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)

Chronic heart failure is a disabling and lethal disorder with high incidence and prevalence in Western societies. Treatment with angiotensin-converting enzyme (ACE) inhibitors and heart transplantations diminish both mortality and morbidity, although both still remain high. Increased understanding of some of the pathophysiologic mechanisms involved in the development of left ventricular dysfunction and the transition from asymptomatic systolic dysfunction to symptomatic heart failure has opened gates to new dimensions for the treatment of this disorder. The initial event in the pathophysiologic process is damage to the myocardium, most frequently a myocardial infarction. Almost simultaneously, activation of different neurohormonal systems occurs. The renin-angiotensin system and sympathetic nervous system are activated. Increased concentrations of hormones with counteractive activity have also been found, such as ANP and BNP. Interestingly, prolonged neurohormonal activation seems to occur only in patients with large infarcts or in patients with poor systolic function of the left ventricle. Moreover, available data from an echocardiographic study indicates that in patients with high concentrations of neurohormones in plasma a week after their infarction, left ventricular dilatation and systolic dysfunction of the left ventricle are highly likely to develop during long-term follow-up. Several studies have showed that ACE inhibitors are efficacious in chronic heart failure and among patients with reduced ejection fraction after myocardial infarction. What these patients have in common is prolonged neurohormonal activation, which theoretically may be harmful to myocardial cell structure and function. ACE inhibitors reduce the breakdown of angiotensin I to angiotensin II and increase the concentration of circulating bradykinins and prostaglandins. Further modulation of neurohormonal activity might be beneficial. Therefore, future treatment of chronic heart failure or asymptomatic left ventricular dysfunction might include beta-adrenergic blockers, neutral endopeptidase inhibitors, ANP, BNP, angiotensin II receptor antagonists, and modulators of sympathetic activity.
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PMID:The role of neurohormonal activation in chronic heart failure and postmyocardial infarction. 867 61

Angiotensin converting enzyme (ACE) inhibition undoubtedly has become the cornerstone of heart failure treatment. Useful in each stage, it should possibly be considered first-line treatment in many patients with mild heart failure in whom fluid retention is not clearly present. Careful consideration of the optimal dose for the individual is important. Until further data are available concerning the efficacy and tolerability of high and low doses, the clinician should consider the target doses used in large controlled heart failure trials. Even under optimal dosing conditions, it is likely that ACE inhibition may not suffice in completely modulating the extensive neurohormonal stimulation extant in heart failure. In part this may result from a breakthrough of the ACE inhibitor effect as well as from activation of hormones and peptides that may not be affected by ACE inhibition. Also, a substantial proportion of patients may not tolerate sufficient ACE inhibition. Alternative or additional therapy aimed at modulating neurohormonal activation concerns interference with other parts of the renin angiotensin system, such as angiotensin II receptor and aldosterone receptor antagonism. Sympathetic activity and catecholamine levels may decrease with dopaminergic D2 agonists and, possibly, beta-blockade; in the latter, this may be confined to patients with pre-existing sympathetic over-activation. Increasing circulating levels of atrial natriuretic peptide via neutral endopeptidase inhibition may offer an alternative way to increase diuresis and natriuresis without neuroendocrine stimulation. Novel possibilities that have not yet been tested sufficiently in patients with heart failure include endothelin receptor antagonism, arginine vasopressin antagonism, and renin inhibition. Finally, digitalis glycosides may be considered neurohormonal modulators in addition to being positive inotropes. Heart failure is a complex condition that involves many organs and systems besides the heart. Polypharmacy tailored to the individual is mandatory. It is thus necessary to investigate approaches to the modulation of neurohormonal activation beyond ACE inhibition.
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PMID:Neurohormonal modulation in heart failure: ACE inhibition and beyond. 868 65

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

The vasoconstrictor angiotensin II and atrial natriuretic peptide (ANP) are oppositely involved in the development of heart failure, as modeled by myocardial infarction (MI) in rats. MI is a model also characterized by sodium retention despite the elevated plasma ANP levels, showing a desensitization of responses to ANP. S21402 (RB105) {N-[2S,3R-(2-mercaptom-ethyl-1-oxo-3-phenylbutyl) L-alanine]} is a dual inhibitor that inhibits both neutral endopeptidase (Ki = 1.7 +/- 0.3 nM) and angiotensin-converting enzyme (Ki = 4.2 +/- 0.5 nM). Inhibition of neutral endopeptidase protects endogenous ANP, and inhibition of angiotensin-converting enzyme blocks angiotensin II production, whereas inhibition of both peptidases is required to protect endogenous bradykinin (BK). Induction of MI in rats, by ligation of the left coronary artery, increased the base-line plasma ANP, cyclic GMP (cGMP) and renin concentrations, which were related to the degree of MI (moderate and severe MI rats). Urinary excretion of ANP, cGMP and BK was also increased in MI rats and was linked to the infarction size. S21402 (RB105) (25 mg/kg bolus plus 25 mg/kg/hr i.v.) decreased the mean blood pressure and increased natriuresis in MI rats whatever the degree of MI. S21402 (RB105) induced an increase in plasma renin in MI rats despite the elevated base-line levels. S21402 (RB105) did not alter the plasma in ANP in MI rats. However, plasma cGMP was increased by the dual inhibitor, as a function of the infarction severity. Urinary excretion of ANP, cGMP and BK was also increased by S21402 (RB105), proportionally to the infarction size. Whatever the degree of MI, S21402 (RB105) was able to induce natriuresis, characterized by a desensitization of ANP-induced renal responses. Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by potentiating endogenous ANP and BK and blocking angiotensin II production could be an interesting therapeutic approach in heart failure.
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PMID:Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by S21402 (RB105) in rats with experimental myocardial infarction. 876 6

