicosanoids through ET(B) receptor activation in the guinea pig perfused lung. Moreover, the inhibitory properties of thiorphan indicate the possible existence of a bioactive metabolite of ET-1 (1-31). We therefore suggest that NEP 24.11 in the pulmonary vasculature, is implicated in the cleavage of ET-1 (1-31) to produce ET-1 which will further act on both ET receptors.
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PMID:Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ET(B) receptors in the guinea pig perfused lung. 1219 70


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