Converting-enzyme inhibitors increase converting-enzyme mRNA and activity in endothelial cells

1992 ◽  
Vol 263 (4) ◽  
pp. C743-C749 ◽  
Author(s):  
S. J. King ◽  
S. Oparil
Keyword(s):  
Endothelial Cells ◽  
Ace Inhibitors ◽  
Active Site ◽  
Ace Inhibitor ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Ace Gene ◽  
Ace Activity

Exposure to angiotensin-converting-enzyme (ACE) inhibitors has been associated with increased ACE activity in vivo and in vitro. In the current study, we examined the effects of the active site-directed ACE inhibitors lisinopril and captopril on ACE gene expression and activity in cultured porcine pulmonary artery endothelial cells. Exposure of endothelial cells to both lisinopril and captopril was associated with increased ACE mRNA levels and concomitant increases in ACE activity. These effects were both concentration and time dependent. ACE mRNA levels began to increase within 30 min of ACE inhibitor exposure and showed an early peak at 2 h and a higher, delayed peak at 48 h. ACE activity peaked at 24 h. Both ACE mRNA levels and activity were highest during incubation with 100 microM inhibitor. Nuclear runoff assays indicated that 48 h of exposure to 100 microM of either captopril or lisinopril increased ACE gene transcription approximately threefold relative to a tubulin control, a level comparable to the increases in ACE mRNA levels and activity observed during ACE inhibitor exposure. These findings support the hypothesis that ACE gene expression endothelial cells is stimulated by active site-directed ACE inhibitors in vitro. This provides a molecular mechanism for the observation that plasma and tissue ACE activity in vivo is increased during chronic exposure to ACE inhibitors.

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

Angiotensin-converting enzyme determination in plasma during therapy with converting enzyme inhibitor: two methods compared

1991 ◽  
Vol 37 (8) ◽  
pp. 1390-1393 ◽  
Author(s):  
T P Gorski ◽  
D J Campbell
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Spectrophotometric Method ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Fluorometric Method ◽  
Converting Enzyme Inhibitor ◽  
Ace Activity

Abstract For normal and above-normal concentrations of angiotensin-converting enzyme (ACE; EC 3.4.15.1) activity in plasma, results of a manual fluorometric method [with hippuryl-histidyl-leucine (HHL), 5 mmol/L, as substrate] correlated well with those of an automated spectrophotometric method [with 3-(2-furylacryloyl)-L-phenylalanyl-glycyl-glycine (FAPGG), 2 mmol/L, as substrate]. However, for patients receiving converting enzyme inhibitor (CEI) therapy, the spectrophotometric method showed much greater suppression of plasma ACE activity than did the fluorometric method. To determine which of the two methods provided a more reliable indication of ACE inhibition in vivo, we measured plasma ACE, angiotensin I (ANG I), and angiotensin II (ANG II) in patients receiving the CEI perindopril. During perindopril therapy, changes in the ratio of ANG II:ANG I, an index of ACE activity in vivo, showed a close agreement with changes in plasma ACE activity measured with FAPGG as substrate, but not with HHL as substrate. We conclude that measurement of ACE activity in vitro with FAPGG as substrate provides a reliable measure of changes in conversion of ANG I to ANG II in vivo during CEI therapy.

Mechanism of enhanced eicosanoid production by isolated glomeruli from rats with bilateral ureteral obstruction

1991 ◽  
Vol 261 (2) ◽  
pp. F248-F255 ◽  
Author(s):  
H. Yanagisawa ◽  
J. Morrissey ◽  
S. Klahr
Keyword(s):  
Ureteral Obstruction ◽  
Ace Inhibitor ◽  
Converting Enzyme ◽  
Isolated Glomeruli ◽  
Eicosanoid Production ◽  
Thromboxane Synthase Inhibitor ◽  
Pg E2 ◽  
Synthase Inhibitor

