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Sample records for angiotensin converting enzyme

  1. Angiotensin converting enzyme of Thalassophryne nattereri venom.

    PubMed

    da Costa Marques, Maria Elizabeth; de Araújo Tenório, Humberto; Dos Santos, Claudio Wilian Victor; Dos Santos, Daniel Moreira; de Lima, Maria Elena; Pereira, Hugo Juarez Vieira

    2016-10-01

    Animal venoms are complex mixtures, including peptides, proteins (i.e., enzymes), and other compounds produced by animals in predation, digestion, and defense. These molecules have been investigated regarding their molecular mechanisms associated with physiological action and possible pharmacological applications. Recently, we have described the presence of a type of angiotensin converting enzyme (ACE) activity in the venom of Thalassophryne nattereri. It is a zinc-dependent peptidase with a wide range of effects. By removing dipeptide His-Leu from terminal C, the ACE converts angiotensinI (AngI) into angiotensin II (AngII) and inactivates bradykinin, there by regulating blood pressure and electrolyte homeostasis. The fractionation of T. nattereri venom in CM-Sepharose indicated a peak (CM2) with angiotensin-converting activity, converting AngI into Ang II. Electrophoresis on polyacrylamide gel (12%) revealed one band with 30kDa for CM2 similar in size to natterins, which are toxins with proteolytic activity found in T. nattereri venom. Mass spectrometry indicated that the protein sequence of the ACE purified from T. nattereri venom corresponds to natterin 1. The isolated protein has also demonstrated inhibition through captopril and EDTA and is characterized as a classic ACE. Thus, the isolated enzyme purified from T. nattereri venom is the first ACE isolated from fish venom. PMID:27327905

  2. Angiotensin converting enzyme inhibition and the kidney

    NASA Technical Reports Server (NTRS)

    Hollenberg, N. K.

    1988-01-01

    Angiotensin II (Ang II) induces a marked reduction in renal blood flow at doses well below those required to induce a pressor response, and as blood flow falls there is a decline in glomerular filtration rate and sodium excretion. This striking sensitivity of the renal blood supply led many workers to consider the possibility that angiotensin functions as a local renal hormone. As angiotensin converting enzyme (ACE) was found in particular abundance in the lung, it seemed reasonable to suspect that most of the conversion occurred there, and that the function of Ang II would be primarily systemic, rather than intrarenal. In this review, I will explore the evidence that has accumulated on these two possibilities, since they have important implications for our current understanding of normal kidney function and derangements of kidney function in disease.

  3. Transdermal delivery of Angiotensin Converting Enzyme inhibitors.

    PubMed

    Helal, Fouad; Lane, Majella E

    2014-09-01

    The Angiotensin Converting Enzyme (ACE) inhibitor class of drugs has been in clinical use since the 1970s for the management of all grades of heart failure, hypertension, diabetic nephropathy and prophylaxis of cardiovascular events. Because of the advantages associated with transdermal delivery compared with oral delivery many researchers have investigated the skin as a portal for administration of ACE inhibitors. This review summarises the various studies reported in the literature describing the development and evaluation of transdermal formulations of ACE inhibitors. Captopril, enalapril maleate, lisinopril dihydrate, perindopril erbumine and trandolapril are the most studied in connection with transdermal preparations. The methodologies reported are considered critically and the limitations of the various skin models used are also highlighted. Finally, opportunities for novel transdermal preparations of ACE inhibitor drugs are discussed with an emphasis on rational formulation design. PMID:24657822

  4. Angiotensin Converting Enzyme Activity in Alopecia Areata

    PubMed Central

    Namazi, Mohammad Reza; Handjani, Farhad; Eftekhar, Ebrahim; Kalafi, Amir

    2014-01-01

    Background. Alopecia areata (AA) is a chronic inflammatory disease of the hair follicle. The exact pathogenesis of AA remains unknown, although recent studies support a T-cell mediated autoimmune process. On the other hand, some studies have proposed that the renin-angiotensin-aldosterone system (RAAS) may play a role in autoimmunity. Therefore, we assessed serum activity of angiotensin converting enzyme (ACE), a component of this system, in AA. Methods. ACE activity was measured in the sera of 19 patients with AA and 16 healthy control subjects. In addition, the relationship between severity and duration of the disease and ACE activity was evaluated. Results. Serum ACE activity was higher in the patient group (55.81 U/L) compared to the control group (46.41 U/L), but the difference was not statistically significant (P = 0.085). Also, there was no correlation between ACE activity and severity (P = 0.13) and duration of disease (P = 0.25) in the patient group. Conclusion. The increased serum ACE activity found in this study may demonstrate local involvement of the RAAS in the pathogenesis of AA. Assessment of ACE in a study with a larger sample size as well as in tissue samples is recommended in order to further evaluate the possible role of RAAS in AA. PMID:25349723

  5. Renin, angiotensins, and angiotensin-converting enzyme in neuroblastoma cells: evidence for intracellular formation of angiotensins.

    PubMed Central

    Okamura, T; Clemens, D L; Inagami, T

    1981-01-01

    The mechanism of formation of various peptide hormones in neuronal cells in the brain is not clear. The question of whether brain angiotensin II is formed by an extracellular mechanism as in the peripheral system or by an intracellular mechanism can be answered by using cloned cells in culture. We have screened several neuroblastoma cell lines of rat and mouse origin and found at least three cell lines that contain renin (EC 3.4.99.19), angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyldipeptide hydrolase, EC 3.4.15.1), and angiotensins I and II. This finding was interpreted to indicate that in these cells angiotensin formation takes place by an intracellular mechanism, in contrast to the extracellular mechanism well known to occur in plasma. This study also demonstrates the existence of viable and cloned cell lines that produce renin. PMID:6273896

  6. Assay for Angiotensin-Converting Enzyme.

    ERIC Educational Resources Information Center

    Russo, Salvatore F.

    1983-01-01

    Describes a three-hour experiment designed to introduce students to chemistry of the angiotensis-converting enzyme, illustrate design of a quenched fluorescence substrate, and examine considerations necessary in designing a clinical assay. Includes background information on the biochemistry of hypertension, reagents/materials needed, procedures…

  7. [Angiotensin-converting enzyme inhibitors as neutralizers of hydroxyl radical].

    PubMed

    Mira, M L; Silva, M M; Queirós, M J; Manso, C

    1992-05-01

    Angiotensin converting enzyme inhibitors are utilized in the treatment of essential hypertension and of chronic cardiac failure. They are also employed in the treatment of the myocardial lesion of ischemia-reperfusion, which involves oxygen free radicals. In the present study we investigated the possibility of three angiotensin converting enzyme inhibitors (captopril, enalapril, lisinopril) to act as hydroxyl radical scavengers. The rate constants for reactions of those compounds with .OH were determined using the deoxyribose method. All there compounds proved to be good scavengers of .OH with rate constants of about 10(10)M-1s-1 and are iron chelators specially enalapril. The fact that captopril possesses a thiol group does not confer an higher antioxidative capacity. These results suggest that scavenging of oxygen free radicals may be a possible mechanism contributing to the therapeutic effect of angiotensin converting enzyme inhibitors. PMID:1325814

  8. Angiotensin-converting enzyme inhibition by Brazilian plants.

    PubMed

    Braga, Fernão C; Serra, Carla P; Viana, Nilton S; Oliveira, Alaíde B; Côrtes, Steyner F; Lombardi, Júlio A

    2007-07-01

    The potential antihypertensive activity of Brazilian plants was evaluated in vitro by its ability to inhibit the angiotensin-converting enzyme (ACE). Forty-four plants belonging to 30 families were investigated. Plants were selected based on their popular use as antihypertensive and/or diuretics. The following plants presented significant ACE inhibition rates: Calophyllum brasiliense, Combretum fruticosum, Leea rubra, Phoenix roebelinii and Terminalia catappa. PMID:17513067

  9. Angiotensin converting enzyme inhibitors as oxygen free radical scavengers.

    PubMed

    Mira, M L; Silva, M M; Queiroz, M J; Manso, C F

    1993-01-01

    The authors have compared the ability of two non-SH-containing angiotensin converting enzyme (ACE) inhibitors (enalaprilat and lisinopril) with an -SH containing ACE inhibitor (captopril) to scavenge the hydroxyl radical (.OH). All three compounds were able to scavenge .OH radicals generated in free solution at approximately diffusion-controlled rates (10(10) M-1 s-1) as established by the deoxyribose assay in the presence of EDTA. The compounds also inhibited deoxyribose degradation in reaction mixtures which did not contain EDTA but not so effectively. This later findings also suggests that they have some degree of metal-binding capability. Chemiluminescence assays of oxidation of hypoxanthine by xanthine oxidase in the presence of luminol, confirm that the three ACE inhibitors are oxygen free radical scavengers. Our results indicate that the presence of a sulphydryl group in the chemical structure of ACE inhibitors is not relevant for their oxygen free radical scavenging ability. PMID:8244086

  10. Primacy of cardiac chymase over angiotensin converting enzyme as an angiotensin-(1-12) metabolizing enzyme.

    PubMed

    Ahmad, Sarfaraz; Varagic, Jasmina; VonCannon, Jessica L; Groban, Leanne; Collawn, James F; Dell'Italia, Louis J; Ferrario, Carlos M

    2016-09-16

    We showed previously that rat angiotensin-(1-12) [Ang-(1-12)] is metabolized by chymase and angiotensin converting enzyme (ACE) to generate Angiotensin II (Ang II). Here, we investigated the affinity of cardiac chymase and ACE enzymes for Ang-(1-12) and Angiotensin I (Ang I) substrates. Native plasma membranes (PMs) isolated from heart and lung tissues of adult spontaneously hypertensive rats (SHR) were incubated with radiolabeled (125)I-Ang-(1-12) or (125)I-Ang I, in the absence or presence of a chymase or ACE inhibitor (chymostatin and lisinopril, respectively). Products were quantitated by HPLC connected to an in-line flow-through gamma detector. The rate of (125)I-Ang II formation from (125)I-Ang-(1-12) by chymase was significantly higher (heart: 7.0 ± 0.6 fmol/min/mg; lung: 33 ± 1.2 fmol/min/mg, P < 0.001) when compared to (125)I-Ang I substrate (heart: 0.8 ± 0.1 fmol/min/mg; lung: 2.1 ± 0.1 fmol/min/mg). Substrate affinity of (125)I-Ang-(1-12) for rat cardiac chymase was also confirmed using excess unlabeled Ang-(1-12) or Ang I (0-250 μM). The rate of (125)I-Ang II formation was significantly lower using unlabeled Ang-(1-12) compared to unlabeled Ang I substrate. Kinetic data showed that rat chymase has a lower Km (64 ± 6.3 μM vs 142 ± 17 μM), higher Vmax (13.2 ± 1.3 μM/min/mg vs 1.9 ± 0.2 μM/min/mg) and more than 15-fold higher catalytic efficiency (ratio of Vmax/Km) for Ang-(1-12) compared to Ang I substrate, respectively. We also investigated ACE mediated hydrolysis of (125)I-Ang-(1-12) and (125)I-Ang I in solubilized membrane fractions of the SHR heart and lung. Interestingly, no significant difference in (125)I-Ang II formation by ACE was detected using either substrate, (125)I-Ang-(1-12) or (125)I-Ang I, both in the heart (1.8 ± 0.2 fmol/min/mg and 1.8 ± 0.3 fmol/min/mg, respectively) and in the lungs (239 ± 25 fmol/min/mg and 248 ± 34 fmol/min/mg, respectively). Compared to chymase, ACE

  11. Angiotensin-converting enzymes modulate aphid-plant interactions.

    PubMed

    Wang, Wei; Luo, Lan; Lu, Hong; Chen, Shaoliang; Kang, Le; Cui, Feng

    2015-01-01

    Angiotensin-converting enzymes (ACEs) are key components of the renin-angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect-plant interaction. In this study, we showed that ACE modulates aphid-plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pisum genome. ACE1 and ACE2 were highly expressed in the salivary glands and are predicted to function as secretory proteins. The ACE2 transcript level decreased in aphids fed on artificial diet compared with aphids fed on Vicia faba. The knockdown of the expression of each ACE by RNAi failed to affect aphid survival. When ACE1 and ACE2 were simultaneously knocked down, aphid feeding was enhanced. Aphids required less time to find the phloem sap and showed longer passive ingestion. However, the simultaneous knockdown of ACE1 and ACE2 resulted in a higher mortality rate than the control group when aphids were fed on plants. These results indicated that ACE1 and ACE2 function together to modulate A. pisum feeding and survival on plants. PMID:25744345

  12. Localization of angiotensin converting enzyme in rat heart

    SciTech Connect

    Yamada, H.; Fabris, B.; Allen, A.M.; Jackson, B.; Johnston, C.I.; Mendelsohn, A.O. )

    1991-01-01

    Angiotensin converting enzyme (ACE) was localized in rat heart by quantitative in vitro autoradiography with 125I-351A as the radioligand. The binding association constant (KA) of the radioligand was measured in membrane-rich fractions of atrium, ventricle, and lung by a radioinhibitor binding assay. A single class of high-affinity binding sites was detected in each tissue, and a significant difference was found between KA values for atria and ventricles with a rank order of atria greater than lungs greater than ventricles. For autoradiography, coronal sections (10 micron) of the frozen heart were incubated with 125I-351A and exposed to x-ray film. The autoradiographs were quantitated by computerized image analysis. The highest density of ACE in the heart was found on valve leaflets (aortic, pulmonary, mitral, and tricuspid), which contrasted markedly with very low ACE labeling in the endocardium. The coronary arteries also showed dense labeling of ACE. The right atrium had a moderate density of ACE, which was higher than the left atrium and the ventricles. Both the endothelial and adventitial layers of the aorta and pulmonary artery displayed high densities of ACE, with very low density in the media. ACE was not detected in either the sinoatrial node or atrioventricular node. These results reveal a markedly nonuniform localization of ACE in the rat heart and suggest possible sites for local angiotensin II generation and bradykinin or other peptide metabolism.

  13. Angiotensin-converting enzymes modulate aphid–plant interactions

    PubMed Central

    Wang, Wei; Luo, Lan; Lu, Hong; Chen, Shaoliang; Kang, Le; Cui, Feng

    2015-01-01

    Angiotensin-converting enzymes (ACEs) are key components of the renin–angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect–plant interaction. In this study, we showed that ACE modulates aphid–plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pisum genome. ACE1 and ACE2 were highly expressed in the salivary glands and are predicted to function as secretory proteins. The ACE2 transcript level decreased in aphids fed on artificial diet compared with aphids fed on Vicia faba. The knockdown of the expression of each ACE by RNAi failed to affect aphid survival. When ACE1 and ACE2 were simultaneously knocked down, aphid feeding was enhanced. Aphids required less time to find the phloem sap and showed longer passive ingestion. However, the simultaneous knockdown of ACE1 and ACE2 resulted in a higher mortality rate than the control group when aphids were fed on plants. These results indicated that ACE1 and ACE2 function together to modulate A. pisum feeding and survival on plants. PMID:25744345

  14. Angiotensin I converting enzyme inhibitory peptide extracted from freshwater zooplankton.

    PubMed

    Lee, Jung Kwon; Lee, Min-Su; Park, Heum Gi; Kim, Se-Kwon; Byun, Hee-Guk

    2010-04-01

    In this study, hydrolysates obtained from the freshwater rotifer Brachionus calyciflonus were investigated for angiotensin I converting enzyme (ACE) inhibitory peptides. Freshwater rotifer protein was hydrolyzed using six separate enzymes in a batch reactor. The peptic hydrolysate had the highest ACE inhibitory activity compared to the other hydrolysates. The highest ACE inhibitory peptide was separated using Sephadex G-25 column chromatography and high-performance liquid chromatography on a C18 column. The 50% inhibitory concentration (IC(50)) value of purified ACE inhibitory peptide was 40.01 microg/mL. ACE inhibitory peptide was identified as being seven amino acid residues of Ala-Gln-Gly-Glu-Arg-His-Arg by N-terminal amino acid sequence analysis. The IC(50) value of purified ACE inhibitory peptide was 47.1 microM, and Lineweaver-Burk plots suggested that the peptide purified from rotifer protein acts as a competitive inhibitor against ACE. The results of this study suggest that peptides derived from freshwater rotifers may be beneficial as antihypertension compounds in functional foods or as pharmaceuticals. PMID:20170338

  15. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  16. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease

    PubMed Central

    2008-01-01

    BACKGROUND Angiotensin-converting-enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. METHODS In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients). RESULTS The mean (±SD) age of the patients was 64±8 years, the mean blood pressure 133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence of the primary end point — death from cardiovascular causes, myocardial infarction, or coronary revascularization — was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-up period of 4.8 years. CONCLUSIONS In patients with stable coronary heart disease and preserved left ventricular function who are receiving “current standard” therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in

  17. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures.

