Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A limited number of ectoenzymes appear to be involved in the inactivation of circulating-regulatory peptides. Neutral endopeptidase 24.11, a metallopeptidase, is known to inactivate atrial natriuretic peptide (ANP), a substance with diuretic, natriuretic, and vasodilatory effects. Synthetic inhibitors of endopeptidase 24.11, which can prolong the activity of ANP, are currently available. These agents are being evaluated as possible innovative therapies for patients with hypertension and congestive heart failure.
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PMID:Neutral endopeptidase inhibitors and atrial natriuretic peptide. 183 18

Angiotensin-converting enzyme inhibitors promise to make important therapeutic contributions to the control of hypertension and congestive heart failure. The nonapeptide teprotide was the first of these inhibitors to be tested clinically. It was followed by orally active inhibitors, captopril in 1977 and enalapril in 1980. The latter is representative of a new design for the inhibition of metallopeptidases and is the subject of this review. The best of the N-carboxyalkyldipeptide inhibitors inhibits angiotensin-converting enzyme with a Ki of 7.6 X 10(-11) M. This compound is the most potent competitive inhibitor of a metallopeptidase yet to have been reported. The basis of this high potency is beginning to be understood and in part is considered to involve precisely arranged multiple interactions within the enzyme active site. X-ray crystallography of a thermolysin-inhibitor complex has been achieved. Assuming that similar interactions within the active site of angiotensin-converting enzyme are mechanistically probable, the authors hypothesize the binding of enalaprilat to converting enzyme as shown in Figure 24. Such interactions are consistent with kinetic studies (Section V) with the understanding that binding to the enzyme is not sensitive to the inhibitor's state of NH protonation. The reason for this surprising conclusion has not been established. Perhaps counterbalancing factors are involved in the energetics of binding or there may be compensating adjustments made in the enzyme which permit NH protonated and nonprotonated inhibitor to bind equally well. Figure 24 also summarizes present understanding of the conformation of enalaprilat when bound to angiotensin-converting enzyme. From studies on conformationally defined analogs of enalaprilat, it seems likely that the Ala-Pro segment of enalaprilat binds in a conformation that is close to a minimum energy conformer. This situation no doubt contributes to the potency of enalaprilat, since little binding energy would be needed to induce conformational changes in this part-structure of enalaprilat when it is bound to the enzyme. The phenethyl group of enalaprilat is believed to be near the alpha-hydrogen of the L-Ala residue in the enzyme-inhibitor complex. However, the synthesis of conformationally restricted analogs to establish this point has not yet been reached. The N-carboxyalkylpeptide design was developed from Wolfenden's collected product inhibitors of carboxypeptidase-A. Whether or not N-carboxyalkyldipeptides should be classified as collected product or transition state inhibitors is unclear.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme. 299 4

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
Hypertension 1995 Aug
PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30