Isolated glomeruli from rats with bilateral ureteral obstruction (BUO) of 24-h duration produced significantly greater amounts of prostaglandin (PG) E2 and 6-keto-PGF1 alpha in vitro than glomeruli from sham-operated control (SOC) rats. This increase was abolished by the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat, given in vivo. To elucidate the mechanisms responsible for enhanced eicosanoid production by glomeruli from rats with BUO, we measured the activities of phospholipase (PL) A2 and C and cyclooxygenase in glomeruli isolated from SOC and BUO rats. L-alpha-Phosphatidylcholine (PC)-specific and L-alpha-phosphatidylethanolamine (PE)-specific PLA2 activities were significantly greater in glomerular membranes from rats with BUO than from SOC rats. Likewise, both the activity and amount of cyclooxygenase were significantly greater in glomerular membranes of rats with BUO. Cyclooxygenase and the PE-specific PLA2 in glomerular membranes of rats with BUO remained at the levels seen in SOC rats when animals were treated in vivo before BUO with the ACE inhibitor, enalaprilat, and the thromboxane synthase inhibitor, OKY-046. Thus inhibition of vasoconstrictor formation leads to subsequent inhibition of vasodilator formation. In contrast to PE-specific PLA2, PC-specific PLA2 activities were further increased in glomerular membranes from both SOC and BUO rats pretreated with the two drugs.s The activity of phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PIP2 PLC) was significantly decreased in glomeruli from rats with BUO compared with SOC rats. We conclude that the increased synthesis of vasodilatory eicosanoids by glomeruli from rats with BUO may be mediated by enhanced activities of PE-specific PLA2 and cyclooxygenase, which are apparently stimulated by the vasoconstrictors angiotensin and thromboxane.

NO synthesis is involved in structural and functional effects of ACE inhibitors in injured arteries

1996 ◽  
Vol 270 (1) ◽  
pp. H298-H305 ◽  
Author(s):  
E. Van Belle ◽  
B. Vallet ◽  
J. L. Auffray ◽  
C. Bauters ◽  
M. Hamon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ace Inhibitors ◽  
Intimal Hyperplasia ◽  
Vascular Function ◽  
Ace Inhibitor ◽  
White Male ◽  
Rabbit Model ◽  
Balloon Injury

Angiotensin-converting enzyme (ACE) inhibitors reduce intimal hyperplasia after balloon injury. A role for nitric oxide (NO) has been suggested in this effect. Because recent data suggest that NO may modulate some features of endothelial cells and because endothelial cells are involved in the control of intimal hyperplasia, we investigated the role of NO synthesis in the effect of an ACE inhibitor, perindopril, on neoendothelial dysfunction and intimal hyperplasia in a rabbit model of unilateral iliac balloon injury. New Zealand White male rabbits received placebo, perindopril, or cotreatment with perindopril and NG-nitro-L-arginine methyl ester (L-NAME) and were evaluated 4 wk after the injury. Fifteen rabbits (5 in each group) were used to assess in vitro vasoreactivity and twenty-four (8 in each group) for morphometric analysis. In injured vessels, neoendothelium-dependent relaxation in ACE inhibitor-treated animals was improved compared with placebo (P < 0.05) and restored to the level of noninjured vessels (NS). The improvement observed with ACE inhibitor was abolished by cotreatment with L-NAME (P < 0.05). In the same vessels, no effect was observed on neoendothelium-independent vasoreactivity. The improved neoendothelial dysfunction with ACE inhibitor was associated with a 66% reduction in intimal thickening (P < 0.01). The effect was also reversed by cotreatment with L-NAME (P < 0.01). In noninjured vessels, treatment did not alter vasoreactivity or morphology of the vessel wall. These results suggest that NO synthesis may play a key role in the improvement of vascular function seen with ACE inhibitor in balloon-injured vessels.

SPC2968—A novel Hif-1α antagonist for treatment of clear cell renal cell carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14581-14581 ◽  
Author(s):  
M. Westergaard ◽  
H. F. Hansen ◽  
C. A. Thrue ◽  
J. B. Hansen ◽  
L. S. Kjaerulff ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Locked Nucleic Acid ◽  
Mrna Levels ◽  
Kidney Liver

14581 Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006. [Table: see text]

Endothelial cells internalize monoclonal antibody to angiotensin-converting enzyme

1996 ◽  
Vol 270 (5) ◽  
pp. L704-L713 ◽  
Author(s):  
V. R. Muzykantov ◽  
E. N. Atochina ◽  
A. Kuo ◽  
E. S. Barnathan ◽  
K. Notarfrancesco ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Umbilical Vein ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Affinity Constant ◽  
Converting Enzyme