    PubMed

    Gowrisankar, Yugandhar V; Clark, Michelle A

    2016-07-01

    Angiotensin (Ang) II plays a critical role in cardiovascular and blood pressure regulation. Ang II is produced by angiotensin-converting enzyme (ACE) and it interacts with the Ang AT1 receptor to cause much of its well-known cardiovascular effects. Ang-(1-7) is another active peptide produced by the rennin-angiotensin system. This peptide is produced from Ang I or Ang II by the catalytic activity of ACE2. Ang-(1-7) interacts with the Mas receptor to counteract many of the effects of Ang II. Thus, the ACE2/Ang-(1-7)/Mas axis acts opposite of the ACE/Ang II/AT1 axis. In this study we investigated how Ang II regulates the key enzymes of these axes, ACE and its homolog ACE2, and determined whether they are dysregulated in the hypertensive condition. Brainstem and cerebellum astrocytes isolated from the spontaneously hypertensive rat (SHR) were used in these studies. Ang II effect on the enzymes' mRNA and protein levels was measured using quantitative PCR and western blotting techniques, respectively. Results from this study showed that Ang II up-regulated ACE protein levels, but down-regulated ACE mRNA levels in brainstem and cerebellum astrocytes in both models. Ang II also reduced ACE2 mRNA expression in SHR and Wistar astrocytes isolated from both brain regions. Ang II effects on ACE2 protein were biphasic. In SHR astrocytes, Ang II-mediated ACE2 protein initially increased then decreased at later time points. In contrast, in Wistar astrocytes, Ang II initially decreased ACE2 protein expression, but up-regulated the protein at later time points. The findings of these studies suggest that Ang II has a differential effect on ACE and ACE2 expression. Furthermore, in the SHR model there may be alteration in the ACE/ACE2 balance in a manner that favors increased Ang II generation and decreased Ang-(1-7) production contributing to the hypertensive phenotype observed in this model. The levels of angiotensin (Ang) II depend on the actions of angiotensin-converting enzyme

  18. Angiotensin-converting enzyme inhibitors in veterinary medicine.

    PubMed

    Lefebvre, H P; Brown, S A; Chetboul, V; King, J N; Pouchelon, J-L; Toutain, P L

    2007-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions. PMID:17506720

  19. Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography

    SciTech Connect

    Sakaguchi, K.; Chai, S.Y.; Jackson, B.; Johnston, C.I.; Mendelsohn, F.A.

    1988-03-01

    Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor (/sup 125/I)351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors.

  20. Observation of high and low molecular weight inhibitors of angiotensin-converting enzyme in rat lung.

    PubMed

    Brecher, A S; Thevananther, S; Wilson, S

    1996-01-01

    Fractionation of the rat lung yielded a 54,000 g supernate, and DOC-solubilized 775 g, 3100 g and 54,000 g sediments, each of these preparations displaying an increasing angiotensin-converting enzyme activity with increasing dilution, suggesting the presence of freely reversible angiotensin-converting enzyme inhibitors. The solubilized 775 g sediment was applied to an immobilized captopril column, eluted successively with 20 mM Pi(K+), pH 7.8 buffer, buffer/0.5 M NaCl, and buffer/0.01M cysteine to obtain four major protein bands, two of which appeared with the cysteine eluant. The first two protein peaks were each pooled and subjected to ultrafiltration with 10,000 molecular weight cutoff filters. The pooled peaks, retentates and ultrafiltrates each inhibited the angiotensin-converting enzyme activity, suggesting the presence of large and small molecular weight reversible angiotensin-converting enzyme inhibitors in association with the solubilized (membranous) particulate angiotensin-converting enzyme fraction. These results expand upon earlier observations on the existence of angiotensin-converting enzyme inhibitors in mammalian serum by observing an increasing angiotensin-converting enzyme activity with increasing dilution. This activity was eluted in multiple peaks, including elution with the cysteine eluate, suggesting that the angiotensin-converting enzyme, as well as other proteins, may react covalently with the sulfhydryl functional group of the immobilized captopril in a transsulfhydration reaction cleaving the disulfide bonds in proteins. Subsequent elution with cysteine affects an additional transsulfhydration reaction, releasing the proteins from the column. It is further postulated that air oxidation of the proteins permits reformation of disulfide bonds, yielding some active angiotensin-converting enzyme. Having in mind the possibility of lipophilic angiotensin-converting enzyme inhibitors crossing the blood-brain barrier as a means of treatment of

  1. Tissue Specificity of Human Angiotensin I-Converting Enzyme

    PubMed Central

    Kryukova, Olga V.; Tikhomirova, Victoria E.; Golukhova, Elena Z.; Evdokimov, Valery V.; Kalantarov, Gavreel F.; Trakht, Ilya N.; Schwartz, David E.; Dull, Randal O.; Gusakov, Alexander V.; Uporov, Igor V.; Kost, Olga A.; Danilov, Sergei M.

    2015-01-01

    Background Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, as well as in reproductive functions, is expressed as a type-1 membrane glycoprotein on the surface of endothelial and epithelial cells. ACE also presents as a soluble form in biological fluids, among which seminal fluid being the richest in ACE content - 50-fold more than that in blood. Methods/Principal Findings We performed conformational fingerprinting of lung and seminal fluid ACEs using a set of monoclonal antibodies (mAbs) to 17 epitopes of human ACE and determined the effects of potential ACE-binding partners on mAbs binding to these two different ACEs. Patterns of mAbs binding to ACEs from lung and from seminal fluid dramatically differed, which reflects difference in the local conformations of these ACEs, likely due to different patterns of ACE glycosylation in the lung endothelial cells and epithelial cells of epididymis/prostate (source of seminal fluid ACE), confirmed by mass-spectrometry of ACEs tryptic digests. Conclusions Dramatic differences in the local conformations of seminal fluid and lung ACEs, as well as the effects of ACE-binding partners on mAbs binding to these ACEs, suggest different regulation of ACE functions and shedding from epithelial cells in epididymis and prostate and endothelial cells of lung capillaries. The differences in local conformation of ACE could be the base for the generation of mAbs distingushing tissue-specific ACEs. PMID:26600189

  2. Angiotensin-Converting Enzyme Inhibitors and Active Tuberculosis

    PubMed Central

    Wu, Jiunn-Yih; Lee, Meng-Tse Gabriel; Lee, Si-Huei; Lee, Shih-Hao; Tsai, Yi-Wen; Hsu, Shou-Chien; Chang, Shy-Shin; Lee, Chien-Chang

    2016-01-01

    Abstract Numerous epidemiological data suggest that the use of angiotensin-converting enzyme inhibitors (ACEis) can improve the clinical outcomes of pneumonia. Tuberculosis (TB) is an airborne bacteria like pneumonia, and we aimed to find out whether the use of ACEis can decrease the risk of active TB. We conducted a nested case–control analysis by using a 1 million longitudinally followed cohort, from Taiwan national health insurance research database. The rate ratios (RRs) for TB were estimated by conditional logistic regression, and adjusted using a TB-specific disease risk score (DRS) with 71 TB-related covariates. From January, 1997 to December, 2011, a total of 75,536 users of ACEis, and 7720 cases of new active TB were identified. Current use (DRS adjusted RR, 0.87 [95% CI, 0.78–0.97]), but not recent and past use of ACEis, was associated with a decrease in risk of active TB. Interestingly, it was found that chronic use (>90 days) of ACEis was associated with a further decrease in the risk of TB (aRR, 0.74, [95% CI, 0.66–0.83]). There was also a duration response effect, correlating decrease in TB risk with longer duration of ACEis use. The decrease in TB risk was also consistent across all patient subgroups (age, sex, heart failure, cerebrovascular diseases, myocardial infraction, renal diseases, and diabetes) and patients receiving other cardiovascular medicine. In this large population-based study, we found that subjects with recent and chronic use of ACEis were associated with decrease in TB risk. PMID:27175655

  3. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

    PubMed

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-02-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  4. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span

    PubMed Central

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-01-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  5. Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response

    PubMed Central

    Bernstein, Kenneth E.; Khan, Zakir; Giani, Jorge F.; Zhao, Tuantuan; Eriguchi, Masahiro; Bernstein, Ellen A.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.

    2016-01-01

    Angiotensin-converting enzyme (ACE) converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA). Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response. PMID:27018193

  6. Angiotensin-Receptor Blocker, Angiotensin-Converting Enzyme Inhibitor, and Risks of Atrial Fibrillation

    PubMed Central

    Hsieh, Yu-Cheng; Hung, Chen-Ying; Li, Cheng-Hung; Liao, Ying-Chieh; Huang, Jin-Long; Lin, Ching-Heng; Wu, Tsu-Juey

    2016-01-01

    Abstract Both angiotensin-receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have protective effects against atrial fibrillation (AF). The differences between ARB and ACEI in their effects on the primary prevention of AF remain unclear. This study compared ARB and ACEI in combined antihypertensive medications for reducing the risk of AF in patients with hypertension, and determined which was better for AF prevention in a nationwide cohort study. Patients aged ≥55 years and with a history of hypertension were identified from Taiwan National Health Insurance Research Database. Medical records of 25,075 patients were obtained, and included 6205 who used ARB, 8034 who used ACEI, and 10,836 nonusers (no ARB or ACEI) in their antihypertensive regimen. Cox regression models were applied to estimate the hazard ratio (HR) for new-onset AF. During an average of 7.7 years’ follow-up, 1619 patients developed new-onset AF. Both ARB (adjusted HR: 0.51, 95% CI 0.44–0.58, P < 0.001) and ACEI (adjusted HR: 0.53, 95% CI 0.47–0.59, P < 0.001) reduced the risk of AF compared to nonusers. Subgroup analysis showed that ARB and ACEI were equally effective in preventing new-onset AF regardless of age, gender, the presence of heart failure, diabetes, and vascular disease, except for those with prior stroke or transient ischemic attack (TIA). ARB prevents new-onset AF better than ACEI in patients with a history of stroke or TIA (log-rank P = 0.012). Both ARB and ACEI reduce new-onset AF in patients with hypertension. ARB prevents AF better than ACEI in patients with a history of prior stroke or TIA. PMID:27196491

  7. Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

    PubMed Central

    Lyons, D; Stewart, D; Webster, J; Benjamin, N

    1994-01-01

    Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects. PMID:7893582

  8. Inhibitory activity of Plantago major L. on angiotensin I-converting enzyme.

    PubMed

    Nhiem, Nguyen Xuan; Tai, Bui Huu; Van Kiem, Phan; Van Minh, Chau; Cuong, Nguyen Xuan; Tung, Nguyen Huu; Thu, Vu Kim; Trung, Trinh Nam; Anh, Hoang Le Tuan; Jo, Sung-Hoon; Jang, Hae-Dong; Kwon, Young-In; Kim, Young Ho

    2011-03-01

    Eight compounds were isolated from methanol extract of Plantago major L. leaves and investigated for their ability to inhibit angiotensin I-converting enzyme activity. Among them, compound 1 showed the most potent inhibition with rate of 28.06 ± 0.21% at a concentration of 100 μM. Compounds 2 and 8 exhibited weak activities. These results suggest that compound 1 might contribute to the ability of P. major to inhibit the activity of angiotensin I- converting enzyme. PMID:21547673

  9. Icatibant in the Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema

    PubMed Central

    Crooks, Neil H.; Patel, Jaimin; Diwakar, Lavanya; Smith, Fang Gao

    2014-01-01

    We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient's trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management. PMID:25328718

  10. Angiotensin receptors and angiotensin I-converting enzyme in rat intestine

    SciTech Connect

    Duggan, K.A.; Mendelsohn, F.A.; Levens, N.R. )

    1989-10-01

    The purpose of this study was to map the distribution of angiotensin II (ANG II) receptors and ANG I-converting enzyme (ACE) in rat intestine. ANG II binding sites were visualized by in vitro autoradiography using iodinated (Sar1, Ile8)ANG II. The distribution of ACE was mapped using an iodinated derivative of lisinopril. Male Sprague-Dawley rats were killed and the interior of the whole intestine washed with ice-cold saline. Segments of duodenum, jejunum, ileum, and colon were quickly frozen in a mixture of isopentane and dry ice. Twenty-micron frozen sections were thaw-mounted onto gelatin-coated slides, incubated with either ligand, and exposed to X-ray film. After exposure and subsequent development, the films were quantitated by computerized densitometry. ANG II receptors were most dense in the colon, followed by the ileum, duodenum, and jejunum. Within each segment of intestine, specific ANG II binding sites were localized exclusively to the muscularis. In contrast, ACE was present in both the mucosa and the muscularis. The colocalization of ANG II receptors and ACE may suggest a role for locally generated ANG II in the control of intestinal function. The luminal orientation of ACE in the mucosa of the small intestine may suggest that at this site ACE serves primarily to hydrolyze dietary peptides.

  11. Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling

    PubMed Central

    de Albuquerque, Felipe Neves; Brandão, Andréa Araujo; da Silva, Dayse Aparecida; Mourilhe-Rocha, Ricardo; Duque, Gustavo Salgado; Gondar, Alyne Freitas Pereira; Neves, Luiza Maceira de Almeida; Bittencourt, Marcelo Imbroinise; Pozzan, Roberto; de Albuquerque, Denilson Campos

    2014-01-01

    Background The role of angiotensin-converting enzyme genetic polymorphisms as a predictor of echocardiographic outcomes on heart failure is yet to be established. The local profile should be identified so that the impact of those genotypes on the Brazilian population could be identified. This is the first study on exclusively non-ischemic heart failure over a follow-up longer than 5 years. Objective To determine the distribution of angiotensin-converting enzyme genetic polymorphism variants and their relation with echocardiographic outcome of patients with non-ischemic heart failure. Methods Secondary analysis of the medical records of 111 patients and identification of the angiotensin-converting enzyme genetic polymorphism variants, classified as DD (Deletion/Deletion), DI (Deletion/Insertion) or II (Insertion/Insertion). Results The cohort means were as follows: follow-up, 64.9 months; age, 59.5 years; male sex, 60.4%; white skin color, 51.4%; use of beta-blockers, 98.2%; and use of angiotensin-converting-enzyme inhibitors or angiotensin receptor blocker, 89.2%. The angiotensin-converting enzyme genetic polymorphism distribution was as follows: DD, 51.4%; DI, 44.1%; and II, 4.5%. No difference regarding the clinical characteristics or treatment was observed between the groups. The final left ventricular systolic diameter was the only isolated echocardiographic variable that significantly differed between the angiotensin-converting enzyme genetic polymorphisms: 59.2 ± 1.8 for DD versus 52.3 ± 1.9 for DI versus 59.2 ± 5.2 for II (p = 0.029). Considering the evolutionary behavior, all echocardiographic variables (difference between the left ventricular ejection fraction at the last and first consultation; difference between the left ventricular systolic diameter at the last and first consultation; and difference between the left ventricular diastolic diameter at the last and first consultation) differed between the genotypes (p = 0.024; p = 0.002; and p = 0