1. The effects of combined inhibition of neutral endopeptidase 24.11 and angiotensin-converting enzyme, with the dual metallopeptidase inhibitor, MDL 100,240 (3 mg kg-1 bolus, 3 mg kg-1, h-1 infusion), on baseline haemodynamics and on responses to a variety of vasoactive peptides were studied in conscious Long Evans rats (350-450 g: n = 9) chronically instrumented for the assessment of regional haemodynamics. 2. The experiments ran over 4 consecutive days. On the first 2 days the animals received the vehicle for MDL 100,240, and were given bolus i.v. injections of angiotensin I (AI; 250 pmol kg-1), angiotensin II (AII; 125 pmol kg-1), bradykinin (BK: 3 nmol kg-1) and endothelin-1 (ET-1; 250 pmol kg-1) on one day and AI (as above), atrial natriuretic peptide (ANP: 500 pmol kg-1) and big endothelin-1 (big ET-1; 500 pmol kg-1) on the other day in a random manner. On the third and fourth experimental days the vasoactive peptides were given in the same order as before, but in the presence of MDL 100,240. 3. Thirty minutes after onset of administration of vehicle, on the first or second experimental day, there were no consistent cardiovascular changes. However, at the same time following onset of MDL 100,240 administration on the third experimental day, there was a significant, but slight, reduction in mean arterial blood pressure (MAP; -5 +/- 2 mmHg) together with tachycardia (41 +/- 12 beats min-1) and increases in renal and mesenteric flows (17 +/- 3 and 13 +/- 4%, respectively) and vascular conductances (23 +/- 4 and 19 +/- 5%, respectively). The mesenteric vasodilator effect of MDL 100,240 was still present on the fourth experimental day before administration of the drug on that day, but otherwise the pattern of response to MDL 100,240 was similar to that on the previous day. 4. In the presence of vehicle, AI caused hypertension, bradycardia, and reductions in renal mesenteric and hindquarters vascular conductances; all these effects were abolished by MDL 100,240. 5. In the presence of vehicle, AII caused effects similar to those of AI. MDL 100,240 did not affect the pressor, bradycardic or hindquarters vasoconstrictor effects of AII. However, in the presence of MDL 100,240, the overall renal and mesenteric vasoconstrictor effects of AII were enhanced, probably because of the renal and mesenteric vasodilatation caused by MDL 100,240. 6. In the presence of vehicle, BK had a slight pressor effect, accompanied by tachycardia and transient increases in conductances in renal, mesenteric and hindquarters vascular beds. In the presence of MDL 100,240 BK caused marked hypotension, but an attenuated tachycardia; renal, mesenteric and hindquarters vasodilator responses were enhanced. 7. In the presence of vehicle, ANP caused slight hypotension and tachycardia, together with reductions in renal and mesenteric vascular conductances, and transient increases in hindquarters conductance. MDL 100,240 enhanced the hypotensive effect of ANP and promoted a delayed hindquarters vasoconstriction. 8. Big ET-1, in the presence of vehicle, caused a marked and prolonged increase in MAP, accompanied by bradycardia and reductions in renal, mesenteric and hindquarters vascular conductances. Although MDL 100,240 significantly attenuated the magnitude of the pressor effect of big ET-1, its bradycardic and renal, mesenteric and hindquarters haemodynamic actions were not reduced significantly. 9. In the presence of vehicle, ET-1 caused an initial hypotension, tachycardia and vasodilatation in the hindquarters, but reductions in renal and mesenteric vascular conductances; thereafter there was a rise in MAP and bradycardia with vasoconstriction in all three vascular beds. MDL 100,240 had no effect on the initial hypotensive, tachycardic or hindquarters haemodynamic effects of ET-1. Moreover the subsequent pressor and bradycardic actions of ET-1 were unchanged, but its renal and mesenteric vasoconstrictor effects were enhanced, possibly because of the dilatation
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PMID:Effects of the dual metallopeptidase inhibitor, MDL 100,240, on regional haemodynamic responses to vasoactive peptides in conscious rats. 942 15