We investigated the fate of MAb 9B9, a monoclonal antibody to angiotensin-converting enzyme (ACE), which binds to endothelium both in vitro and in vivo. Using cultured human umbilical vein endothelial cells (HUVEC) and isolated perfused rat lungs (IPL), we demonstrated specific and saturable binding of 125I-labeled MAb 9B9 at 4 degrees C [affinity constant (Kd) = 20-50 nM, maximal number of binding sites (Bmax) = 1.5-3.0 x 10(5) sites/cell]. When 125I-MAb 9B9 was bound to HUVEC at 37 degrees C, only 40% of cell-associated radioactivity was acid elutable, suggesting antibody internalization. This was confirmed by finding that 1) the amount of MAb 9B9 uptake at 37 degrees C was higher than at 4 degrees C both in HUVEC and IPL; 2) binding of 125I-labeled streptavidin with HUVEC and IPL pretreated with biotinylated MAb 9B9 (b-MAb 9B9) was diminished in a temperature- and time-dependent fashion at 37 degrees C; and 3) b-MAb 9B9 bound to HUVEC at 37 degrees C was found intracellularly by ultrastructural analysis using streptavidin gold. Intracellular 125I-MAb 9B9 was found in microsomal fractions of lung homogenate from IPL and after intravenous (iv) injections in rats. Degradation of internalized MAb 9B9 was minimal, since > 90% of cell-associated 125I label remained precipitable by trichloracetic acid in HUVEC, IPL, and in vivo. Autoradiography of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lung homogenates made as late as several days after iv injections of 125I-MAb 9B9 in rats demonstrated a predominant band above 140 kDa. These data indicate that endothelial cells either in vitro or in vivo internalize the ACE ligand MAb 9B9 without significant intracellular degradation. Therefore MAb 9B9 may be useful for selective intracellular delivery of drugs to the pulmonary vascular endothelium after systemic administration.

Ontogeny of Big endothelin-1 effects in newborn piglet pulmonary vasculature

1993 ◽  
Vol 265 (1) ◽  
pp. H139-H145 ◽  
Author(s):  
S. Liben ◽  
D. J. Stewart ◽  
J. De Marte ◽  
T. Perreault
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Vasculature ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Amino Acid Peptide ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

Endothelin-1 (ET-1), a 21-amino acid peptide produced by endothelial cells, results from the cleavage of preproendothelin, generating Big ET-1, which is then cleaved by the ET-converting enzyme (ECE) to form ET-1. Big ET-1, like ET-1, is released by endothelial cells. Big ET-1 is equipotent to ET-1 in vivo, whereas its vasoactive effects are less in vitro. It has been suggested that the effects of Big ET-1 depend on its conversion to ET-1. ET-1 has potent vasoactive effects in the newborn pig pulmonary circulation, however, the effects of Big ET-1 remain unknown. Therefore, we studied the effects of Big ET-1 in isolated perfused lungs from 1- and 7-day-old piglets using the ECE inhibitor, phosphoramidon, and the ETA receptor antagonist, BQ-123Na. The rate of conversion of Big ET-1 to ET-1 was measured using radioimmunoassay. ET-1 (10(-13) to 10(-8) M) produced an initial vasodilation, followed by a dose-dependent potent vasoconstriction (P < 0.001), which was equal at both ages. Big ET-1 (10(-11) to 10(-8) M) also produced a dose-dependent vasoconstriction (P < 0.001). The constrictor effects of Big ET-1 and ET-1 were similar in the 1-day-old, whereas in the 7-day-old, the constrictor effect of Big ET-1 was less than that of ET-1 (P < 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo visualization of subendocardial arteriolar response in renovascular hypertensive hearts

2003 ◽  
Vol 284 (5) ◽  
pp. H1785-H1792 ◽  
Author(s):  
Toyotaka Yada ◽  
Masami Goto ◽  
Osamu Hiramatsu ◽  
Hiroyuki Tachibana ◽  
Eiji Toyota ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renovascular Hypertension ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Early Stage ◽  
Converting Enzyme ◽  
Charge Coupled Device ◽  
Vascular Responses