  12. Transepithelial transport and stability in blood serum of angiotensin-I-converting enzyme inhibitory dipeptides.

    PubMed

    Pentzien, Anne-Kathrin; Meisel, Hans

    2008-01-01

    The dipeptides Ala-Trp, Val-Phe, and Val-Tyr inhibit the angiotensin-I-converting enzyme. They are encrypted within the primary sequences of different food proteins, e.g. milk proteins. The angiotensin-I-converting enzyme inhibitory potency of these synthetic dipeptides was quantified using a spectrophotometric assay. The dipeptides showed no adverse effects on differentiated Caco-2 cells (model for human intestinal epithelium), as confirmed by transepithelial electrical resistance, microscopy and the activity of the brush-border enzyme dipeptidyl aminopeptidase IV. Furthermore, the transport of these bioactive dipeptides through intact Caco-2 monolayers and their stability to incubation in human blood serum has been demonstrated for the first time. Low molecular mass peptides represent the minimal structures required for angiotensin-I-converting enzyme inhibition which have a high potential bioavailability. Therefore, they may act as target peptides in enriched hydrolysates for the preparation of an angiotensin-I-converting enzyme inhibitory peptide and for the use in special formulations as functional foods/foods of specified health use. PMID:18669035

  13. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Angiotensin converting enzyme (A.C.E.) test system. 862.1090 Section 862.1090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  14. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin converting enzyme (A.C.E.) test system. 862.1090 Section 862.1090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  15. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Angiotensin converting enzyme (A.C.E.) test system. 862.1090 Section 862.1090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  16. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Angiotensin converting enzyme (A.C.E.) test system. 862.1090 Section 862.1090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  17. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Angiotensin converting enzyme (A.C.E.) test system. 862.1090 Section 862.1090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  18. Postanesthetic Severe Oral Angioedema in Patient's Taking Angiotensin-Converting Enzyme Inhibitor

    PubMed Central

    Marques, Acílio; Retroz-Marques, Carla; Mota, Sara; Cabral, Raquel; Campos, Matos

    2014-01-01

    Angiotensin-converting enzyme (ACE) inhibitors are the leading cause of a drug-induced angioedema. This occurrence is frequently underdiagnosed, but its relapse can be life-threatening. The authors' intention in reporting this clinical case is to sound a warning about reviewing attitudes and surveillance to try to improve patient perioperative safety. PMID:25431681

  19. Renal angiotensin-converting enzyme localization in diabetic rats and the effect of low protein diet.

    PubMed

    Mizuiri, S; Kobayashi, M; Nakanishi, T; Yoshikawa, H; Miyagi, M; Tanegashima, M; Sakai, K; Hayashi, I; Fushimi, T; Hasegawa, A

    1997-01-01

    Recent evidence suggests a role of angiotensin-converting enzyme (ACE) in diabetic nephropathy. The effect of diabetes and low protein diet on renal immunohistochemical ACE localization was studied in streptozotocin-induced DM rats. Immunohistochemical ACE localization was reduced in DM rats, and a low protein diet partially resolved this abnormality while inhibiting the progression of diabetic nephropathy. PMID:9200410

  20. Angiotensin converting enzyme and memory: preclinical and clinical data.

    PubMed

    Sudilovsky, A; Turnbull, B; Croog, S H; Crook, T

    Results from both preclinical and clinical studies described here suggest that ACE may have a role in the modulation of cognitive memory processes in the rat and in humans. The finding of improved cognitive performance among patients treated with captopril relative to those treated with propranolol or methyldopa is consistent with other clinical and prec-clinical data. Clinical data derive primarily from quality of life measures based on interviews with patients in the same clinical trial from which our other cognitive data are drawn. For example, mental acuity in the workplace was reported to have improved significantly from baseline to week 24 in patients on captopril (p less than 0.05), although it did not change in patients treated with propranolol and worsened in those receiving methyldopa (Croog et al, 1987). The difference between captopril and methyldopa was significant (p less than 0.01). Pre-clinical data come primarily from studies demonstrating that inhibitors of ACE delay CAE in rats when compared not only with methyldopa, but also with saline (Sudilovsky et al, 1984, 1986). A fundamental question is how could inhibition of ACE improve cognitive functioning independent of blood pressure control. It is known that captopril exerts its antihypertensive effects primarily through inhibition of the ACE and that this is present in the brain as well as in non-neuronal tissues elsewhere (Ganten et al, 1982; Strittmatter et al, 1983, 1984). The activity of the enzyme has been found to be significantly increased in the caudate nucleus, the frontal cortex, parahyppocampal gyrus, and medial hippocampus of patients dying with Alzheimer's disease when compared to age-matched controls (Arregui et al, 1982). In addition, AII has been shown to impair performance on various learning and memory paradigms in animals (Melo and Graeff, 1975; Morgan and Routtenberg, 1977). Raising the level of endogenous AII by intravenous administration of its precursor renin has similar

  1. Angiotensin-Converting Enzyme 2 as a Therapeutic Target for Heart Failure

    PubMed Central

    Chamsi-Pasha, Mohammed A.R.; Shao, Zhili; Tang, W. H. Wilson

    2014-01-01

    The renin-angiotensin system (RAS) plays a major role in the pathophysiology of cardiovascular disorders. Angiotensin II (Ang-II), the final product of this pathway, is known for its vasoconstrictive and proliferative effects. Angiotensin-converting enzyme 2 (ACE2), a newly discovered homolog of ACE, plays a key role as the central negative regulator of the RAS. It diverts the generation of vasoactive Ang-II into the vasodilatory and growth inhibiting peptide angiotensin(1-7) [Ang(1-7)], thereby providing counter-regulatory responses to neurohormonal activation. There is substantial experimental evidence evaluating the role of ACE2/Ang(1-7) in hypertension, heart failure, and atherosclerosis. In this review, we aim to focus on the conceptual facts of the ACE2-Ang(1-7) axis with regards to clinical implications and therapeutic targets in cardiovascular disorders, with emphasis on the potential therapeutic role in cardiovascular diseases. PMID:24293035

  2. SALT SENSITIVITY IN RESPONSE TO RENAL INJURY REQUIRES RENAL ANGIOTENSIN-CONVERTING ENZYME

    PubMed Central

    Giani, Jorge F.; Bernstein, Kenneth E.; Janjulia, Tea; Han, Jiyang; Toblli, Jorge E.; Shen, Xiao Z.; Rodriguez-Iturbe, Bernardo; McDonough, Alicia A.; Gonzalez-Villalobos, Romer A.

    2015-01-01

    Recent evidence indicates that salt-sensitive hypertension can result from a subclinical injury that impairs the kidneys’ capacity to properly respond to a high salt diet. However, how this occurs is not well understood. Here, we showed that while previously salt resistant wild-type mice became salt-sensitive after the induction of renal injury with the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); mice lacking renal angiotensin-converting enzyme, exposed to the same insult, did not become hypertensive when faced with a sodium load. This is because the activity of renal angiotensin-converting enzyme plays a critical role in: 1) augmenting the local pool of angiotensin II and, 2) the establishment of the anti-natriuretic state via modulation of glomerular filtration rate and sodium tubular transport. Thus, this study demonstrates that the presence of renal angiotensin-converting enzyme plays a pivotal role in the development of salt sensitivity in response to renal injury. PMID:26150439

  3. Angiotensin-I-Converting Enzyme (ACE) Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    PubMed Central

    Wijesekara, Isuru; Kim, Se-Kwon

    2010-01-01

    Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS) and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension. PMID:20479968

  4. Identification of angiotensin-converting enzyme inhibitory proteins from mycelium of Pleurotus pulmonarius (oyster mushroom).

    PubMed

    Ibadallah, Badjie Xietaqieuallah; Abdullah, Noorlidah; Shuib, Adawiyah Suriza

    2015-01-01

    Pleurotus pulmonarius (grey oyster mushroom) has been acknowledged as a recuperative agent for many diseases in addition to its recognition as a nutritious provision. We performed a study on P. pulmonarius mycelium for an antihypertensive effect via the angiotensin-converting enzyme inhibitory activity. The preliminary assay on the mycelial water extract demonstrated that the angiotensin-converting enzyme inhibitory activity had an IC50 value of 720 µg/mL. Further protein purifications via ammonium sulphate precipitation and RP-HPLC resulted in 60× stronger angiotensin-converting enzyme inhibitory activity than that of the mycelial water extract (IC50 = 12 µg/mL). Protein identification and characterisation by MALDI-TOF/TOF, later corroborated by LC-MS/MS, indicated three proteins that are responsible for the blood pressure lowering effects via different mechanisms: serine proteinase inhibitor-like protein, nitrite reductase-like protein, and DEAD/DEAH box RNA helicase-like protein. PMID:25590365

  5. The variable effects of angiotensin converting enzyme inhibition on myocardial ischaemia in chronic stable angina.

    PubMed

    Simon, J; Gibbs, R; Crean, P A; Mockus, L; Wright, C; Sutton, G C; Fox, K M

    1989-08-01

    The effect of angiotensin converting enzyme inhibition on myocardial ischaemia was studied in 12 normotensive patients with chronic stable angina and exercise induced ST segment depression. The study was randomised, double blind, placebo controlled, and crossover with treatment periods of two weeks. Enalapril was used to inhibit angiotensin converting enzyme. Assessment was by angina diaries and maximum symptom limited treadmill exercise tests. The results for the whole group showed a significant reduction in systolic blood pressure at rest and at peak exercise. Mean total exercise duration was 466 s (95% confidence interval 406 to 525) when the patients were taking placebo and 509 s (436 to 583) when they were taking enalapril. Four patients prolonged their total exercise time (mean 450 to mean 591 s) by more than 20%. Two patients, however, developed ischaemia earlier on exercise and reduced their total exercise duration (mean 490 to mean 390 s). Although angiotensin converting enzyme inhibition tended to reduce myocardial ischaemia in the group as a whole, some patients improved while others deteriorated. Thus the effects of enalapril are variable and this may have important implications when enalapril is used to treat heart failure in patients with underlying severe ischaemic heart disease. PMID:2548548

  6. The variable effects of angiotensin converting enzyme inhibition on myocardial ischaemia in chronic stable angina.

    PubMed Central

    Simon, J; Gibbs, R; Crean, P A; Mockus, L; Wright, C; Sutton, G C; Fox, K M

    1989-01-01

    The effect of angiotensin converting enzyme inhibition on myocardial ischaemia was studied in 12 normotensive patients with chronic stable angina and exercise induced ST segment depression. The study was randomised, double blind, placebo controlled, and crossover with treatment periods of two weeks. Enalapril was used to inhibit angiotensin converting enzyme. Assessment was by angina diaries and maximum symptom limited treadmill exercise tests. The results for the whole group showed a significant reduction in systolic blood pressure at rest and at peak exercise. Mean total exercise duration was 466 s (95% confidence interval 406 to 525) when the patients were taking placebo and 509 s (436 to 583) when they were taking enalapril. Four patients prolonged their total exercise time (mean 450 to mean 591 s) by more than 20%. Two patients, however, developed ischaemia earlier on exercise and reduced their total exercise duration (mean 490 to mean 390 s). Although angiotensin converting enzyme inhibition tended to reduce myocardial ischaemia in the group as a whole, some patients improved while others deteriorated. Thus the effects of enalapril are variable and this may have important implications when enalapril is used to treat heart failure in patients with underlying severe ischaemic heart disease. PMID:2548548

  7. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    PubMed Central

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  8. Aliskiren – an alternative to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the therapy of arterial hypertension

    PubMed Central

    Hoffmann, Karolina; Bryl, Wiesław; Minczykowski, Andrzej

    2013-01-01

    There has been enormous progress in antihypertensive therapy over the last few decades. However, the management of arterial hypertension is still insufficient and more efforts are needed to improve both non-pharmacological and pharmacological treatment of this widely prevalent disease. Renin-angiotensin-aldosterone system (RAAS) inhibition is crucial both for blood pressure (BP) control and for prevention of organ damage or its development in patients with hypertension. Angiotensin-converting enzyme inhibitors and/or sartans block RAAS incompletely. Aliskiren is one of the novel drugs that has been introduced to antihypertensive therapy recently. Up to now no trial has confirmed that aliskiren is efficacious in reducing cardiovascular events. Double RAAS blockade with aliskiren was not always safe. This review article presents the current view on the place of aliskiren in the therapy of arterial hypertension. PMID:25276171

  9. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits.

    PubMed

    Pucci, Mark; Sarween, Nadia; Knox, Ellen; Lipkin, Graham; Martin, Una

    2015-03-01

    Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients. PMID:25612630

  10. Aliskiren - an alternative to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the therapy of arterial hypertension.

    PubMed

    Zaporowska-Stachowiak, Iwona; Hoffmann, Karolina; Bryl, Wiesław; Minczykowski, Andrzej

    2014-08-29

    There has been enormous progress in antihypertensive therapy over the last few decades. However, the management of arterial hypertension is still insufficient and more efforts are needed to improve both non-pharmacological and pharmacological treatment of this widely prevalent disease. Renin-angiotensin-aldosterone system (RAAS) inhibition is crucial both for blood pressure (BP) control and for prevention of organ damage or its development in patients with hypertension. Angiotensin-converting enzyme inhibitors and/or sartans block RAAS incompletely. Aliskiren is one of the novel drugs that has been introduced to antihypertensive therapy recently. Up to now no trial has confirmed that aliskiren is efficacious in reducing cardiovascular events. Double RAAS blockade with aliskiren was not always safe. This review article presents the current view on the place of aliskiren in the therapy of arterial hypertension. PMID:25276171

  11. Intrarenal distributions and changes of Angiotensin-converting enzyme and Angiotensin-converting enzyme 2 in feline and canine chronic kidney disease.

    PubMed

    Mitani, Sawane; Yabuki, Akira; Sawa, Mariko; Chang, Hye-Sook; Yamato, Osamu

    2014-01-01

    Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system (RAS). ACE2 is a newly identified member of the RAS. The present immunohistochemical study focused on changes in intrarenal ACE and ACE2 immunoreactivity in feline and canine chronic kidney disease (CKD). ACE immunoreactivity was predominantly observed in the brush border of the proximal tubules in dogs and cats. ACE immunoreactivity was lower in CKD kidneys than in normal kidneys, and quantitative analysis demonstrated negative correlations between ACE and renal tissue damage in dogs. ACE2 immunoreactivity was also detected in the proximal tubules; it increased or decreased with CKD in dogs, depending on the renal region assessed. The changes in ACE and ACE2 in CKD were associated with the plasma creatinine concentration in dogs. Findings from dogs with glomerulonephritis were similar to those from dogs with non-glomerulonephritis. The present study suggests that changes in the intrarenal expression of ACE and ACE2 contribute to the pathological mechanisms of canine CKD, but not to the mechanisms of feline CKD. PMID:24004970

  12. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    PubMed

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question. PMID:27246933

  13. Enzyme Hydrolysates from Stichopus horrens as a New Source for Angiotensin-Converting Enzyme Inhibitory Peptides

    PubMed Central

    Forghani, Bita; Ebrahimpour, Afshin; Bakar, Jamilah; Abdul Hamid, Azizah; Hassan, Zaiton; Saari, Nazamid

    2012-01-01

    Stichopus horrens flesh was explored as a potential source for generating peptides with angiotensin-converting enzyme (ACE) inhibitory capacity using 6 proteases, namely alcalase, flavourzyme, trypsin, papain, bromelain, and protamex. Degree of hydrolysis (DH) and peptide profiling (SDS-PAGE) of Stichopus horrens hydrolysates (SHHs) was also assessed. Alcalase hydrolysate showed the highest DH value (39.8%) followed by flavourzyme hydrolysate (32.7%). Overall, alcalase hydrolysate exhibited the highest ACE inhibitory activity (IC50 value of 0.41 mg/mL) followed by flavourzyme hydrolysate (IC50 value of 2.24 mg/mL), trypsin hydrolysate (IC50 value of 2.28 mg/mL), papain hydrolysate (IC50 value of 2.48 mg/mL), bromelain hydrolysate (IC50 value of 4.21 mg/mL), and protamex hydrolysate (IC50 value of 6.38 mg/mL). The SDS-PAGE results showed that alcalase hydrolysate represented a unique pattern compared to others, which yielded potent ACE inhibitory peptides with molecular weight distribution lower than 20 kDa. The evaluation of the relationship between DH and IC50 values of alcalase and flavourzyme hydrolysates revealed that the trend between those parameters was related to the type of the protease used. We concluded that the tested SHHs would be used as a potential source of functional ACE inhibitory peptides for physiological benefits. PMID:22927875

  14. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

    PubMed Central

    Chhabra, Kavaljit H.; Xia, Huijing; Pedersen, Kim Brint; Speth, Robert C.

