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)

Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) produces cardiovascular effects greater than those elicited by selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are single molecules that inhibit both NEP and ACE and produce cardiovascular effects in animal models similar to those elicited by the combination of NEP and ACE inhibitors. The purpose of this study was to determined the duration of antihypertensive activity of the dual metalloprotease inhibitor omapatrilat in rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE (Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to angiotensin I in rats after intravenous administration with a potency and duration of action similar to those of the long acting ACE inhibitor fosinoprilat. After single dose administration, omapatrilat lowered mean arterial blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive rats (high renin model) from 148+/-5 to 106+/-3 mm Hg (baseline to 24 h), in deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167+/-4 to 141+/-5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162+/-4 to 138+/-3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic blood pressure (tail cuff) in spontaneously hypertensive rats during 11 days of treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic catheter) was lower (P < .05) in the group receiving omapatrilat (133+/-5 mm Hg) than in the group receiving vehicle (149+/-2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent.
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PMID:Effects of omapatrilat in low, normal, and high renin experimental hypertension. 954 78

Accumulating evidence suggests that angiotensin-(1-7) is an important component of the renin-angiotensin system, having actions that are either identical to or opposite that of angiotensin II. Angiotensin I can be directly converted to angiotensin-(1-7), bypassing formation of angiotensin II. This pathway is under the control of three enzymes: neutral endopeptidases 24.11 (neprilysin) and 24.15 and prolyl-endopeptidase 24.26. Two of the three angiotensin-forming enzymes (neprilysin and endopeptidase 24.15) also contribute to the breakdown of bradykinin and the atrial natriuretic peptide. Furthermore, angiotensin-(1-7) is a major substrate for angiotensin-converting enzyme. These observations suggest that the process of biotransformation between the various Ang peptides of the renin-angiotensin system and other vasodepressor peptides are intertwined through this enzymatic pathway. Substantial evidence suggests that angiotensin-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, and nitric oxide, while also augmenting the metabolic actions of bradykinin. In addition, angiotensin-(1-7) alters tubular sodium and bicarbonate reabsorption, decreases Na+-K+-ATPase activity, induces diuresis, and exerts a vasodilator effect. These physiologic effects of angiotensin-(1-7) favor a blood pressure-lowering effect. The majority of the data currently available suggest that angiotensin-(1-7) mediates its effects through a novel non-AT1/AT2 receptor subtype.
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PMID:Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis. 972 81

Major discoveries have been made of new type-I and type-III peptidomimetic inhibitors of peptide-derived systems. Innovative reversible inhibitors of cysteine proteases and renin, and additional examples of peptidomimetic inhibitors of interleukin-1 beta-converting enzyme, neutral endopeptidase, herpes simplex virus protease, thrombin, HIV protease, Ras farnesyltransferase, the RGD motif, Factor Xa and various aspartic proteases have been discovered.
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PMID:Peptidomimetic design. 973 16

It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.
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PMID:Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. 977 79

It has been recently shown that angiotensin II (Ang II) is not the only active peptide of the renin-angiotensin system. Several of its degradation products including Ang III (obtained by deletion of the N terminal amino acids), Ang IV (obtained by deletion of the two N terminal amino acids), and Ang II (1-7) (obtained by deletion of the C terminal amino acid), also possess biological functions. These peptides are formed via the activity of several enzymes: angiotensin--converting enzyme, aminopeptidases A and N, neutral endopeptidase and prolylendopeptidase. Ang III possesses most of the properties of Ang II and shares the same receptors AT1 and AT2. In addition this peptide is particularly important in brain physiology and plays a major role in the secretion of arginine vasopressine. Ang IV possesses its own receptors distinct from AT1 and AT2. Some of its effects (for example, stimulation of the synthesis of the type 1 inhibitor of plasminogen activator by endothelial cells) were previously attributed to Ang II. Others effects, like renal and cerebral vasodilatation, are opposed to Ang II effects. The role of Ang IV in renal physiology remains to be determined. Ang II (1-7) exhibits direct and indirect effects, the latter resulting from Ang II (1-7)-dependent formation of nitric oxide and vasodilatory prostaglandins. Ang II (1-7) potentiates the hypotensive effect of bradykinin and plays also a major role in the control of the hydroelectrolytic balance. It possesses its own receptor: AT1-7, recognizable by (sar1-thr8) Ang II or Sarthran. Finally Ang II (1-7) is converted into Ango II (1-5), by angiotensin-converting enzyme. This peptide is inactive. All of these enzymes, peptides and receptors are present in kidney. Thus the renin-angiotensin system appears to be much more complicated than thought a few years ago, setting the problem of new therapeutic tools for the treatment of hypertension and glomerulosclerosis.
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PMID:[Active metabolites derived from angiotensin II]. 985 79