Cyclosporin A (CyA) is today used for the treatment of autoimmune diseases and in the past was given also to patients with recent-onset insulin-dependent diabetes mellitus (IDDM). Hypertension is a major hazard in patients receiving CyA. In this study we have evaluated the effect of CyA administered to IDDM patients on blood pressure and serum angiotensin-converting enzyme (SACE), an endopeptidase that is an integral part of the renin-angiotensin and bradykinin systems. Sera from patients affected by recent-onset IDDM who were treated with CyA at the dose of 5 mg/kg body weight in addition to insulin therapy were included in the study (n = 13). Sera from 9 IDDM patients with the same clinical characteristics and followed up for 12 months represented the control group (insulin therapy only). SACE levels were measured at diagnosis and after 12 months. The results showed that SACE levels were elevated in IDDM patients at diagnosis and remained significantly high at 12 months in CyA-treated patients as compared to control patients (P < 0.006). Systolic and diastolic blood pressure were increased at 12 months in CyA-treated patients (p < 0.005 and p < 0.05, respectively). CyA therapy administered even at low doses to IDDM patients may increase SACE levels and also blood pressure. These findings should be considered when CyA is used for therapy of autoimmune diseases.
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PMID:Serum angiotensin-converting enzyme levels in patients with recent-onset insulin-dependent diabetes after one year of low-dose cyclosporin therapy. IMDIAB Study Group. 883 19

The cardiovascular consequences of neutral endopeptidase (NEP) inhibition with the NEP inhibitor ecadotril were evaluated by determining acute and long-term effects of the compound on hemodynamic, hormonal, renal, and structural parameters in hypertensive transgenic rats harboring a mouse renin gene (TGR (m(Ren2)27) and in normotensive controls (Sprague-Dawley rats, SDR). Acute administration of ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent decrease in systolic blood pressure with a maximal effect of -23 mm Hg between 2 and 4 h after oral administration. The NEP activity in plasma was significantly inhibited and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides and their second messenger, cyclic GMP, were distinctly raised after oral administration. In addition, ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent increase in the urinary excretion of sodium and cyclic GMP. These effects were more pronounced in TGR (mRen2)27 than in the normotensive SDR without an activated natriuretic peptide system. In the long-term study, the systolic pressure in control TG (m(Ren2)27) rats increased from 213 +/- 5 to 255 +/- 7 mm Hg, whereas, in animals treated with ecadotril (30 mg/kg, orally twice daily), the blood pressure increased only from 213 +/- 5 to 227 +/- 6 mm Hg during the observation period of 13 weeks. The increases in heart weight and in kidney weight were also delayed. At the end of the study, cyclic GMP was elevated and ANP tended to be higher, whereas plasma renin activity had decreased. These data indicate a beneficial pharmacological profile of neutral endopeptidase inhibition that could prove useful in the treatment of cardiovascular diseases like hypertension.
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PMID:Renal and antihypertensive effects of neutral endopeptidase inhibition in transgenic rats with an extra renin gene. 886 26

1. Atrial and brain natriuretic peptide are both circulating hormones subject to degradation by neutral endopeptidase 24.11. Whereas endogenous levels of atrial natriuretic peptide are increased by neutral endopeptidase inhibition in most pathophysiological states, the effect on brain natriuretic peptide and the influence of cardiac status is less clear. To further evaluate the role of neutral endopeptidase 24.11, we directly compared the responses of atrial and brain natriuretic peptide, together with the effects on other vasoactive hormones, haemodynamics and renal indices, to a neutral endopeptidase inhibitor, SCH32615, and a vehicle control in eight conscious sheep before and during pacing-induced heart failure. 2. In normal animals, SCH32615 significantly increased concentrations of plasma atrial natriuretic peptide (22 +/- 5 pmol/l compared with 14 +/- 2 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (6.5 +/- 1.2 pmol/l compared with 4.1 +/- 0.7 pmol/l in control, 1.6-fold increase), whereas in heart failure, plasma levels of atrial natriuretic peptide (306 +/- 38 pmol/l compared with 187 +/- 25 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (93 +/- 11 pmol/l compared with 55 +/- 9 pmol/l in control, 1.7-fold increase) were elevated to a significantly greater absolute, but proportionately similar, extent. In both normal and heart-failed animals, SCH32615 induced reductions in mean arterial pressure and left atrial pressure and increases in haematocrit, plasma cGMP and endogenous creatinine clearance. However, only in heart failure did neutral endopeptidase inhibition induce a significant and marked natriuresis (> 10-fold increase) and diuresis (4-fold increase), together with suppression of renin activity and haemodynamic effects including decreased peripheral resistance and raised cardiac output. 3. In conclusion, neutral endopeptidase inhibition increases plasma concentrations of atrial and brain natriuretic peptide to a proportionately similar extent in both normal and heart-failed sheep. The striking natriuresis and diuresis and additional haemodynamic effects demonstrated in sheep with heart failure, where natriuretic peptide levels are elevated compared with normal sheep, supports the concept that neutral endopeptidase inhibition augments endogenous atrial and brain natriuretic peptide.
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PMID:Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. 886 10