    2013-01-01

    An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7–8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS. PMID:23462816

  15. Activity Prediction and Molecular Mechanism of Bovine Blood Derived Angiotensin I-Converting Enzyme Inhibitory Peptides

    PubMed Central

    Zhang, Ting; Nie, Shaoping; Liu, Boqun; Yu, Yiding; Zhang, Yan; Liu, Jingbo

    2015-01-01

    Development of angiotensin I-converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides from food protein is under extensive research as alternative for the prevention of hypertension. However, it is difficult to identify peptides released from food sources. To accelerate the progress of peptide identification, a three layer back propagation neural network model was established to predict the ACE-inhibitory activity of pentapeptides derived from bovine hemoglobin by simulated enzyme digestion. The pentapeptide WTQRF has the best predicted value with experimental IC50 23.93 μM. The potential molecular mechanism of the WTQRF / ACE interaction was investigated by flexible docking. PMID:25768442

  16. Glial high-affinity binding site with specificity for angiotensin II not angiotensin III: a possible N-terminal-specific converting enzyme

    SciTech Connect

    Printz, M.P.; Jennings, C.; Healy, D.P.; Kalter, V.

    1986-01-01

    Anomalous binding properties of angiotensin II to fetal rat brain primary cultures suggested a possible contribution from contaminating glia. To investigate this possibility, cultures of C6 glioma, a clonal rat cell line, were examined for the presence of angiotensin II receptors. A specific high-affinity site for (/sup 125/I)angiotensin II was measured both by traditional methodology using whole cells and by autoradiography. This site shared properties similar to that found with the brain cells, namely low ligand internalization and markedly decreased affinity for N-terminal sarcosine or arginine-angiotensin analogs. The competition rank order was angiotensin II much greater than (Sar1,Ile8)angiotensin II greater than or equal to des(Asp1,Arg2)angiotensin II. Angiotensin III did not compete for binding to the site. High-pressure liquid chromatography analysis indicated that the ligand either in the incubation or bound to the site was stable at 15 degrees C, but there was very rapid and extensive degradation by the C6 glioma cells at 37 degrees C. It is concluded that the site exhibits unusual N-terminal specificity for angiotensin with nanomolar affinity for angiotensin II. If angiotensin III is an active ligand in the brain, the site may have a converting enzyme function. Alternatively, it may form the des-Asp derivatives of angiotensin for subsequent degradation by other enzymatic pathways. Either way, it is proposed that the site may modulate the brain-angiotensin system.

  17. A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

    PubMed Central

    Ong, Frank S.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Giani, Jorge F.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Fuchs, Sebastien

    2013-01-01

    Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors. PMID:23257181

  18. Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis

    PubMed Central

    Cao, Xi; Yang, Fangyuan; Shi, Tingting; Yuan, Mingxia; Xin, Zhong; Xie, Rongrong; Li, Sen; Li, Hongbing; Yang, Jin-Kui

    2016-01-01

    The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2−/y) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2−/y mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1–7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what’s more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1–7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1–7)/Mas axis in prevention and treatment of hepatic lipid metabolism. PMID:26883384

  19. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis.

    PubMed

    Cao, Xi; Yang, Fangyuan; Shi, Tingting; Yuan, Mingxia; Xin, Zhong; Xie, Rongrong; Li, Sen; Li, Hongbing; Yang, Jin-Kui

    2016-01-01

    The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2(-/y)) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2(-/y) mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1-7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what's more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1-7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1-7)/Mas axis in prevention and treatment of hepatic lipid metabolism. PMID:26883384

  20. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus

    PubMed Central

    Gu, Hongjing; Xie, Zhengde; Li, Tieling; Zhang, Shaogeng; Lai, Chengcai; Zhu, Ping; Wang, Keyu; Han, Lina; Duan, Yueqiang; Zhao, Zhongpeng; Yang, Xiaolan; Xing, Li; Zhang, Peirui; Wang, Zhouhai; Li, Ruisheng; Yu, Jane J.; Wang, Xiliang; Yang, Penghui

    2016-01-01

    Respiratory syncytial virus (RSV) infection is a major cause of severe lower respiratory illness in infants and young children, but the underlying mechanisms responsible for viral pathogenesis have not been fully elucidated. To date, no drugs or vaccines have been employed to improve clinical outcomes for RSV-infected patients. In this paper, we report that angiotensin-converting enzyme-2 (ACE2) protected against severe lung injury induced by RSV infection in an experimental mouse model and in pediatric patients. Moreover, ACE2 deficiency aggravated RSV-associated disease pathogenesis, mainly by its action on the angiotensin II type 1 receptor (AT1R). Furthermore, administration of a recombinant ACE2 protein alleviated the severity of RSV-induced lung injury. These findings demonstrate that ACE2 plays a critical role in preventing RSV-induced lung injury, and suggest that ACE2 is a promising potential therapeutic target in the management of RSV-induced lung disease. PMID:26813885

  1. Development and Validation of a Clinical Prediction Rule for Angiotensin-converting Enzyme Inhibitor-induced Cough

    PubMed Central

    Morimoto, Takeshi; Gandhi, Tejal K; Fiskio, Julie M; Seger, Andrew C; So, Joseph W; Cook, E Francis; Fukui, Tsuguya; Bates, David W

    2004-01-01

    BACKGROUND Angiotensin-converting enzyme inhibitors are effective for many cardiovascular diseases and are widely prescribed, but cough sometimes necessitates their withdrawal. OBJECTIVE To develop and validate a model that predicts, by using information available at first prescription, whether a patient will develop cough within 6 months. DESIGN Retrospective cohort study with derivation and validation sets. SETTING Outpatient clinics affiliated with an urban tertiary care hospital. PATIENTS Clinical data were collected from electronic charts. The derivation set included 1,125 patients and the validation set included 567 patients. INTERVENTIONS None. MEASUREMENTS Angiotensin-converting enzyme inhibitorinduced cough assessed by predetermined criteria. RESULTS In the total cohort, 12% of patients developed angiotensin-converting enzyme inhibitor-induced cough. Independent multivariate predictors of cough were older age, female gender, non-African American (with East Asian having highest risk), no history of previous angiotensin-converting enzyme inhibitor use, and history of cough due to another angiotensin-converting enzyme inhibitor. Patients with a history of angiotensin-converting enzyme inhibitor-induced cough were 29 times more likely to develop a cough than those without this history. These factors were used to develop a model stratifying patients into 4 risk groups. In the derivation set, low-risk, average-risk, intermediate-risk, and highrisk groups had a 6%, 9%, 22%, and 55% probability of cough, respectively. In the validation set, 4%, 14%, 20%, and 60% of patients in these 4 groups developed cough, respectively. CONCLUSIONS This model may help clinicians predict the likelihood of a particular patient developing cough from an angiotensin-converting enzyme inhibitor at the time of prescribing, and may also assist with subsequent clinical decisions. PMID:15209608

  2. An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms.

    PubMed

    Nylocks, K M; Michopoulos, V; Rothbaum, A O; Almli, L; Gillespie, C F; Wingo, A; Schwartz, A C; Habib, L; Gamwell, K L; Marvar, P J; Bradley, B; Ressler, K J

    2015-06-01

    Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n=  803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD. PMID:25921615

  3. Renal scintigraphy following angiotensin converting enzyme inhibition in the diagnosis of renovascular hypertension (captopril scintigraphy)

    SciTech Connect

    Sfakianakis, G.N. )

    1989-09-01

    This article describes the pathophysiology and primary causes of renovascular hypertension (RVH). No historical or physical finding is specific in the diagnosis of RVH, although onset of hypertension before the age of 30 years may suggest the possible presence of RVH. The physiology of the kidney is described along with the biochemistry of angiotensin converting enzyme inhibitors. The main thrust of the article is nuclear medicine techniques useful in the diagnosis of this disease. Several diagnositic methods are described but captopril scintigraphy is presented as a method that may give more optimal results in the diagnosis of RVH.

  4. Primary Systemic Amyloidosis and High Levels of Angiotensin-Converting Enzyme: Two Case Reports

    PubMed Central

    Praena-Segovia, J.; Sanchez-Gastaldo, A.; Bernabeu-Wittel, M.; Ocete-Pérez, R.; Ávila-Polo, R.; Martino, M. L.

    2013-01-01

    Infiltrative heart diseases are caused by a heterogeneous group of disorders; amyloidosis and sarcoidosis are two frequent causes of myocardial infiltration, which differ in clinical and biological outcome and treatment issues. The presence of high levels of angiotensin-converting enzyme (ACE) in a patient with infiltrative heart disease may increase suspicion of sarcoidosis. Nevertheless, no mention about increased ACE levels in extracerebral primary systemic amyloidosis is available. We present two cases of primary systemic amyloidosis, which are cardiac involvement and elevated ACE levels. PMID:24826302

  5. Bronchoalveolar lavage, serum angiotensin-converting enzyme, and /sup 67/Ga scanning in extrathoracic sarcoidosis

    SciTech Connect

    Wallaert, B.; Ramon, P.; Fournier, E.; Tonnel, A.B.; Voisin, C.

    1982-11-01

    Results of bronchoalveolar lavage (BAL), 67Ga scanning, and serum angiotensin-converting enzyme (SACE) assay are compared in the assessment of pulmonary involvement in ten cases of extrathoracic sarcoidosis. Standard clinical, radiologic, and pulmonary function tests detected no pulmonary changes in these patients, but BAL demonstrated an increased alveolar lymphocytosis in eight of ten cases. SACE levels were increased in two cases, and the thoracic gallium uptake was normal in all cases. BAL appears to be the best technique for diagnosing latent pulmonary involvement in extrathoracic sarcoidosis.

  6. Angiotensin-converting enzyme (ACE-I/D) polymorphism frequency in Brazilian soccer players.

    PubMed

    Coelho, Daniel Barbosa; Pimenta, Eduardo; Rosse, Izinara Cruz; Veneroso, Christiano; Pussieldi, Guilherme; Becker, Lenice Kapes; Carvalho, Maria-Raquel; Silami-Garcia, Emerson

    2016-06-01

    This study aimed to analyze the angiotensin-converting enzyme (ACE-I/D) allelic and genotypic frequencies in Brazilian soccer players of different ages. The study group comprised 353 players from first-division clubs in the under (U)-14, U-15, U-17, U-20, and professional categories. The allelic and genotypic frequencies did not differ significantly in any of the categories between the group of players and the control group. This was the first study of ACE-I/D polymorphism in Brazilian soccer players. PMID:27232187

  7. Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors 1 and 2

    PubMed Central

    Clayton, Daniel; Hanchapola, Iresha; Thomas, Walter G.; Widdop, Robert E.; Smith, Alexander I.; Perlmutter, Patrick; Aguilar, Marie-Isabel

    2015-01-01

    Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin–angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1–7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R, and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here, we further explore this region for the potential to modulate ligand specificity. In this study, (1) a library of 47 peptides derived from the C-terminal tetrapeptide sequence (-IHPF) of Ang II was synthesized and assessed for ACE2 binding, (2) the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, (3) high affinity ACE2 binding chimeric AngII analogs were then synthesized and assessed, (4) the structure of the full-length Ang II analogs were assessed by circular dichroism, and (5) the Ang II analogs were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity. PMID

  8. Effects of altered ventilatory patterns of rabbit pulmonary endothelial angiotensin converting enzyme function, in vivo

    SciTech Connect

    Toivonen, H.J.; Catravas, J.D.

    1986-03-01

    Because alveolar pressure can influence pulmonary blood flow, volume and surface area, the authors have studied the effects of airway pressure on endothelial angiotensin converting enzyme (ACE) function in rabbit lungs in vivo, utilizing indicator dilution techniques with /sup 3/H-Benzoyl-Phe-Ala-Pro (BPAP) as substate. Static inclation of the lungs to a pressure of 0 or 5 mmHg did not change percent transpulmonary metabolism and Amax/Km ratio in comparison to control measurements during conventional mechanical ventilation. When the inflation pressure was increased to 10 mmHg, percent metabolism of /sup 3/H-BPAP remained unaltered but Amax/Km decreased over 40% from control. This decrease was in close relation to the reduction in pulmonary blood flow. Addition of 5 cm H/sub 2/O positive end-expiratory pressure (PEEP) to the mechanical ventilation also decreased Amax/Km values and pulmonary blood flow but did not influence percent metabolism of /sup 3/H-BPAP. These results suggest that the detected alterations in ACE kinetics were more likely due to hemodynamic changes than enzyme dysfunction. The authors propose that high static alveolar pressures as well as PEEP did not affect angiotensin converting enzyme function, but reduced the fraction of perfused microvessels reflected in changes in Amax/Km ratios.

  9. Characterization of angiotensin I-converting enzyme from anterior gills of the mangrove crab Ucides cordatus.

    PubMed

    Bersanetti, Patrícia A; Nogueira, Regina F; Marcondes, Marcelo F; Paiva, Paulo B; Juliano, Maria A; Juliano, Luiz; Carmona, Adriana K; Zanotto, Flavia P

    2015-03-01

    Angiotensin I-converting enzyme (ACE) is a well-known metallopeptidase that is found in vertebrates, invertebrates and bacteria. We isolated from the anterior gill of the crab Ucides cordatus an isoform of ACE, here named crab-ACE, which presented catalytic properties closely resembling to those of mammalian ACE. The enzyme was purified on Sepharose-lisinopril affinity chromatography to apparent homogeneity and a band of about 72 kDa could be visualized after silver staining and Western blotting. Assays performed with fluorescence resonance energy transfer (FRET) selective ACE substrates Abz-FRK(Dnp)P-OH, Abz-SDK(Dnp)P-OH and Abz-LFK(Dnp)-OH, allowed us to verify that crab-ACE has hydrolytic profile very similar to that of the ACE C-domain. In addition, we observed that crab-ACE can hydrolyze the ACE substrates, angiotensin I and bradykinin. The enzyme was strongly inhibited by the specific ACE inhibitor lisinopril (Ki of 1.26 nM). However, in contrast to other ACE isoforms, crab-ACE presented a very particular optimum pH, being the substrate Abz-FRK(Dnp)-P-OH hydrolyzed efficiently at pH 9.5. Other interesting characteristic of crab-ACE was that the maximum hydrolytic activity was reached at around 45°C. The description of an ACE isoform in Ucides cordatus is challenging and may contribute to a better understanding of the biochemical function of this enzyme in invertebrates. PMID:25544039

  10. In vitro autoradiographic localization of angiotensin-converting enzyme in sarcoid lymph nodes

    SciTech Connect

    Allen, R.K.; Chai, S.Y.; Dunbar, M.S.; Mendelsohn, F.A.

    1986-09-01

    Angiotensin-converting enzyme (ACE) was localized in sarcoid lymph nodes by an in vitro autoradiographic technique using a synthetic ACE inhibitor of high affinity, /sup 125/I-labelled 351A. The lymph nodes were from seven patients with active sarcoidosis who underwent mediastinoscopy and from six control subjects who had nodes resected at either mediastinoscopy or laparotomy. Angiotensin-converting enzyme was localized in the epithelioid cells of sarcoid granulomata in markedly increased amounts compared with control nodes, where it was restricted to vessels and some histiocytes. In sarcoid lymph nodes, there was little ACE present in lymphocytes or fibrous tissue. Sarcoid nodes with considerable fibrosis had much less intense ACE activity than the nonfibrotic nodes. The specific activity of ACE measured by an enzymatic assay in both the control and sarcoid lymph nodes closely reflected the ACE activity demonstrated by autoradiography. Sarcoid lymph nodes with fibrosis had an ACE specific activity of half that of nonfibrotic nodes (p less than 0.05). There was a 15-fold increase in specific ACE activity in sarcoid nodes (p less than 0.05) compared to normal. Serum ACE was significantly higher in those sarcoid patients whose lymph nodes were not fibrosed compared with those with fibrosis (p less than 0.01). This technique offers many advantages over the use of polyclonal antibodies. The 351A is a highly specific ACE inhibitor, chemically defined and in limitless supply. This method enables the quantitation of results, and autoradiographs may be stored indefinitely for later comparison.