Accumulating evidence suggests that angiotensin-(1-7)(Ang-(1-7)) is an important component of the renin-angiotensin system and that the actions of the peptide may either contribute to or oppose those of Ang II. Ang-(1-7) can be converted directly from Ang I bypassing prerequisite formation of Ang II. Formation of Ang-(1-7) is under the control of at least three endopeptidases depending on the tissue compartment and include neprilysin, thimet oligopeptidase and prolyl oligopeptidase. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. These enzymatic pathways may contribute to a complex relationship between the hypertensive actions of Ang II and various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. Ang-(1-7) is devoid of the vasoconstrictor, central pressor, or thirst-stimulating actions associated with Ang II. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, Ang-(1-7) may oppose the actions of Ang II directly or as a result of increasing prostaglandins or nitric oxide. In this review, we examine the mechanisms by which Ang-(1-7) may contribute to cardiovascular regulation.
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PMID:Antihypertensive effects of angiotensin-(1-7). 987 88

Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.
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PMID:Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. 987 42

The orally active neutral metalloendopeptidase (NEP) inhibitor SCH34826 was given by oral gavage in a dose of 90 mg/kg twice daily for 3 days to rats with subtotal nephrectomy (n = 7) and effects were compared to a placebo group receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the specific radioligand [125I]-SCH 47896. Treatment with the NEP inhibitor SCH34826 caused a 60% reduction in the neutral endopeptidase radioligand-binding site density in the kidneys of the SCH34826-treated animals compared to the placebo group (81.6+/-3.7 versus 214.5+/-4.2 dpm/mm2, p<0.01). This was associated with a marked increase in urinary atrial natriuretic peptide (ANP) from 3,930+/-295 to 9,094+/-1,089 pg/24 h in the SCH34826-treated group (p<0.01). Concomitantly there was a transient increase in natriuresis in the SCH34826-treated group [baseline 2.03+/-0.55 to 3.77+/-0.58 mmol/24 h on treatment day 1 (p = 0.02) and 2.58+/-0.19 mmol/24 h on treatment day 3 (p = 0.09)] which was not observed in the placebo group. Urinary protein excretion, glomerular filtration rate (determined by 99mTc-DTPA clearance), systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest that oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alteration of systemic blood pressure, plasma ANP and renin level, glomerular filtration or protein excretion.
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PMID:Effects of neutral endopeptidase inhibition in the rat remnant kidney model. 993 26

Brain natriuretic peptide (BNP) is increased in left ventricular impairment and neutral endopeptidase (NEP) is involved in its metabolism. In random order, eight patients with left ventricular impairment received placebo, a 4-h infusion of human BNP (3.0 pmol/kg min), a single oral dose of NEP inhibitor (SCH 42495, 300 mg), and combined BNP and SCH 42495. Plasma BNP, cGMP, and cortisol were significantly increased by all three treatments (P < 0.05-P < 0.001). Combined treatment had a synergistic effect on plasma cGMP. The metabolic clearance rate of exogenous BNP was reduced (25%) by NEP inhibition. Endogenous plasma ANP was augmented more than BNP by NEP inhibition. Plasma aldosterone, unchanged during infusions, rose markedly after BNP and after the combined treatment (P < 0.05 for both). Urine sodium excretion, increased by NEP inhibition (P < 0.05) and by BNP (P = 0.05), was unchanged during combined treatment. Urine cGMP excretion was increased, whereas blood pressure was reduced by all active treatments (P < 0.05-0.01 for all). Heart rate increased only with combined treatment (P = 0.007). Plasma renin activity, norepinephrine, and cardiac output were unaffected. BNP infusion and NEP inhibition both induced significant hemodynamic and renal responses. The augmented hypotensive effect of combined treatments, and consequent fall in renal perfusion pressure, may underly the observed blunting of the natriuretic response that occurred despite greater than additive increments in plasma BNP, ANP, and cGMP.
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PMID:Brain natriuretic peptide and neutral endopeptidase inhibition in left ventricular impairment. 1002 44

Of the active fragments studied to-date, Ang-(l-7) is the most pleiotropic of the Ang I metabolities because it exerts effects that may be identical or opposite to those of Ang II. While much research remains to be done, accumulating evidence suggests that Ang-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, augments the metabolic actions of bradykinin, and increases the release of nitric oxide. This explains why Ang-(1-7) activates antihypertensive mechanisms, particularly in situations of increased Ang II activity. In other words, Ang-(1-7) may act as a negative feedback hormone of the pressor and trophic actions of Ang II. The enzymes forming Ang-( 1-7) reinforce the idea that this peptide is a component of a vasodepressor system that regulates blood pressure. Both neprilysin and metalloendopeptidase 24.15 form Ang-(1-7) but also cleave bradykinin and atrial natriuretic peptide to smaller fragments. Our recent discovery that Ang-(1-7) is a major substrate for angiotensin converting enzyme (ACE) adds a new and important dimension to the understanding of the biochemical physiology of the renin angiotensin system. Moreover, these data explain why Ang-(1-7) augmentes the hypotensive effects of bradykinin and contributes to the antihypertensive actions of ACE inhibitors. While the bulk of the research in hypertension continues to emphasize the investigation of the cellular actions of Ang II, our research has introduced new concepts and uncovered new mechanisms through which angiotensin peptides control homeostasis and influence the pathogenesis of cardiovascular disease.
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PMID:Angiotension-(1-7) and antihypertensive mechanisms. 1004 92


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