The cardiovascular consequences of mixed angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibition with alatriopril/alatrioprilat were compared with the consequences of endopeptidase (NEP) inhibition alone with (S)-thiorphan/ecadotril by determining the acute effects of the compounds on hemodynamic, hormonal, and renal parameters in hypertensive transgenic rats harboring an additional mouse renin gene (TGR(mRen2)27). Infusion of alatrioprilat and (S)-thiorphan in anesthetized TGR decreased blood pressure in a dose-dependent manner, but heart rate remained unchanged. The renal excretion of water, sodium, and cGMP also increased dose-dependently, with nearly the same maximal effects after infusion of (S)-thiorphan and alatrioprilat. At the end of infusion, plasma ANP and cGMP were elevated both after (S)-thiorphan and after alatrioprilat, whereas plasma renin activity increased only after alatrioprilat. The ACE inhibition effect was studied in ganglion-blocked rats receiving a continous infusion of angiotensin I. Alatrioprilat decreased the mean blood pressure dose-dependently, but about 30 times higher concentrations were needed to produce the same effects as the ACE inhibitor captopril. At a dose of 30 mg/kg p.o., ecadotril, the orally active prodrug of (S)-thiorphan, decreased the systolic blood pressure in conscious TGR by 22 mmHg for 6 h, whereas alatriopril (100 mg/kg p.o.) also reduced the systolic pressure in these rats with a maximal reduction of 22 mmHg. In addition, ecadotril and alatriopril significantly increased the urinary excretion of sodium. In contrast, ACE inhibition with captopril decreased the excretion of sodium dose-dependently in conscious TGR. In conclusion, combined ACE/NEP inhibition produced a comparable lowering of blood pressure and improvement in renal function as those with NEP inhibition in TGR. Dual ACE/NEP inhibition may therefore be useful in cardiovascular conditions such as hypertension or heart failure.
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PMID:Cardiorenal consequences of dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibition in transgenic rats with an extra renin gene. 889 43

In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.
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PMID:Renal and depressor activities of inhibitors of neutral endopeptidase and angiotensin converting enzyme in monkeys infused with angiotensin II. 894 78

To evaluate the interaction between renal nerves, the atrial natriuretic peptide (ANP), and the renin-angiotensin system (RAS), electrical stimulation of renal nerves was performed in spontaneously hypertensive rats (SHR) and in their normotensive controls, Wistar Kyoto rats (WKY), before and after pharmacologic treatment with (a) a neutral endopeptidase inhibitor (NEP-i) to enhance the intrarenal ANP activity; (b) an ACE inhibitor (ACE-i) to block RAS; (c) both NEP-i and ACE-i; and (d) the vehicle of the drugs. Renal nerve stimulation did not change arterial pressure (AP) but reduced renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNa+V) in both WKY and SHR. NEP-i treatment in WKY and SHR had no systemic or renal hemodynamic effects but increased GFR and urinary cyclic guanosine monophosphate (GMP) excretion; UNa+V increased (+2.78 +/- 0.31 microEq/min) in WKY, whereas it did not change in SHR (+0.83 +/- 0.79 microEq/min). In both strains, ACE-i treatment reduced AP, increased RBF, and did not change GFR and UNa+V. The combined treatment with NEP-i and ACE-i did not modify the natriuretic effect observed in NEP-i treated WKY (+4.29 +/- 1.25 microEq/min), but it elicited a natriuretic effect in SHR (+3.98 +/- 1.29 microEq/min). Pharmacologic treatment did not change the hemodynamic and excretory responses to renal nerve stimulation in both WKY and SHR. In conclusion, NEP-i treatment increased UNa+V in normotensive rats without changing AP. In hypertensive rats, the natriuretic effect of NEP-i became evident only after block of RAS by ACE-i. Neither NEP-i nor ACE-i, even in combination, could modify the renal responses to sympathetic stimulation.
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PMID:Excretory responses to renal nerve stimulation during inhibition of neutral metalloendopeptidase and angiotensin-converting enzyme in the rat. 894 80


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