  11. A quantitative peptidomics approach to unravel immunological functions of angiotensin converting enzyme in Locusta migratoria.

    PubMed

    Duressa, Tewodros Firdissa; Boonen, Kurt; Huybrechts, Roger

    2016-09-01

    Locusta migratoria angiotensin converting enzyme (LmACE) is encoded by multiple exons displaying variable number of genomic duplications. Treatments of lipopolysaccharide (LPS) as well as peptidoglycan but not β-1-3 glucan resulted in enhanced expression of angiotensin converting enzyme in hemocytes of Locusta migratoria. No such effect was observed in fat body cells. Differential peptidomics using locust plasma samples post infection with LPS in combination with both an LmACE transcript knockdown by RNAi and a functional knockdown using captopril allowed the identification of 5 circulating LPS induced peptides which only appear in the hemolymph of locust having full LmACE functionality. As these peptides originate from larger precursor proteins such as locust hemocyanin-like protein, having known antimicrobial properties, the obtained results suggest a possible direct or indirect role of LmACE in the release of these peptides from their precursors. Additionally, this experimental setup confirmed the role of LmACE in the clearance of multiple peptides from the hemolymph. PMID:27320038

  12. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to?

    PubMed

    Sindone, A; Erlich, J; Lee, C; Newman, H; Suranyi, M; Roger, S D

    2016-03-01

    Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends. PMID:26968600

  13. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    PubMed Central

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. PMID:19926893

  14. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    SciTech Connect

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  15. QM/MM investigation of the catalytic mechanism of angiotensin-converting enzyme.

    PubMed

    Mu, Xia; Zhang, Chunchun; Xu, Dingguo

    2016-06-01

    Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II and degrades bradykinin and other vasoactive peptides. ACE inhibitors are used to treat diseases such as hypertension and heart failure. It is thus highly desirable to understand the catalytic mechanism of ACE, as this should facilitate the design of more powerful and selective ACE inhibitors. ACE exhibits two different active domains, the C-domain and the N-domain. In this work, we systematically investigated the inhibitor- and substrate-binding patterns in the N-domain of human ACE using a combined quantum mechanical and molecular mechanical approach. The hydrolysis of hippuryl-histidyl-leucine (HHL) as catalyzed by the N-domain of human somatic ACE was explored, and the effects of chloride ion on the overall reaction were also investigated. Two models, one with and one without a chloride ion at the first binding position, were then designed to examine the chloride dependence of inhibitor-substrate binding and the catalytic mechanism. Our calculations indicate that the hydrolysis reaction follows a stepwise general base/general acid catalysis path. The estimated mean free energy barrier height in the two models is about 15.6 kcal/mol, which agrees very well with the experimentally estimated value of 15.8 kcal/mol. Our simulations thus suggest that the N-domain is in a mixed form during ACE-catalyzed hydrolysis, with the single-chloride-ion and the double-chloride-ion forms existing simultaneously. Graphical Abstract Superposition of ACE C- and N- domains. PMID:27184002

  16. Contributions of Leukocytic Angiotensin-converting Enzyme to Development of Atherosclerosis

    PubMed Central

    Chen, Xiaofeng; Lu, Hong; Zhao, Mingming; Tashiro, Katsuya; Cassis, Lisa A.; Daugherty, Alan

    2013-01-01

    Objective This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I (AngI)-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme. Approach and Results To define the contribution of ACE-dependent activity to AngII synthesis in atherosclerotic development, male LDL receptor -/- mice were fed a fat-enriched diet and infused with either AngI or AngII. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Co-infusion of an ACE inhibitor, enalapril, ablated AngI augmented atherosclerosis, but had no effect on AngII-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted AngII, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male LDL receptor -/- mice were repopulated with bone marrow-derived cells from either ACE +/+ or -/- mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches, but had no effects in aortic roots. Conclusions ACE mediates AngI-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice. PMID:23846498

  17. Is angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy protective against prostate cancer?

    PubMed Central

    Mao, Yeqing; Xu, Xin; Wang, Xiao; Zheng, Xiangyi; Xie, Liping

    2016-01-01

    Emerging evidence suggests that renin-angiotensin system (RAS) may act as a molecular and therapeutic target for treating site-specific cancers, including prostate cancer. However, previous observational studies regarding the association between RAS inhibitors and prostate cancer risk have reported inconsistent results. We examined this association by performing a systematic review and meta-analysis. A total of 20,267 patients from nine cohort studies were enrolled. Compared with non-users of RAS inhibitors, individuals using RAS inhibitors had a reduced risk of prostate cancer (RR 0.92, 95 % CI 0.87-0.98), without statistically significant heterogeneity among studies (P = 0.118 for heterogeneity, I2 = 37.6 %). In addition, when subgroup analyses by study quality and number of cases, more statistically significant associations were observed in studies of high quality (RR 0.93, 95 % CI 0.88-0.97) and large sample size (RR 0.94, 95 % CI 0.91-0.98). There was no evidence of significant publication bias with Begg's test (P = 0.602) or with Egger's test (P = 0.350). Overall, this study indicates that use of RAS inhibitors may be associated with a decreased risk of prostate cancer. Large-scale well designed studies are needed to further explore this association. PMID:26760503

  18. Essential residues in angiotensin converting enzyme: Modification with 1-fluoro-2,4-dinitrobenzene

    SciTech Connect

    Bunning, P.; Kleemann, S.G.; Riordan, J.F. )

    1990-11-01

    The peptidase and esterase activities of rabbit pulmonary angiotensin converting enzyme (ACE) are rapidly abolished on reaction with 1-fluoro-2,4-dinitrobenzene (Dnp-F). Inactivation follows first-order kinetics with respect to the reagent and is accompanied by stoichiometric incorporation of 3,5-({sup 3}H)Dnp, indicating that the effect is due to a specific modification of the enzyme. Thin-layer chromatography of an acid hydrolysate of the modifed enzyme indicates that most of the radioactive label is present as O-Dnp-tyrosine (65 to >95{percent}) and the rest at N{epsilon}-Dnp-lysine. The pH dependence of the reaction is consistent with modification of either tyrosine or lysine. The presence of a competitive inhibitor effectively protects the enzyme against inactivation by Dnp-F. Acetylation of ACE with N-acetylimidazole also protects the enzyme against modification with Dnp-F. The results indicate the presence of catalytically essential tyrosine and lysine residues at the active site of ACE.

  19. Preparation of lisinopril-capped gold nanoparticles for molecular imaging of angiotensin-converting enzyme

    NASA Astrophysics Data System (ADS)

    Li, Yuan; Baeta, Cesar; Aras, Omer; Daniel, Marie-Christine

    2009-05-01

    Overexpression of angiotensin-converting enzyme (ACE) has been associated with the pathophysiology of cardiac and pulmonary fibrosis. Moreover, the prescription of ACE inhibitors, such as lisinopril, has shown a favorable effect on patient outcome for patients with heart failure or systemic hypertension. Thus targeted imaging of the ACE would be of crucial importance for monitoring tissue ACE activity as well as the treatment efficacy in heart failure. In this respect, lisinopril-coated gold nanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging. The preparation involved non-modified lisinopril, using its primary amine group as the anchoring function on the gold nanoparticles surface. The stable lisinopril-coated gold nanoparticles obtained were characterized by UV-vis spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM). Their zeta potential was also measured in order to assess the charge density on the modified gold nanoparticles (GNPs).

  20. Distribution of angiotensin converting enzyme in sheep hypothalamus and medulla oblongata visualized by in vitro autoradiography

    SciTech Connect

    Chai, S.Y.; McKinley, M.J.; Mendelsohn, F.A.

    1987-01-01

    In vitro autoradiographic mapping of angiotensin converting enzyme (ACE) in sheep brain using the specific ACE inhibitor, /sup 125/I-351A, revealed very high densities of binding in large blood vessels and choroid plexus. In the a very high density of labelling occurred in the organum vasculosum of the lamina terminalis and median eminence and a high density in the subfornical organ and moderate density in supraoptic, suprachiasmatic, arcuate and paraventricular nuclei. All fiber tracts were unlabelled. In the medulla oblongata, a very high density of binding was detected in the area postrema and a high density in the nucleus of the solitary tract and dorsal motor nucleus of the vagus; a moderate density was found in the substantia gelatinosa of the spinal tract and the inferior olivary nucleus.

  1. Renal hemodynamic changes induced by captopril and angiotensin-converting enzyme gene polymorphism.

    PubMed

    Mizuiri, S; Hemmi, H; Inoue, A; Takano, M; Kadomatsu, S; Tanimoto, H; Tanegashima, M; Hayashi, I; Fushimi, T; Hasegawa, A

    1997-01-01

    We studied the relationship between renal hemodynamic changes induced by a single acute administration of captopril (50 mg p.o.) and angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in 27 healthy human volunteers, 7 with DD genotype, 10 with ID, and 10 with II genotype. The increase in effective renal plasma flow (p < 0.02) and the fall in renal vascular resistance (p < 0.01) in response to captopril were significantly less in subjects with the DD genotype than in subjects with the other genotypes. These data suggest that intrarenal ACE inhibition by captopril differs according to ACE gene ID polymorphism in healthy humans. PMID:9069453

  2. Angiotensin I converting enzyme inhibitory peptides purified from bovine skin gelatin hydrolysate.

    PubMed

    Kim, S K; Byun, H G; Park, P J; Shahidi, F

    2001-06-01

    Bovine skin gelatin was hydrolyzed with sequential protease treatments in the order of Alcalase, Pronase E, and collagenase using a three-step ultrafiltration membrane reactor. The molecular weight distributions of the first, second, and third hydrolysates were 4.8-6.6, 3.4-6.6, and 0.9-1.9 kDa, respectively. The angiotensin I converting enzyme (ACE) inhibitory activity of the third hydrolysate (IC(50) = 0.689 mg/mL) was higher than that of the first and second hydrolysates. Two different peptides showing strong ACE inhibitory activity were isolated from the hydrolysate using consecutive chromatographic methods including gel filtration chromatography, ion-exchange chromatography, and reversed-phase high-performance liquid chromatography. The isolated peptides were composed of Gly-Pro-Leu and Gly-Pro-Val and showed IC(50) values of 2.55 and 4.67 microM, respectively. PMID:11409999

  3. Angiotensin-Receptor Blocker, Angiotensin-Converting Enzyme Inhibitor, and Risks of Atrial Fibrillation: A Nationwide Cohort Study.

    PubMed

    Hsieh, Yu-Cheng; Hung, Chen-Ying; Li, Cheng-Hung; Liao, Ying-Chieh; Huang, Jin-Long; Lin, Ching-Heng; Wu, Tsu-Juey

    2016-05-01

    Both angiotensin-receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have protective effects against atrial fibrillation (AF). The differences between ARB and ACEI in their effects on the primary prevention of AF remain unclear. This study compared ARB and ACEI in combined antihypertensive medications for reducing the risk of AF in patients with hypertension, and determined which was better for AF prevention in a nationwide cohort study.Patients aged ≥55 years and with a history of hypertension were identified from Taiwan National Health Insurance Research Database. Medical records of 25,075 patients were obtained, and included 6205 who used ARB, 8034 who used ACEI, and 10,836 nonusers (no ARB or ACEI) in their antihypertensive regimen. Cox regression models were applied to estimate the hazard ratio (HR) for new-onset AF.During an average of 7.7 years' follow-up, 1619 patients developed new-onset AF. Both ARB (adjusted HR: 0.51, 95% CI 0.44-0.58, P < 0.001) and ACEI (adjusted HR: 0.53, 95% CI 0.47-0.59, P < 0.001) reduced the risk of AF compared to nonusers. Subgroup analysis showed that ARB and ACEI were equally effective in preventing new-onset AF regardless of age, gender, the presence of heart failure, diabetes, and vascular disease, except for those with prior stroke or transient ischemic attack (TIA). ARB prevents new-onset AF better than ACEI in patients with a history of stroke or TIA (log-rank P = 0.012).Both ARB and ACEI reduce new-onset AF in patients with hypertension. ARB prevents AF better than ACEI in patients with a history of prior stroke or TIA. PMID:27196491

  4. Impact of Angiotensin Converting Enzyme Inhibitor versus Angiotensin Receptor Blocker on Incidence of New-Onset Diabetes Mellitus in Asians

    PubMed Central

    Park, Ji Young; Choi, Byoung Geol; Choi, Se Yeon; Choi, Jae Woong; Ryu, Sung Kee; Lee, Se Jin; Kim, Seunghwan; Noh, Yung-Kyun; Akkala, Raghavender Goud; Li, Hu; Ali, Jabar; Kim, Ji Bak; Lee, Sunki; Na, Jin Oh; Choi, Cheol Ung; Lim, Hong Euy; Kim, Jin Won; Kim, Eung Ju; Park, Chang Gyu; Seo, Hong Seog; Oh, Dong Joo

    2016-01-01

    Purpose Angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are associated with a decreased incidence of new-onset diabetes mellitus (NODM). The aim of this study was to compare the protective effect of ACEI versus ARBs on NODM in an Asian population. Materials and Methods We investigated a total of 2817 patients who did not have diabetes mellitus from January 2004 to September 2009. To adjust for potential confounders, a propensity score matched (PSM) analysis was performed using a logistic regression model. The primary end-point was the cumulative incidence of NODM, which was defined as having a fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5%. Multivariable cox-regression analysis was performed to determine the impact of ACEI versus ARB on the incidence of NODM. Results Mean follow-up duration was 1839±1019 days in all groups before baseline adjustment and 1864±1034 days in the PSM group. After PSM (C-statistics=0.731), a total 1024 patients (ACEI group, n=512 and ARB group, n=512) were enrolled for analysis and baseline characteristics were well balanced. After PSM, the cumulative incidence of NODM at 3 years was lower in the ACEI group than the ARB group (2.1% vs. 5.0%, p=0.012). In multivariate analysis, ACEI vs. ARB was an independent predictor of the lower incidence for NODM (odd ratio 0.37, confidence interval 0.17-0.79, p=0.010). Conclusion In the present study, compared with ARB, chronic ACEI administration appeared to be associated with a lower incidence of NODM in a series of Asian cardiovascular patients. PMID:26632399

  5. Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril

    PubMed Central

    Bönner, G; Bakris, G L; Sica, D; Weber, M A; White, W B; Perez, A; Cao, C; Handley, A; Kupfer, S

    2013-01-01

    Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150–180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1–2 hypertension with AZL-M was more effective than RAM and better tolerated. PMID:23514842

  6. Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and acute kidney injury in patients undergoing cardiac surgery

    PubMed Central

    Coca, Steven G.; Garg, Amit X.; Swaminathan, Madhav; Garwood, Susan; Hong, Kwangik; Thiessen-Philbrook, Heather; Passik, Cary; Koyner, Jay L.; Parikh, Chirag R.; Jai, Raman; Jeevanandam, Valluvan; Akhter, Shahab; Devarajan, Prasad; Bennett, Michael; Edelsteinm, Charles; Patel, Uptal; Chu, Michael; Goldbach, Martin; Guo, Lin Ruo; McKenzie, Neil; Myers, Mary Lee; Novick, Richard; Quantz, Mac; Zappitelli, Michael; Dewar, Michael; Darr, Umer; Hashim, Sabet; Elefteriades, John; Geirsson, Arnar