Time-sequential responses to endothelium-dependent and -independent vasodilators and angiotensin-converting enzyme (ACE) inhibitors were studied in the subendocardial arterioles (Endo) of canine renovascular hypertension (HT) compared with subepicardial arterioles (Epi; both <120 μm) by charge-coupled device intravital microscope. Vascular responses to acetylcholine, papaverine, and cilazaprilat were compared between normotensive (NT) and HT dogs [4 wk and 12 wk of HT (4wHT and 12wHT)]. The acetylcholine-induced vasodilation of Endo in both 4wHT and 12wHT was smaller than that of NT (both P< 0.01 vs. 4wHT and 12wHT), and that of Epi was smaller than that of NT only in 12wHT ( P < 0.05). The papaverine-induced vasodilation of Endo, but not Epi, was impaired only in 12wHT (both P < 0.01 vs. NT and 4wHT). Vasodilation by cilazaprilat remained unchanged at 4wHT and 12wHT in both Epi and Endo. In conclusion, at the early stage, the endothelium-dependent response of Endo was impaired, whereas at the later stage, the endothelium-dependent and -independent responses of Endo and the endothelium-dependent response of Epi were impaired. However, the vasodilatory responses to the ACE inhibitor were maintained in both Endo and Epi of HT.

Hormonal influence on endothelial cell angiotensin-converting enzyme activity

1984 ◽  
Vol 247 (3) ◽  
pp. C163-C168 ◽  
Author(s):  
A. H. Krulewitz ◽  
W. E. Baur ◽  
B. L. Fanburg
Keyword(s):  
Endothelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Protein Content ◽  
Hormonal Regulation ◽  
Converting Enzyme ◽  
Cell Counts ◽  
Ace Activity ◽  
Sites Of Action ◽  
Culture Supernatants

The influence of various hormones on angiotensin-converting enzyme (ACE) production and release by bovine endothelial cells in culture was studied. Dexamethasone, thyroxine (T4), and triiodothyronine (T3) stimulated ACE activity in cells and their culture supernatants without affecting cell number or protein content. The stimulating effects of dexamethasone and thyroid hormones were additive, suggesting that these hormones may have different sites of action. In addition, their stimulating effects were blocked by cycloheximide, indicating that increased enzymatic activity occurred through new protein synthesis. The exposure of cells to insulin reduced ACE activity of cells and their culture supernatants without influencing cell counts or protein content; insulin also partially inhibited the stimulation of ACE activity by dexamethasone or T3. Our studies suggest that the production of ACE by endothelial cells is under hormonal regulation. Release of ACE activity into culture supernatants parallels changes in cellular ACE activity. The results supplement previous observations made in vitro and in vivo.

scholarly journals Angiotensin-converting enzyme inhibitors attenuate propofol-induced pro-oxidative and antifibrinolytic effect in human endothelial cells

2017 ◽  
Vol 18 (1) ◽  
pp. 147032031668719 ◽  
Author(s):  
Marzena Wojewodzka-Zelezniakowicz ◽  
Anna Gromotowicz-Poplawska ◽  
Wioleta Kisiel ◽  
Emilia Konarzewska ◽  
Janusz Szemraj ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitors ◽  
Umbilical Vein ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors

Introduction: The aim of this study was to investigate the effects of plasma and tissue angiotensin-converting enzyme inhibitors (ACE-Is) against propofol-induced endothelial dysfunction and to elucidate the involved mechanisms in vitro. Materials and methods: We examined the effects of propofol (50 μM), quinaprilat and enalaprilat (10−5 M) on fibrinolysis (t-PA, PAI-1, TAFI antigen levels), oxidative stress parameters (H2O2 and MDA antigen levels and SOD and NADPH oxidase mRNA levels) and nitric oxide bioavailability (NO2/NO3 concentration and NOS expression at the level of mRNA) in human umbilical vein endothelial cells (HUVECs). Results: We found that both ACE-Is promoted similar endothelial fibrinolytic properties and decreased oxidative stress in vitro. Propofol alone increased the release of antifibrinolytic and pro-oxidative factors from the endothelium and increased mRNA iNOS expression. We also found that the incubation of HUVECs in the presence of propofol following ACE-Is pre-incubation caused weakness of the antifibrinolytic and pro-oxidative potential of propofol and this effect was similar after both ACE-Is. Conclusions: This observation suggests that the studied ACE-Is exerted protective effects against endothelial cell dysfunction caused by propofol, independently of hemodynamics.

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