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 acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure. 128 Jul 35

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.
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PMID:Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension. 183 59

Atrial natriuretic factor (ANF) is a recently discovered, volume responsive hormone with multiple potent antihypertensive actions. This article reviews data supporting hypothetical associations between ANF and essential hypertension, examines reports of plasma ANF concentrations in hypertension, discusses the efficacy of ANF and its analogs in the treatment of hypertension, and reviews future issues in ANF research. ANF has been shown to elicit vasodilatation, suppress plasma renin activity, inhibit the synthesis and release of aldosterone, antagonize sympathetically-mediated release of norepinephrine, and promote diuresis and natriuresis. A metaanalysis of plasma ANF concentrations reported in normal and hypertensive subjects reveals a 5 +/- 19 pg/mL (pooled, weighted mean and standard deviation) higher ANF level in age-matched, untreated hypertensives without evidence of end-organ damage. This difference may be inappropriately low given the increase in atrial filling pressures found in hypertension. Low doses of ANF elicit greater reductions in blood pressure in hypertensive subjects than in normals. Recently, inhibitors of the ANF-degrading enzyme, neutral endopeptidase, and of the ANF "clearance" receptor have enhanced the antihypertensive actions of endogenous or exogenously administered ANF. Human studies are currently in progress testing the antihypertensive efficacy of orally administered neutral endopeptidase inhibitors. The discovery of ANF has led to the elucidation of a family of natriuretic peptides from brain, heart, and kidney, and promises to enlarge our understanding of volume regulation in normal and pathophysiological states. The possibility that essential hypertension is associated with inappropriately low plasma ANF levels or altered responsiveness to ANF may offer new insights into the pathogenesis and treatment of hypertension.
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PMID:Atrial natriuretic factor and hypertension. A review and metaanalysis. 145 90

Atrial natriuretic factor (ANF) is a cardiac hormone exerting potent cardiovascular and renal effects but its poor intestinal absorption and rapid inactivation have prevented so far its therapeutic utilisation. However inhibition of endogenous ANF metabolism progressively emerges as a novel therapeutic approach in cardiovascular and renal disorders. The critical role played by enkephalinase (membrane metalloendopeptidase, EC 3.4.24.11) in ANF inactivation was deduced from the effects of inhibitors. These compounds not only protect partially exogenous ANF from hydrolysis by some tissue preparations in vitro but also, in vivo, they increase the half-life of the exogenous hormone in plasma and, even more markedly, its recovery in intact form in kidney, a major target organ. In addition, enkephalinase inhibitors increase by two- to three-fold the circulating level of endogenous ANF, even when the latter is already markedly elevated, such as in patients with chronic heart failure. Finally, enkephalinase inhibitors induce a series of ANF-like responses such as natriuresis, diuresis or increase in cGMP excretion which are attributable to the hormone. These pharmacological observations, as well as preliminary clinical trials, suggest that enkephalinase inhibitors may represent a novel class of therapeutic agents with potential applications in congestive heart failure, essential hypertension and various sodium-retaining states.
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PMID:Enkephalinase (EC 3.4.24.11) inhibitors: protection of endogenous ANF against inactivation and potential therapeutic applications. 214 57

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.
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PMID:Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan. 252 43

The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.
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PMID:Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension. 784 19

Due to its physiological and pharmacological action ANF could be an ideal diuretic and vasorelaxation product in the treatment of oedema and essential hypertension. Experimental and clinical investigations in oedematous conditions revealed a very slight diuretic and natriuretic effect of ANF, as compared with healthy subjects. This is due to the reduced renal perfusion pressure, the increased RAAS activity, enzymatic degradation of ANF by endopeptidase and also its inactivation via C-receptors. Moreover the use of ANF is very limited due to its short half-life and peptide structure. In recent years therefore new possibilities are sought how to influence the metabolism of endogenous ANF and thus increase its activity. Neutral endopeptidase inhibitors (NEP) inhibit ANF degradation, increase thus its plasma level and in cardiac weakntlakess have a marked diuretic and natriuretic effect. The administration of NEP inhibitors in patients with essential hypertension did not reveal so far an adequate effect on blood pressure. Inhibitors of C-receptors potentiate also the effect of endogenous ANF. In experiments they enhance Na excretion and lead to a drop of blood pressure. Recently another natriuretic peptide was detected--urodilatine. In experimental and clinical studies in cardiac failure urodilatine administration leads to an increase of diuresis and natriuresis greater than after ANF. Haemodynamic effects after urodilatine are also greater than after ANF whereby urodilatine does not cause reflex tachycardia and is resistant to peptidase degradation. Its therapeutic administration is a new perspective in the treatment of oedematous conditions and essential hypertension.
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PMID:[Use of natriuretic peptides in clinical practice]. 818 76

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension. 834 Jan 58

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension. 839 13

The purpose of this study was to determine whether tissue neutral endopeptidase (NEP) 24.11 activity, a membrane-bound metalloenzyme widely distributed in the peripheral circulation that cleaves and inactivates vasodilator peptides, is increased in spontaneously hypertensive hamsters relative to genetically/age-matched normotensive hamsters. Mean arterial pressure and heart rate were 163 +/- 11 mm Hg and 312 +/- 7 beats/min in spontaneously hypertensive hamsters and 99 +/- 3 mm Hg and 302 +/- 10 beats/min in normotensive hamsters, respectively (mean +/- SEM). NEP 24.11 activity is significantly increased in the kidney, cheek pouch, and spinotrapezius muscle, and significantly decreased in the heart and aorta of spontaneously hypertensive hamsters relative to controls (P < .05). Lung and brain NEP 24.11 activity is similar in both groups. Renal NEP 24.11 activity increases and to a similar extent in spontaneously hypertensive and normotensive hamsters as chloride anion concentration in the assay buffer is increased. Substituting citrate for chloride anion significantly attenuates renal NEP 24.11 activity. Taken together, these data indicate that NEP 24.11 activity in spontaneously hypertensive hamsters is increased in two organs that contribute appreciably to peripheral vascular resistance, skeletal muscle, and kidney. We suggest that the spontaneously hypertensive hamster is a suitable model to study the role of skeletal muscle and renal NEP 24.11 in regulating vasomotor tone in essential hypertension.
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PMID:Increased tissue neutral endopeptidase 24.11 activity in spontaneously hypertensive hamsters. 963 95


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