    2013-01-01

    Background Using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) the morning of surgery may lead to ‘functional’ postoperative acute kidney injury (AKI), measured by an abrupt increase in serum creatinine. Whether the same is true for ‘structural’ AKI, measured with new urinary biomarkers, is unknown. Methods The TRIBE-AKI study was a prospective cohort study of 1594 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2010. We classified the degree of exposure to ACEi/ARB into three categories: ‘none’ (no exposure prior to surgery), ‘held’ (on chronic ACEi/ARB but held on the morning of surgery) or ‘continued’ (on chronic ACEi/ARB and taken the morning of surgery). The co-primary outcomes were ‘functional’ AKI based upon changes in pre- to postoperative serum creatinine, and ‘structural AKI’, based upon peak postoperative levels of four urinary biomarkers of kidney injury. Results Across the three levels (none, held and continued) of ACEi/ARB exposure there was a graded increase in functional AKI, as defined by AKI stage 1 or worse; (31, 34 and 42%, P for trend 0.03) and by percentage change in serum creatinine from pre- to postoperative (25, 26 and 30%, P for trend 0.03). In contrast, there were no differences in structural AKI across the strata of ACEi/ARB exposure, as assessed by four structural AKI biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18 or liver-fatty acid-binding protein). Conclusions Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted. PMID:24081864

  7. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study

    PubMed Central

    Schrader, Harald; Stovner, Lars Jacob; Helde, Grethe; Sand, Trond; Bovim, Gunnar

    2001-01-01

    Objective To determine the efficacy of an angiotensin converting enzyme inhibitor in the prophylaxis of migraine. Design Double blind, placebo controlled, crossover study. Setting Neurological outpatient clinic. Participants Sixty patients aged 19-59 years with migraine with two to six episodes a month. Interventions Treatment period of 12 weeks with one 10 mg lisinopril tablet once daily for one week then two 10 mg lisinopril tablets once daily for 11 weeks, followed by a two week wash out period. Second treatment period of one placebo tablet once daily for one week and then two placebo tablets for 11 weeks. Thirty participants followed this schedule, and 30 received placebo followed by lisinopril. Main outcome measures Primary end points: number of hours with headache, number of days with headache, number of days with migraine. Secondary end points: headache severity index, use of drugs for symptomatic relief, quality of life and number of days taken as sick leave, acceptability of treatment. Results In the 47 participants with complete data, hours with headache, days with headache, days with migraine, and headache severity index were significantly reduced by 20% (95% confidence interval 5% to 36%), 17% (5% to 30%), 21% (9% to 34%), and 20% (3% to 37%), respectively, with lisinopril compared with placebo. Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and 17 patients for active treatment versus run-in period. Days with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. Intention to treat analysis of data from 55 patients supported the differences in favour of lisinopril for the primary end points. Conclusion The angiotensin converting enzyme inhibitor, lisinopril, has a clinically important prophylactic effect in migraine. PMID:11141144

  8. Local actions of angiotensin II: quantitative in vitro autoradiographic localization of angiotensin II receptor binding and angiotensin converting enzyme in target tissues

    SciTech Connect

    Chai, S.Y.; Allen, A.M.; Adam, W.R.; Mendelsohn, F.A.

    1986-01-01

    In order to gain insight into the local actions of angiotensin II (ANG II) we have determined the distribution of a component of the effector system for the peptide, the ANG II receptor, and that of an enzyme-catalysing ANG II formation, angiotensin converting enzyme (ACE), by in vitro autoradiography in several target tissues. The superagonist ANG II analog, /sup 125/I(Sar1)ANG II, or the antagonist analog, /sup 125/I(Sar1,Ile8)ANG II, were used as specific radioligands for ANG II receptors. A derivative of the specific ACE inhibitor, lysinopril, called /sup 125/I-351A, was used to label ACE in tissues. In the adrenal, a high density of ANG II receptors occurs in the glomerulosa zone of the cortex and in the medulla. ACE is also localized in these two zones, indicating that local production of ANG II may occur close to its sites of action in the zona glomerulosa and adrenal medulla. In the kidney, a high density of ANG II receptors is associated with glomeruli in the cortex and also with vasa recta bundles in the inner stripe of the outer medulla. ACE is found in very high concentration in deep proximal convoluted tubules of the cortex, while much lower concentrations of the enzyme occur in the vascular endothelium throughout the kidney. In the central nervous system three classes of relationships between ANG II receptors and ACE are observed: In the circumventricular organs, including the subfornical organ and organum vasculosum of the lamina terminalis, a high concentration of both components occurs. Since these structures have a deficient blood-brain barrier, local conversion of circulating angiotensin I (ANG I) to ANG II may contribute to the action of ANG II at these sites.

  9. Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization.

    PubMed

    Kondoh, Gen; Tojo, Hiromasa; Nakatani, Yuka; Komazawa, Nobuyasu; Murata, Chie; Yamagata, Kazuo; Maeda, Yusuke; Kinoshita, Taroh; Okabe, Masaru; Taguchi, Ryo; Takeda, Junji

    2005-02-01

    The angiotensin-converting enzyme (ACE) is a key regulator of blood pressure. It is known to cleave small peptides, such as angiotensin I and bradykinin and changes their biological activities, leading to upregulation of blood pressure. Here we describe a new activity for ACE: a glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACE inhibitor and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by high-performance liquid chromatography-mass spectrometry predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activity. PMID:15665832

  10. Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood

    PubMed Central

    de Picoli Souza, Kely; da Silva, Elton D.; Batista, Elice C.; Reis, Felipe C. G.; Silva, Sylvia M. A.; Castro, Charlles H. M.; Luz, Jaqueline; Pesquero, Jorge L.; dos Santos, Edson L.; Pesquero, João B.

    2015-01-01

    We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system (RAS) is expressed and functional in the white adipose tissue (WAT) and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass) or saline, starting at the first day of life until the age of 16 days. Between days ninetieth and hundred and eightieth, a group of these animals received high fat diet (HFD). Molecular, biochemical, histological, and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight, and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) gene expression in hypothalamus, fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) gene expression in retroperitoneal WAT, and decreases peroxixome proliferators-activated receptor (PPAR)γ, PPARα, uncoupling protein (UCP)2, and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood. PMID:25926796

  11. Angiotensin Converting Enzyme Inhibitor-related Angioedema: A Case of an Unexpected Death.

    PubMed

    Atalay, Eray; Özdemir, Mehmet Tamer; Çiğsar, Gülşen; Omurca, Ferhat; Aslan, Nurullah; Yildiz, Mehmet; Gey, Zehra Bahar

    2015-11-01

    Angioedema is an asymmetric non-pitting oedema on face, lips, tongue and mucous membranes; any delay in diagnosis and treatment can be fatal. Treatment with lisinopril as an angiotensin converting enzyme (ACE) inhibitor, can be a reason of angioedema. Here we report a case who developed oral-facial edema four years after using lisinopril/hydrochlorothiazide. Laryngeal oedema is a main cause of death in angioedema. The treatment of choice in angioedema including fresh frozen plasma, C1 inhibitor concentrations and BRK-2 antagonists (bradykinin B2 receptor antagonists) were used. In this case; a 77 years old female patient suffering from hypertension was considered. This patient was suffering two days from swelling on her face and neck. Non- allergic angioedema was distinguished in five major forms; acquired (AAO), hereditary (HAE), renin-angiotensin-aldosterone system (RAAS) blocker-dependent, pseudoallergic angioedema (PAS) and an idiopathic angioedema (IAO). She was admitted to our clinic with the diagnosis of hereditary angioedema. Patient had skin edema and life threatening laryngeal edema. In emergency department treatment was started using intravenous methylprednisolone, diphenydramine as well as inhaled and subcutaneous epinephrine simultaneously. Despite the initial treatment, the patient died due to the insufficient respiration and cardiac arrest. The patient has no history of kidney disease. PMID:26725563

  12. Anti-hypertensive Effects of Diminazene Aceturate: An Angiotensin- Converting Enzyme 2 Activator in Rats.

    PubMed

    De Maria, Marilda L A; Araújo, Liliane D; Fraga-Silva, Rodrigo A; Pereira, Letícia A S; Ribeiro, Heder J; Menezes, Gustavo B; Shenoy, Vinayak; Raizada, Mohan K; Ferreira, Anderson J

    2016-01-01

    Previous studies have shown that activation of endogenous angiotensin-converting enzyme 2 (ACE2) results in various beneficial effects in the cardiovascular system. Recently, a new ACE2 activator, named diminazene aceturate (DIZE), was described. Here, we evaluated the actions of this compound in blood pressure (BP) and heart rate (HR) of conscious normotensive and hypertensive rats, as well as explored its mechanism of actions using isolated vessels. The renovascular model of hypertension was utilized. The participation of the Angiotensin-(1-7) receptor Mas and nitric oxide (NO) in the effects of DIZE was evaluated using A-779 and L-NAME, respectively. It was observed that DIZE caused a marked decrease in BP with a compensatory increase in HR in nornotensive rats. Accordingly, a significant reduction in the blood flow of the mesenteric bed was evidenced using intravital microscopy. Moreover, in rats with renovascular hypertension, DIZE caused a decrease in BP similar to the hypotensive effect induced by captopril. Importantly, this compound also prevented the development of cardiac hypertrophy induced by hypertension. The isolated vessels technique revealed that the vasodilator effects of DIZE were dependent on Mas activation and NO release. Thus, our findings demonstrated that DIZE reduces the BP of normotensinve and hypertensive rats possibly by a mechanism involving Mas and NO. PMID:26458404

  13. Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study

    PubMed Central

    Firouzabadi, Negar; Erfani, Nasrallah; Fathi, Farshid; Bazrafkan, Mozhdeh; Bahramali, Ehsan

    2016-01-01

    Background Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. Methods Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR–restriction fragment length polymorphism (PCR–RFLP) methods. Results There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64–5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37–3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26–2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008). Conclusion Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism. PMID:27082637

  14. Effect of the Angiotensin I Converting Enzyme Inhibitor, MK-421, on Experimentally Induced Drinking

    NASA Technical Reports Server (NTRS)

    Fregley, Melvin J.; Fater, Dennis C.; Greenleaf, John E.

    1982-01-01

    MK-421, the ethyl ester maleate salt of N-(S)-1-(ethoxycarbonyl)-3-phenyl-propyl- Ala-L-Pro, is an angiotensin I converting enzyme inhibitor. An initial objective was to determine whether MK-421, administered at 0, 2.5, 5.0, 10.0, 20.0 and 40.0 mg/kg, ip to 96 female rats 15 min prior to administration of the beta-adrenergic agonist, isoproterenol (25 microgram/kg, ip), would inhibit the drinking induced by isoproterenol during 2 h after its administration. The water intake induced by isoproterenol was inhibited significantly by 2.5 mg MK-421/kg. When a similar experiment was performed using Angiotensin I (AI) (200 microgram/kg, ip) as the dipsogenic agent, MK-421 (5 mg/kg, ip), administered 15 min prior to AI, inhibited significantly both the dipsogenic and the diuretic effect of AI. However, administration of angiotensin II (AII, 200 microgram/kg, ip) 15 min after MK-421 (5mg/kg) was accompanied by a water intake that did not differ from AII alone. The drink induced by ip administration of 1.0 m NaCl solution (1% of body wt, ip) was not inhibited by administration of MK-421 (5 mg/kg) 15 min prior to allowing access to water while the drink induced by a 24 h dehydration was partially inhibited. Thus, the drinks induced by administraition of either isoproterenol or AI are dependent on formation of AII. That induced by dehydration is partially dependent, while that induced by hypertonic siilinc is independent of the formation of AII.

  15. Effect of zinc concentration on the activity of angiotensin converting enzyme in human plasma and serum

    SciTech Connect

    Reeves, P.G.; Carl, G.F.; Smith, D.K.; O'Dell, B.L.

    1986-03-05

    The activity of angiotensin converting enzyme is measured clinically to assist in the diagnosis of sarcoidosis and to monitor therapy with steroids, and with antihypertensive drugs that inhibit the enzyme. Even though it has been known for some time that ACE is a zinc dependent enzyme, it was discovered only recently that zinc, in addition to endogenous levels in the assay mixture, is required for maximal activity of rat serum ACE. The present experiment was designed to determine if additional zinc is required for maximal activation of ACE in plasma and serum of human subjects. Plasma or serum samples were incubated at 37/sup 0/ in a zinc-free medium, pH 7.4, containing hippurylglyclglycine as the substrate. The addition of 20 ..mu..M zinc significantly increased ACE activity in plasma (95.4 +/- 11.9 vs 192.8 +/- 24.3 U/L) and in serum (89.9 +/- 5.6 vs 195.7 +/- 9.3 U/L) compared to samples without added zinc. Enzyme activity was increased 2.4-fold when zinc was added to plasma from a patient with low plasma zinc. These data suggest that the endogenous level of zinc in the assay mixture resulting from the addition of an aliquot of plasma or serum is insufficient to obtain maximal activity of ACE. The addition of zinc to zinc deficient plasma increased ACE activity even more.

  16. Evaluating molecular mechanism of hypotensive peptides interactions with renin and angiotensin converting enzyme.

    PubMed

    He, Rong; Aluko, Rotimi E; Ju, Xing-Rong

    2014-01-01

    Our previous study showed that three rapeseed protein-derived peptides (TF, LY and RALP) inhibited the in vitro activities of angiotensin converting enzyme (ACE) and renin. Oral administration of these peptides to spontaneously hypertensive rats led to reductions in systolic blood pressure. In the present work, we examined the potential molecular mechanisms responsible for the ACE- and renin-inhibitory activities of these peptides. Enzyme inhibition kinetics showed competitive, non-competitive and mixed-type peptide-dependent inhibition of renin and ACE activities. Intrinsic fluorescence intensity data showed that LY and RALP have stronger binding effects on ACE molecule compared to that of TF. LY and RALP showed the highest inhibition of ACE and renin activities, respectively. Circular dichroism data showed that the inhibitory mechanism involved extensive peptide-dependent reductions in α-helix and β-sheet fractions of ACE and renin protein conformations. Molecular docking studies confirmed that the higher renin-inhibitory activity of RALP may be due to formation of several hydrogen bonds (H-bonds) with the enzyme's active site residues. The rapeseed peptides inhibited renin and ACE activities mostly through binding to enzyme active site or non-active sites and forming extensive H-bonds that distorted the normal configuration required for catalysis. Data presented from this work could enhance development of highly potent antihypertensive natural peptides or peptidomimetics. PMID:24603692

  17. Endocrinological control and cellular localization of rat testicular angiotensin-converting enzyme (EC 3. 4. 15. 1)

    SciTech Connect

    Velletri, P.A.; Aquilano, D.R.; Bruckwick, E.; Tsai-Morris, C.H.; Dufau, M.L.; Lovenberg, W.

    1985-06-01

    Hypophysectomy of prepubescent (3-week-old) rats prevented the pubertal development of testicular, but not pulmonary, angiotensin-converting enzyme (EC 3.4.15.1). Additionally, hypophysectomy resulted in a loss of testicular converting enzyme activity in 10-week-old rats that had achieved puberty and had developed enzyme activity. Hormone regimens consisting of FSH/LH (7.5 U/rat X day), hCG (10 U/rat X day), or testosterone (1 mg/rat X day) were employed to ascertain their ability to maintain activity in hypophysectomized rats. All three of the above hormone regimens, if initiated on the first day after hypophysectomy of 10-week-old rats, were capable of maintaining testicular converting enzyme activity. Centrifugal elutriation of dispersed testicular cells indicated that the majority of enzyme activity in mature rats was associated with the germinal cells, a result consistent with the data accumulated from the hormonal studies. Lastly, (/sup 3/H)captopril bound specifically to cellular fractions enriched in germinal cells. The above studies suggest that the pituitary gland is required for the development and maintenance of testicular angiotensin-converting enzyme in the rat by stimulating steroidogenesis in the testes. Furthermore, the sensitivity of converting enzyme activity to androgen coupled with the centrifugal elutriation and (/sup 3/H) captopril binding studies strongly support the notion that testicular converting enzyme is associated with germinal cells.

  18. Angiotensin converting enzyme in the brain, testis, epididymis, pituitary gland and adrenal gland

    SciTech Connect

    Strittmatter, S.M.