Angiotensin-converting enzyme (ACE) is a well known zinc-metallopeptidase that converts angiotensin I to the potent vasoconstrictor angiotensin II and that degrades bradykinin, a powerful vasodilator, both for regulation of vascular tone and cardiac functions. Other natural substrates of ACE were identified broadening the functions of this enzyme within different physiological contexts such as neuronal metabolism, hematopoiesis, digestion and reproduction. Synthetic substrates were developed for the determination of ACE activity in various biological fluids, mostly human plasma, for the diagnosis of sarcoidosis and other granulomatous diseases. After the successful use of captopril, the first ACE inhibitor in the treatment of hypertension, a number of molecules were synthesized and used in the treatment of congestive heart failure and for preventing cardiac impairment after myocardial infarction. This class of antihypertensive drugs benefited from structural data on carboxypeptidases active site, as ACE molecule has not yet been crystallized. In the last two decades ACE gene has been cloned that allowed the identification (i) of two isoenzymes, one called somatic ACE resulting from gene duplication and primarily expressed in endothelial cells, and the other, called germinative or testicular ACE, resulting from the transcription in the male reproductive system of a more simple gene, (ii) of an hydrophobic C-terminal peptide for membrane-anchoring and specifically cleaved by a metalloprotease to release soluble forms of both isoenzymes, and (iii) of several allelic polymorphisms, one of them consisting of an insertion/deletion (I/D) polymorphism in a short intronic Alu sequence that could account for half the variance in plasma ACE level and resulting in a large inter-individual variability; moreover this I/D polymorphism was proposed as a genetic marker for identifying individuals at high risk of ischemic heart disease and of anticipating in one individual the efficacy of the antihypertensive therapy, although conflicting data arose from the past decade literature. Moreover, ACE gene cloning has confirmed the expression of the enzyme in endothelial cell, in particular as an ecto-enzyme facing the vascular lumen, but not to the same extent with regard to the vascular origin of the cells. Plasma ACE in healthy subjects arises essentially from the endothelium. On the other hand, in granulomatous diseases where a local stimulation of macrophages leads to an abnormal ACE secretion, it can also be found in other biological fluids such as cerebrospinal and broncho-alveolar fluids. Low plasma ACE levels result from endothelium impairment such as in deep vein thrombosis or in endothelio-toxic anticancer therapies. Another cause of low, sometimes undetectable, plasma ACE levels is the use of an ACE inhibitor, but this is without any significance with regard to its clinical benefits. Albeit molecular cloning has provided a number of new details on ACE structure and function, many questions still remain, in particular about its tertiary structure including glycosylations, about its tissue-specific expression and regulation, and also about the exact significance of the I/D polymorphism in cardiovascular pathology including the pharmacogenomic field.
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PMID:New aspects on angiotensin-converting enzyme: from gene to disease. 1200 16

Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B(2) receptor in Chinese hamster ovary cells transfected to express human ACE and B(2) (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B(2) receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC(50)s) with ACE. They probably induce conformational changes in the ACE/B(2) receptor complex via interaction with ACE.
Hypertension 2002 May
PMID:Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A. 1201 79

The metallopeptidase Angiotensin Converting Enzyme (ACE) is an important drug target for the treatment of hypertension, heart, kidney, and lung disease. Recently, a close and unique human ACE homologue termed ACE2 has been identified and found to be an interesting new cardiorenal disease target. With the recently resolved inhibitor-bound ACE2 crystal structure available, we have attempted a structure-based approach to identify novel potent and selective inhibitors. Computational approaches focus on pharmacophore-based virtual screening of large compound databases. Selectivity was ensured by initial screening for ACE inhibitors within an internal database and the Derwent World Drug Index, which could be reduced to zero false positives and 0.1% hit rate, respectively. An average hit reduction of 0.44% was achieved with a five feature hypothesis, searching approximately 3.8 million compounds from various commercial databases. Seventeen compounds were selected based on high fit values as well as diverse structure and subjected to experimental validation in a bioassay. We show that all compounds displayed an inhibitory effect on ACE2 activity, the six most promising candidates exhibiting IC50 values in the range of 62-179 microM.
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PMID:Structure-based pharmacophore design and virtual screening for novel angiotensin converting enzyme 2 inhibitors. 1656 1

