UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
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PMID:Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 875 37

1. We assessed the changes of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats (RHR). 2. Two-kidney, one-clip hypertensive rats (6-week-old male Wistar) were made and studied 6 (RHR-1) and 10 weeks (RHR-2) after the procedure. Regression of cardiac hypertrophy was induced by nephrectomy at 6 weeks after constriction, and the nephrectomized rats were maintained further for 4 weeks (nephrectomized rat: NEP). Sham operation was performed, and the rats were studied after 6 (Sham-1) and 10 weeks (Sham-2). Atrial natriuretic peptide and brain natriuretic peptide gene expression in the left ventricle was analysed by Northern blotting. 3. Plasma atrial natriuretic peptide and brain natriuretic peptide were significantly higher in RHR-1 and RHR-2 than in Sham-1, Sham-2 and NEP. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels in RHR-1 were approximately 7.2-fold and 1.8-fold higher than those in Sham-1, respectively, and the corresponding levels in RHR-2 were 13.0-fold and 2.4-fold higher than those in Sham-2, respectively. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels of NEP were normalized. Levels of atrial natriuretic peptide and brain natriuretic peptide mRNA were well correlated positively with left ventricular weight/body weight ratios. There was a significant positive correlation between the levels of atrial natriuretic peptide and brain natriuretic peptide mRNA (r = 0.86, P < 0.01). 4. We conclude that the expression of atrial natriuretic peptide and brain natriuretic peptide genes is regulated in accordance with the degree of myocardial hypertrophy and that the augmented expression of these two natriuretic peptides may play an important role in the maintenance of cardiovascular haemodynamics in renovascular hypertension.
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PMID:Alteration of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats. 877 25

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

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

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure.
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PMID:Neutral endopeptidase inhibition potentiates the effects of natriuretic peptides in renin transgenic rats. 898 53

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
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PMID:Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 917 67

C-type natriuretic peptide (CNP) is a newly described 22-amino acid peptide of endothelial and renal cell origin with selective cardiovascular actions. Recent in vitro studies have reported that CNP is the most susceptible of all natriuretic peptides to enzymatic degradation by neutral endopeptidase 24.11 (NEP). The present study was undertaken to define the role of NEP in total and regional CNP metabolism and the modulatory actions of NEP inhibition on the biological actions of CNP. CNP (10 ng x kg(-1) x min(-1)) followed by candoxatrilat (240 microg x kg(-1) bolus and 8 microg x kg(-1) x min(-1)), a potent and selective NEP inhibitor, was administered intravenously to a group of anesthetized mongrel dogs (group 1) to permit calculation of total metabolic clearance rate (MCR); results were compared with those in a group receiving vehicle infusion followed by candoxatrilat (group 2; both groups, n=7). NEP inhibition increased circulating CNP achieved by exogenous infusion and reduced total MCR in group 1. The regional CNP MCRs increased after CNP administration. While the pulmonary MCR did not change during concomitant candoxatrilat infusion, renal MCR was suppressed. Hemodynamic changes were not different between groups. A mild natriuretic and diuretic effect in association with an increase in circulating and urinary ANP levels was not different between groups. Urinary CNP excretion did not change with CNP infusion but markedly increased after NEP inhibition. We conclude that (1) circulating CNP achieved by exogenous CNP infusion is regulated by NEP in vivo, (2) regional MCRs are heterogeneous with NEP inhibition, (3) NEP inhibition does not potentiate acute cardiovascular actions of CNP, and (4) a mild natriuretic and diuretic effect observed with CNP and NEP inhibition may be ANP dependent.
Hypertension 1997 Aug
PMID:Neutral endopeptidase regulates C-type natriuretic peptide metabolism but does not potentiate its bioactivity in vivo. 926 Sep 78

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.
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PMID:[Natriuretic peptide system]. 928 3

This study examined the long-term effects of CGS 30440 on blood pressure, heart rate, cardiac hypertrophy, and urinary parameters in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in mean arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 producing a maximal sustained response of 40 mm Hg. CGS 30440 significantly inhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) were inhibited by >60 and >90%, respectively. Urinary cyclic guanosine monophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose of an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respectively. Heart-rate responses were not different between treatment groups. Left ventricular hypertrophy (LV weight/body weight ratio) was reduced significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.26 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats receiving only vehicle. These results demonstrate that CGS 30440 is a potent, orally active antihypertensive agent with a long duration of action. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, has been shown to be a novel antihypertensive agent with dual ACE/NEP inhibitory activity in SHRs.
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PMID:Effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, CGS 30440, on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats. 938 46

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