    1986-01-01

    (/sup 3/H)Captopril binds to angiotensin converting enzyme (ACE) in rat tissue homogenates. The pharmacology, regional distribution and copurification of (/sup 3/H)captopril binding with enzymatic activity demonstrate the selectivity of (/sup 3/H)captopril labeling of ACE. (/sup 3/H)Captopril binding to purified ACE reveals differences in cationic dependence and anionic regulation between substrate catalysis and inhibitor recognition. (/sup 3/H)Captopril association with ACE is entropically driven. The selectivity of (/sup 3/H)captopril binding permits autoradiographic localization of the ACE in the brain, male reproductive system, pituitary gland and adrenal gland. In the brain, ACE is visualized in a striatonigral neuronal pathway which develops between 1 and 7 d after birth. In the male reproductive system, (/sup 3/H)captopril associated silver grains are found over spermatid heads and in the lumen of seminiferous tubules in stages I-VIII and XII-XIV. In the pituitary gland, ACE is localized to the posterior lobe and patches of the anterior lobe. The adrenal medulla contains moderate ACE levels while low levels are found in the adrenal cortex. Adrenal medullary ACE is increased after hypophysectomy and after reserpine treatment. The general of ligand binding techniques for the study of enzymes is demonstrated by the specific labeling of another enzyme, enkephaline convertase, in crude tissue homogenates by the inhibitor (/sup 3/H)GEMSA.

  19. A continuous fluorescence resonance energy transfer angiotensin I-converting enzyme assay.

    PubMed

    Carmona, Adriana K; Schwager, Sylva L; Juliano, Maria A; Juliano, Luiz; Sturrock, Edward D

    2006-01-01

    Angiotensin I-converting enzyme (ACE) is involved in various physiological and physiopathological conditions; therefore, the measurement of its catalytic activity may provide essential clinical information. This protocol describes a sensitive and rapid procedure for determination of ACE activity using fluorescence resonance energy transfer (FRET) substrates containing o-aminobenzoic acid (Abz) as the fluorescent group and 2,4-dinitrophenyl (Dnp) as the quencher acceptor. Hydrolysis of a peptide bond between the donor/acceptor pair generates fluorescence that can be detected continuously, allowing quantitative measurement of the enzyme activity. The FRET substrates provide a useful tool for kinetic studies and for ACE determination in biological fluids and crude tissue extracts. An important benefit of this method is the use of substrates selective for the two active sites of the enzyme, namely Abz-SDK(Dnp)P-OH for N-domain, Abz-LFK(Dnp)-OH for C-domain and Abz-FRK(Dnp)P-OH for somatic ACE. This methodology can be adapted for determinations using a 96-well fluorescence plate reader. PMID:17487185

  20. Studies on Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Genotype Distributions in Turkish Preeclampsia Patients

    PubMed Central

    Bereketoğlu, Ceyhun; Kasap, Mülkiye; Pazarbaşı, Ayfer

    2012-01-01

    Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)'s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism (D allele) has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls (P = 0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P = 0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P = 0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls. PMID:22545216

  1. Effects of Angiotensin Converting Enzyme Inhibition or Angiotensin Receptor Blockade in Dialysis Patients: A Nationwide Data Survey and Propensity Analysis

    PubMed Central

    Wu, Cho-Kai; Yang, Yao-Hsu; Juang, Jyh-Ming Jimmy; Wang, Yi-Chih; Tsai, Chia-Ti; Lai, Ling-Ping; Hwang, Juey-Jen; Chiang, Fu-Tien; Chen, Pau-Chung; Lin, Jiunn-Lee; Lin, Lian-Yu

    2015-01-01

    Abstract Long-term benefit of using a renin–angiotensin–aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients already receiving dialysis remains undetermined. The aim of this study is to assess the efficacy and safety of ACEI or ARB use in dialysis patients. We performed a population-based cohort study with time-to-event analyses to estimate the relation between the use of ACEI/ARB and their outcomes. We used a nationwide database (Registry for Catastrophic Illnesses) for Taiwan, which has data from 1995 to 2008 nearly of all patients who received dialysis therapy. The records of all dialysis patients aged ≥18 with no evidence of cardiovascular (CV) events in 1997 and 1998 (133,564 patients) were examined. Users (n = 50,961) and nonusers (n = 59,913) of an ACEI/ARB were derived. We then used propensity score matching and Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) for all-cause mortality and CV events in users and nonusers of an ACRI/ARB. The 15,182 patients, who used an ACEI/ARB, and the 15,182 nonusers had comparable baseline characteristics during the 14 years of follow-up. The mortality was significantly greater in patients who did not use an ACEI/ARB (HR = 0.90, 95% confidence interval = 0.86–0.93). Subgroup analysis of 3 tertiles of patients who used different total amounts of ACEI/ARB during the study period indicated that CV events were more common in patients who used an ACEI/ARB for a short duration (tertile 1: HR = 1.63), but less common in those who used an ACEI/ARB for long durations (tertile 2: HR = 1.05; tertile 3: HR = 0.94; trend for declining HR from tertile 1 to 3: P < 0.001). The mortality benefit provided by use of an ACEI/ARB was consistent across most patient subgroups, as was the benefit of ARB monotherapy rather than ACEI monotherapy. Independent of traditional risk factors

  2. Abalone Protein Hydrolysates: Preparation, Angiotensin I Converting Enzyme Inhibition and Cellular Antioxidant Activity

    PubMed Central

    Park, Soo Yeon; Je, Jae-Young; Hwang, Joung-Youl; Ahn, Chang-Bum

    2015-01-01

    Abalone protein was hydrolyzed by enzymatic hydrolysis and the optimal enzyme/substrate (E/S) ratios were determined. Abalone protein hydrolysates (APH) produced by Protamex at E/S ratio of 1:100 showed angiotensin I converting enzyme inhibitory activity with IC50 of 0.46 mg/mL, and APH obtained by Flavourzyme at E/S ratio of 1:100 possessed the oxygen radical absorbance capacity value of 457.6 μM trolox equivalent/mg sample. Flavourzyme abalone protein hydrolysates (FAPH) also exhibited H2O2 scavenging activity with IC50 of 0.48 mg/mL and Fe2+ chelating activity with IC50 of 2.26 mg/mL as well as high reducing power. FAPH significantly (P<0.05) protected H2O2-induced hepatic cell damage in cultured hepatocytes, and the cell viability was restored to 90.27% in the presence of FAPH. FAPH exhibited 46.20% intracellular ROS scavenging activity and 57.89% lipid peroxidation inhibition activity in cultured hepatocytes. Overall, APH may be useful as an ingredient for functional foods. PMID:26451354

  3. Serum activity of angiotensin converting enzyme 2 is decreased in patients with acute ischemic stroke.

    PubMed

    Bennion, Douglas M; Rosado, Christian A; Haltigan, Emily A; Regenhardt, Robert W; Sumners, Colin; Waters, Michael F

    2016-07-01

    Levels of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, are dynamically altered after stroke in preclinical models. We sought to characterize the previously unexplored changes in serum ACE2 activity of stroke patients and the mechanism of these changes. Serum samples were obtained from patients during acute ischemic stroke (n=39), conditions mimicking stroke (stroke-alert, n=23), or from control participants (n=20). Enzyme activity levels were analyzed by fluorometric assay and correlated with clinical variables by regression analyses. Serum ACE2 activity was significantly lower in acute ischemic stroke as compared to both control and stroke-alert patients, followed by an increase to control levels at three days. Serum ACE2 activity significantly correlated with the presence of ischemic stroke after controlling for other factors (P=0.01). Additional associations with ACE2 activity included a positive correlation with systolic blood pressure at presentation in stroke-alert (R(2)=0.24, P=0.03), while stroke levels showed no correlation (R(2)=0.01, P=0.50). ACE2 sheddase activity was unchanged between groups. These dynamic changes in serum ACE2 activity in stroke, which concur with preclinical studies, are not likely to be driven primarily by acute changes in blood pressure or sheddase activity. These findings provide new insight for developing therapies targeting this protective system in ischemic stroke. PMID:27488276

  4. Angiotensin I-Converting Enzyme Inhibitory Peptides of Chia (Salvia hispanica) Produced by Enzymatic Hydrolysis

    PubMed Central

    Segura Campos, Maira Rubi; Peralta González, Fanny; Chel Guerrero, Luis

    2013-01-01

    Synthetic angiotensin I-converting enzyme (ACE-I) inhibitors can have undesirable side effects, while natural inhibitors have no side effects and are potential nutraceuticals. A protein-rich fraction from chia (Salvia hispanica L.) seed was hydrolyzed with an Alcalase-Flavourzyme sequential system and the hydrolysate ultrafiltered through four molecular weight cut-off membranes (1 kDa, 3 kDa, 5 kDa, and 10 kDa). ACE-I inhibitory activity was quantified in the hydrolysate and ultrafiltered fractions. The hydrolysate was extensive (DH = 51.64%) and had 58.46% ACE-inhibitory activity. Inhibition ranged from 53.84% to 69.31% in the five ultrafiltered fractions and was highest in the <1 kDa fraction (69.31%). This fraction's amino acid composition was identified and then it was purified by gel filtration chromatography and ACE-I inhibition measured in the purified fractions. Amino acid composition suggested that hydrophobic residues contributed substantially to chia peptide ACE-I inhibitory strength, probably by blocking angiotensin II production. Inhibitory activity ranged from 48.41% to 62.58% in the purified fractions, but fraction F1 (1.5–2.5 kDa) exhibited the highest inhibition (IC50 = 3.97 μg/mL; 427–455 mL elution volume). The results point out the possibility of obtaining bioactive peptides from chia proteins by means of a controlled protein hydrolysis using Alcalase-Flavourzyme sequentional system. PMID:26904588

  5. Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese.

    PubMed

    Niu, Wenquan; Qi, Yue; Hou, Shuqin; Zhou, Wenyu; Qiu, Changchun

    2007-12-01

    Experimental evidence indicates that angiotensin-converting enzyme 2 (ACE2), a homologue of human ACE, might negatively regulate the activated renin-angiotensin-aldosterone system (RAAS) and might function as a protective regulator in the pathogenesis of hypertension. However, association studies regarding ACE2 are sparse in the literature, with negative results in the majority of cases. Here we conducted an association study between 2 intronic polymorphisms (A1075G and G8790A) of the ACE2 gene and stage 2 hypertension in Han Chinese. We genotyped the 2 polymorphisms in 1494 subjects (808 stage 2 hypertensives and 686 normotensives) recruited from the Fangshan district (Beijing). Data were analyzed using chi(2) test, 1-way analysis of variance, and logistic regression where appropriate. The frequency of A1075G allele distribution in males differed significantly (P < 0.0001), whereas the genotype and allele distributions of G8790A polymorphism were similar, between stage 2 hypertensives and normotensives. Systolic blood pressure (SBP) differed significantly in females across both genotypes: SBP was significantly lower in subjects with the 1075AA and 8790GG genotypes, higher in the 1075GG (+13.65 mm Hg versus AA) and 8790AA (+13.36 mm Hg versus GG) genotypes, and intermediate in the 1075AG (+5.76 mm Hg versus AA) and 8790GA (+5.65 mm Hg versus GG) genotypes. Our data suggest that the polymorphism (A1075G) might be a risk factor-at least a marker-for stage 2 hypertension in males and that the 2 studied polymorphisms might be the indicators of systolic hypertension in females. PMID:18022600

  6. Inhibitors of angiotensin-converting enzyme modulate mitosis and gene expression in pancreatic cancer cells

    SciTech Connect

    Reddy, M.K.; Baskaran, K.; Molteni, A.

    1995-12-01

    The angiotensin-converting enzyme (ACE) inhibitor captopril inhibits mitosis in several cell types that contain ACE and renin activity. In the present study, we evaluated the effect of the ACE inhibitors captopril and CGS 13945 (10{sup {minus}8} to 10{sup {minus}2}M) on proliferation and gene expression in hamster pancreatic duct carcinoma cells in culture. These cells lack renin and ACE activity. Both ACE inhibitors produced a dose-dependent reduction in tumor cell proliferation within 24 hr. Captopril at a concentration of 0.36 mM and CGS 13945 at 150 {mu}M decreased cellular growth rate to approximately half that of the control. Neither drug influenced the viability or the cell cycle distribution of the tumor cells. Slot blot analysis of mRNA for four genes, proliferation associated cell nuclear antigen (PCNA), K-ras, protein kinase C-{Beta} (PKC-{Beta}) and carbonic anhydrase II (CA II) was performed. Both ACE inhibitors increased K-ras expression by a factor of 2, and had no effect on CA II mRNA levels. Captopril also lowered PCNA by 40% and CGS 13945 lowered PKC-{Beta} gene expression to 30% of the control level. The data demonstrate that ACE inhibitors exhibit antimitotic activity and differential gene modulation in hamster pancreatic duct carcinoma cells. The absence of renin and ACE activity in these cells suggests that the antimitotic action of captopril and CGS 13945 is independent of renin-angiotensin regulation. The growth inhibition may occur through downregulation of growth-related gene expression. 27 refs., 5 figs.

  7. Angiotensin I-Converting Enzyme Inhibitory Peptides of Chia (Salvia hispanica) Produced by Enzymatic Hydrolysis.

    PubMed

    Segura Campos, Maira Rubi; Peralta González, Fanny; Chel Guerrero, Luis; Betancur Ancona, David

    2013-01-01

    Synthetic angiotensin I-converting enzyme (ACE-I) inhibitors can have undesirable side effects, while natural inhibitors have no side effects and are potential nutraceuticals. A protein-rich fraction from chia (Salvia hispanica L.) seed was hydrolyzed with an Alcalase-Flavourzyme sequential system and the hydrolysate ultrafiltered through four molecular weight cut-off membranes (1 kDa, 3 kDa, 5 kDa, and 10 kDa). ACE-I inhibitory activity was quantified in the hydrolysate and ultrafiltered fractions. The hydrolysate was extensive (DH = 51.64%) and had 58.46% ACE-inhibitory activity. Inhibition ranged from 53.84% to 69.31% in the five ultrafiltered fractions and was highest in the <1 kDa fraction (69.31%). This fraction's amino acid composition was identified and then it was purified by gel filtration chromatography and ACE-I inhibition measured in the purified fractions. Amino acid composition suggested that hydrophobic residues contributed substantially to chia peptide ACE-I inhibitory strength, probably by blocking angiotensin II production. Inhibitory activity ranged from 48.41% to 62.58% in the purified fractions, but fraction F1 (1.5-2.5 kDa) exhibited the highest inhibition (IC50 = 3.97 μg/mL; 427-455 mL elution volume). The results point out the possibility of obtaining bioactive peptides from chia proteins by means of a controlled protein hydrolysis using Alcalase-Flavourzyme sequentional system. PMID:26904588

  8. Angiotensin converting enzyme inhibition in chronic stable angina: effects on myocardial ischaemia and comparison with nifedipine.

    PubMed Central

    Ikram, H.; Low, C. J.; Shirlaw, T. M.; Foy, S. G.; Crozier, I. G.; Richards, A. M.; Khurmi, N. S.; Horsburgh, R. J.

    1994-01-01

    OBJECTIVES--To determine the anti-ischaemic effects of a new angiotensin converting enzyme inhibitor, benazepril, compared with nifedipine, alone and in combination, in chronic stable angina caused by coronary artery disease. DESIGN--Placebo controlled, double blind, latin square design. SETTING--Regional cardiology service for a mixed urban and rural population. SUBJECTS--40 patients with stable exertional angina producing at least 1 mm ST segment depression on exercise test with the Bruce protocol. 34 patients completed all four phases of the trial. INTERVENTIONS--Each patient was treated with placebo, benazepril (10 mg twice daily), nifedipine retard (20 mg twice daily), and a combination of benazepril and nifedipine in the same doses, in random order for periods of two weeks. MAIN OUTCOME MEASURES AND RESULTS--Total duration of exercise was not increased by any treatment. Exercise time to the development of 1 mm ST segment depression was not significantly changed with benazepril alone or in combination with nifedipine but was increased with nifedipine from 4.18 (1.8) min to 4.99 (1.6) min (95% confidence interval (95% CI) 0.28 to 1.34; p < 0.05). There was a significant relation between increase in duration of exercise and resting renin concentration (r = 0.498; p < 0.01). Myocardial ischaemia during daily activity, as assessed by ambulatory electrocardiographic monitoring, was reduced by benazepril and by the benazepril and nifedipine combination. This was significant for total ischaemic burden (451(628) min v 231(408) min; 95% CI -398 to -41 min; p < 0.05) and maximal depth of ST segment depression (-2.47(1.2) mm v -2.16 mm; 95% CI 0.04 to 0.57; p < 0.05) for the combination and for maximal ST segment depth for benazepril monotherapy (-2.47 (1.2) mm v -1.96(1.2) mm; 95% CI 0.18 to 0.91; p < 0.05). Benazepril significantly altered the circadian rhythm of cardiac ischaemia, abolishing the peak ischaemic periods at 0700 to 1200 and 1700 to 2300 (p < 0

  9. Irreversible tubulointerstitial damage associated with chronic aminonucleoside nephrosis. Amelioration by angiotensin I converting enzyme inhibition.