BMI represents an internal metabolic and physiological environment that plays a key role in development of high blood pressure (BP) for many Americans. African-American women have a higher prevalence of high BP and being overweight than men or other ethnic groups. This study examines the genetic-environmental interaction effects of single nucleotide polymorphisms and BMI on BP among African-American women using 1418 African-American women and men from the Genetic Epidemiology Network of Arteriopathy study. A total of 403 tests of single nucleotide polymorphism-BMI interaction were conducted using methods of internal replication, cross-validation, and false discovery rate. One single nucleotide polymorphism (located in the ATP6B1 gene, rs2266917) passed adjustments for multiple testing and had a significant independent main effect (P = 0.0018) on diastolic BP among African-American women. A significant sex-specific interaction effect was found between MMP3_rs679620 and BMI in African-American women (P = 0.0009). MMP3_rs679620 (A-G polymorphism) encodes a Lys-Glu nonsynonymous variant at the 45th amino acid of metallopeptidase 3 and indicates a putative functional modification of metallopeptidase 3. These findings were not identified in African-American men. MMP3_rs679620 appears to have a protective effect on diastolic BP in women with high BMI. Surprisingly, MMP3_rs679620 had the opposite effect on women with low BMI, resulting in higher diastolic BP.
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PMID:Interactions between metallopeptidase 3 polymorphism rs679620 and BMI in predicting blood pressure in African-American women with hypertension. 1900 10

Reduced neprilysin (NEP), a cell surface metallopeptidase, which cleaves and inactivates proinflammatory and vasoactive peptides, predisposes the lung vasculature to exaggerated remodeling in response to hypoxia. We hypothesize that loss of NEP in pulmonary artery smooth muscle cells results in increased migration and proliferation. Pulmonary artery smooth muscle cells isolated from NEP(-/-) mice exhibited enhanced migration and proliferation in response to serum and platelet-derived growth factor, which was attenuated by NEP replacement. Inhibition of NEP by overexpression of a peptidase dead mutant or knockdown by small interfering RNA in NEP(+/+) cells increased migration and proliferation. Loss of NEP led to an increase in Src kinase activity and phosphorylation of PTEN, resulting in activation of the platelet-derived growth factor receptor (PDGFR). Knockdown of Src kinase with small interfering RNA or inhibition with PP2, a src kinase inhibitor, decreased PDGFR(Y751) phosphorylation and attenuated migration and proliferation in NEP(-/-) smooth muscle cells. NEP substrates, endothelin 1 or fibroblast growth factor 2, increased activation of Src and PDGFR in NEP(+/+) cells, which was decreased by an endothelin A receptor antagonist, neutralizing antibody to fibroblast growth factor 2 and Src inhibitor. Similar to the observations in pulmonary artery smooth muscle cells, levels of phosphorylated PDGFR, Src, and PTEN were elevated in NEP(-/-) lungs. Endothelin A receptor antagonist also attenuated the enhanced responses in NEP(-/-) pulmonary artery smooth muscle cells and lungs. Taken together our results suggest a novel mechanism for the regulation of PDGFR signaling by NEP substrates involving Src and PTEN. Strategies that increase lung NEP activity/expression or target key downstream effectors, like Src, PTEN, or PDGFR, may be of therapeutic benefit in pulmonary vascular disease.
Hypertension 2013 Apr
PMID:Neprilysin regulates pulmonary artery smooth muscle cell phenotype through a platelet-derived growth factor receptor-dependent mechanism. 2338 89

Cardiovascular diseases (CVD) continue to represent the major cause of death, morbidity and healthcare expenditure worldwide. Current medical therapy fails to effectively halt disease progression and to reduce adverse clinical outcomes, reflecting incomplete understanding of pathomechanisms as well as the need to expand current pharmacotherapeutic strategies. Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues. The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy. Combined blockers of NEP and the endothelin system demonstrated efficacy in preclinical studies but have not been evaluated in clinical trials. A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-inhibitors) were promising agents for hypertension and heart failure. Despite greater efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target effects in some cohorts, most notably increased frequency of angioedema in hypertensive subjects. Novel angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and hopefully do so with improved clinical safety. We herein review current knowledge of NEPi as stand-alone and combined pharmacotherapeutic agents in hypertension and heart failure.
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PMID:Current role of neprilysin inhibitors in hypertension and heart failure. 2483 26


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