    PubMed Central

    Diamond, J. R.; Anderson, S.

    1990-01-01

    Chronic aminonucleoside nephrosis is variably associated with tubulointerstitial damage, depending on the route and frequency of drug administration. Recently, different groups have shown this injurious tubulointerstitial process to be reversible, coinciding with the resolution of heavy proteinuria to normal values. The authors have previously shown that a single jugular intravenous administration of puromycin aminonucleoside (PA) to male Munich-Wistar rats produces a triphasic pattern of glomerular injury and proteinuria, which culminates in focal glomerulosclerosis 70 weeks after drug administration. The authors now report the later progression of the tubulointerstitial morphologic abnormalities associated with acute nephrosis (phase I), despite spontaneous resolution of glomerular injury during the intermediate period (phase II) in this model. Although treatment of rats with the angiotensin I converting enzyme inhibitor enalapril (50 mg/l drinking water) over the 70-week period did not affect the magnitude of proteinuria during the acute nephrotic phase, enalapril prevented the recurrence of proteinuria (phase III), as well as significantly reducing the severity of interstitial fibrosis, extent of tubular dilatation, and number of intratubular casts on semiquantitative scoring at the conclusion of the study. In addition, enalapril-treated rats had less low-molecular-weight protein excretion during the recurrent phase of proteinuria, suggesting a preservation of tubular functional capacity to reabsorb these proteins. In vitro cytotoxicity studies showed only the glomerular visceral epithelial cell to be sensitive to PA, in contrast with rat tubular epithelium and other cellular controls. Although the exact pathogenetic mechanism responsible for the development of the tubulointerstitial damage remains unknown, PA in vitro does not adversely affect rat tubular epithelium; there is however a clear correlation between the magnitude of recurrent proteinuria and the

  10. Angioedema in the emergency department: the impact of angiotensin-converting enzyme inhibitors.

    PubMed

    Pigman, E C; Scott, J L

    1993-07-01

    Angiotensin-converting enzyme (ACE) inhibitors have been reported to cause angioedema. The purpose of this study was to establish what proportion of patients who present to the emergency department (ED) with angioedema were concomitantly taking any of the ACE inhibitors and to show how this group differed in presentation and response to treatment from the larger population of patients with non-ACE inhibitor-related angioedema. An 8-year retrospective chart review of all patients with the diagnosis of angioedema observed from January 1, 1984 to December 31, 1991 was undertaken in the ED of an urban teaching hospital. Forty-nine patients ranging from 12 to 88 years of age with symptoms and physical examination that was consistent with the diagnosis of angioedema were entered onto the study. Twelve cases of ACE inhibitor-related angioedema were identified, all occurring in the last 4 years of the review, and when compared with the non-ACE inhibitor-related group were older (mean age, 63.3 vs 43.0 years), had less of an allergic history (0% vs 49%; P = .013), but demonstrated the same severity of symptoms and response to medical therapy. No case required an artificial or surgical airway. ACE inhibitor related angioedema is becoming a common type of angioedema observed in this ED. These patients are older and free of other allergic disease and respond well to traditional therapy. PMID:8216515

  11. CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors.

    PubMed

    Wang, X; Wang, G; Shi, J; Aa, J; Comas, R; Liang, Y; Zhu, H-J

    2016-06-01

    The aim of the study was to determine the effect of carboxylesterase 1 (CES1) genetic variation on the activation of angiotensin-converting enzyme inhibitor (ACEI) prodrugs. In vitro incubation study of human liver, intestine and kidney s9 fractions demonstrated that the ACEI prodrugs enalapril, ramipril, perindopril, moexipril and fosinopril are selectively activated by CES1 in the liver. The impact of CES1/CES1VAR and CES1P1/CES1P1VAR genotypes and diplotypes on CES1 expression and activity on enalapril activation was investigated in 102 normal human liver samples. Neither the genotypes nor the diplotypes affected hepatic CES1 expression and activity. Moreover, among several CES1 nonsynonymous variants studied in transfected cell lines, the G143E (rs71647871) was a loss-of-function variant for the activation of all ACEIs tested. The CES1 activity on enalapril activation in human livers with the 143G/E genotype was approximately one-third of that carrying the 143G/G. Thus, some functional CES1 genetic variants (for example, G143E) may impair ACEI activation, and consequently affect therapeutic outcomes of ACEI prodrugs. PMID:26076923

  12. Angiotensin I-converting enzyme inhibitor derived from cross-linked oyster protein.

    PubMed

    Xie, Cheng-Liang; Kim, Jin-Soo; Ha, Jong-Myung; Choung, Se-Young; Choi, Yeung-Joon

    2014-01-01

    Following cross-linking by microbial transglutaminase, modified oyster proteins were hydrolyzed to improve inhibitory activity against angiotensin-converting enzyme (ACE) inhibitory activity with the use of a single protease, or a combination of six proteases. The oyster hydrolysate with the lowest 50% ACE inhibitory concentration (IC50) of 0.40 mg/mL was obtained by two-step hydrolysis of the cross-linked oyster protein using Protamex and Neutrase. Five ACE inhibitory peptides were purified from the oyster hydrolysate using a multistep chromatographic procedure comprised of ion-exchange, size exclusion, and reversed-phase liquid chromatography. Their sequences were identified as TAY, VK, KY, FYN, and YA, using automated Edman degradation and mass spectrometry. These peptides were synthesized, and their IC50 values were measured to be 16.7, 29.0, 51.5, 68.2, and 93.9 μM, respectively. Toxicity of the peptides on the HepG2 cell line was not detected. The oyster hydrolysate also significantly decreased the systolic blood pressure of spontaneously hypertensive rats (SHR). The antihypertensive effect of the oyster hydrolysate on SHR was rapid and long-lasting, compared to commercially obtained sardine hydrolysate. These results suggest that the oyster hydrolysate could be a source of effective nutraceuticals against hypertension. PMID:25140307

  13. Assessing the teratogenic potential of angiotensin-converting enzyme inhibitors in pregnancy.

    PubMed

    Burrows, R F; Burrows, E A

    1998-08-01

    To assess the teratogenic potential of angiotensin-converting enzyme (ACE) inhibitors, we report on 20 prospective pregnancies and 85 identified from articles in the literature. The anomaly rate was 20.6% in small series <10 entrants (95% CI 8.7-37.9%) and 1.4% in larger series > or =10 entrants (95% CI 0.03-7.3%) p=0.0016. The most consistent anomaly seen, skull hypoplasia, along with renal dysfunction appear to be more related to prolonged or late pregnancy exposure than to first trimester exposure. There is little supportive evidence that ACE inhibitors (captopril or enalapril) are teratogenic. There seems to be no absolute reason to discontinue these 2 medications prior to pregnancy, nor to create anxiety when a patient is identified with the combination of early pregnancy and treatment with these medications. There appears to be reason to discontinue the medication in pregnancy but the adverse event rate cannot be assessed because of inadequate prospective information. PMID:9761159

  14. Diagnostic use of angiotensin converting enzyme inhibitors in radioisotope evaluation of unilateral renal artery stenosis

    SciTech Connect

    Kremer Hovinga, T.K.; de Jong, P.E.; Piers, D.A.; Beekhuis, H.; van der Hem, G.K.; de Zeeuw, D.

    1989-05-01

    Iodine-123 hippurate renography, (/sup 99m/Tc)diethylenetriaminepentaacetic acid (DTPA) renography, and (/sup 99m/Tc)dimercapto succinic acid (DMSA) renal scintigraphy were performed before and during angiotensin converting enzyme (ACE) inhibition in a group of 15 hypertensive patients with angiographically ''significant'' unilateral renal artery stenosis. Visual and quantitative evaluation of the three radioisotope methods before ACE inhibition already disclosed abnormalities suggestive of renal artery stenosis in a high percentage (87%, 60%, and 60%, respectively) in this group of patients, but ACE inhibition further improved the diagnostic yield in all three methods (93%, 86%, and 80%). Iodine-123 hippurate renography was at least as useful as (/sup 99m/Tc)DTPA renography in this respect, while (/sup 99m/Tc)DMSA scintigraphy can be used particularly in segmental stenosis. Despite a large drop in blood pressure after ACE inhibition little adverse reactions were seen and overall renal function was fairly well maintained, the exceptions noted in patients with initially a more impaired renal function.

  15. [A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

    PubMed

    Nakamura, Rintaro; Nihei, Shun-Ichi; Arai, Hideaki; Nagata, Keiji; Isa, Yasuki; Harayama, Nobuya; Aibara, Keiji; Kamochi, Msayuki

    2016-03-01

    Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment. PMID:26972946

  16. Lung is the target organ for a monoclonal antibody to angiotensin-converting enzyme

    SciTech Connect

    Danilov, S.M.; Muzykantov, V.R.; Martynov, A.V.; Atochina, E.N.; Sakharov, I.Yu.; Trakht, I.N.; Smirnov, V.N. )

    1991-01-01

    125I-labeled mouse monoclonal antibody (MoAb) to human angiotensin-converting enzyme (ACE), termed 9B9 and cross-reacting with rat and monkey ACE, when injected into the circulation, accumulates in the lung in up to 10 to 20 greater concentrations than in other organs and blood. That 111In-labeled MoAb 9B9 also accumulates in the lungs of both rats and monkeys very selectively, was clearly revealed by gamma-scintigraphy. Unlike polyclonal anti-ACE antibodies that induce an immunodependent lethal reaction when administered intravenously, MoAb 9B9 was well tolerated by rats even at very high doses (up to 300 mg/kg/body weight). At the same time, the administration of this antibody (which does not inhibit the catalytic activity of ACE) resulted in both a 3-fold decrease of the lung ACE activity and an increase in the activity of serum ACE. The highly organ-specific, nondamaging accumulation of the MoAb 9B9 makes it a promising vector for targeted drug delivery to the lung, for modeling of lung pathology, and for gamma-scintigraphic visualization of the lung vascular bed. We also suggest that MoAb 9B9 accumulation in the lung may serve as a highly sensitive marker of lung vessel damage upon various lung pathology.

  17. [Preplacentation pregnancy loss in cases of angiotensin-converting enzyme insertion/deletion polymorphism].

    PubMed

    Ivanov, P; Konova, E; Komsa-Penkova, R; Kovacheva, K; Nikolov, N; Simeonova, M; Tanchev, St

    2014-01-01

    The balance between coagulation and fibrinolysis processes is critical for establishment and development of early pregnancy. Angiotensin-converting enzyme (ACE) is related with plasminogen activator inhibitor-1 activity which is a key regulator in embryo implantation. Therefor polymorphisms in ACE gene and variation in ACE activity could be associated with an early pregnancy wastage risk. This study investigated carrier status for insertion/deletion (I/D) polymorphism in introne 16 of ACE gene in 71 women with two or more pregnancy loss in preplacentation period (between 10 and 14 weeks of gestation) and 75 women without pregnancy complications. DD genotype for I/D polymorphism was found respectively in 31% and 24% in patients and controls. Heterozygosity of D allele was found correspondingly in 47.9% and 54.7%. The dominant genetic model was used for allele prevalence comparison. D allele in DD genotype was not significantly prevalent in women with early pregnancy wastage compared with the control subjects, OR = 1.42, 95% CI (0.64-3.15). The study found a weak association between I/D polymorphism and preplacentation pregnancy loss. The additive effect over the pregnancy loss risk of I/D polymorphism could be supposed in a presence of other inherited or acquired factors connected with endometrial receptivity and implantation process. PMID:25510065

  18. /sup 67/Ga citrate scanning and serum angiotensin converting enzyme levels in sarcoidosis

    SciTech Connect

    Gupta, R.G.; Bekerman, C.; Sicilian, L.; Oparil, S.; Pinsky, S.M.; Szidon, J.P.

    1982-09-01

    /sup 67/Ga citrate scans and serum angiotensin converting enzyme (ACE) levels were obtained in 54 patients with sarcoidosis and analyzed in relation to clinical manifestations. /sup 67/Ga scans were abnormal in 97% of patients with clinically active disease (n . 30) and in 71% of patients with inactive disease (n . 24). Serum ACE levels were abnormally high (2 standard deviations above the control mean) in 73% of patients with clinically active disease and in 54% of patients with inactive disease. Serum ACE levels correlated significantly with /sup 67/Ga uptake score (r..436; p less than .005). The frequency of abnormal /sup 67/Ga scans and elevated serum ACE levels suggests that inflammatory activity with little or no clinical expression is common in sarcoidosis. Abnormal /sup 67/Ga scans were highly sensitive (97%) but had poor specificity (29%) to clinical disease activity. The accuracy of negative prediction of clinical activity by normal scans (87%) was better than the accuracy of positive prediction of clinical activity by abnormal scans (63%). /sup 67/Ga scans can be used to support the clinical indentification of inactive sacoidosis.

  19. Increased risk of pneumonia associated with angiotensin-converting enzyme (CD143) rs4340 polymorphism.

    PubMed

    Zhang, Xiaofang; Liu, Fangzhu

    2016-08-01

    The study aims to investigate the genetic association between rs4340 polymorphism at intron 16 of the angiotensin-converting enzyme (CD143) gene and pneumonia predisposition. Electronic database of PubMed, Embase, and CNKI (China National Knowledge Infrastructure) was searched for the studies addressing the association between CD143 rs4340 genotypes and pneumonia risk. The odds ratio (OR) with its 95 % confidence interval (CI) was employed to estimate the association. In total, ten case-control studies, including 1239 pneumonia cases and 2400 healthy controls, met the inclusion criteria. Our results showed a significant association between rs4340 SNP and pneumonia risk using the recessive model (OR 1.43, 95 % CI 1.20-1.70). A significantly increased risk was also indicated under the recessive model in Asian populations (OR 1.63, 95 % CI 1.16-2.30), Caucasian populations (OR 1.34, 95 % CI 1.09-1.65), community-acquired pneumonia (OR 1.42, 95 % CI 1.16-1.75) rather than nosocomial pneumonia (OR 1.47, 95 % CI 0.97-2.23). However, further studies with gene-gene and gene-environmental interactions should be considered to confirm this association. PMID:25982566

  20. Chebulin: Terminalia chebula Retz. fruit-derived peptide with angiotensin-I-converting enzyme inhibitory activity.

    PubMed

    Sornwatana, Thakorn; Bangphoomi, Kunan; Roytrakul, Sittiruk; Wetprasit, Nuanchawee; Choowongkomon, Kiattawee; Ratanapo, Sunanta

    2015-01-01

    Angiotensin-I-converting enzyme (ACE) plays an important role in blood pressure regulation. In this study, an ACE-hexapeptide inhibitor (Asp-Glu-Asn-Ser-Lys-Phe) designated as chebulin was produced from the fruit protein of Terminalia chebula Retz. by pepsin digestion, ultrafiltrated through a 3 KDa cut-off membrane, a reverse-phase high-performance liquid chromatography, and nano-liquid chromatography tandem mass spectrometry analysis. Chebulin was found to inhibit ACE in a noncompetitive manner, as supported by the structural model. It bounds to ACE by the hydrogen bond, hydrophobic and ionic interactions via the interactions of C-terminal Phe (Phe-6), and N-terminal residues (Asp-1 and Glu-2) with the amino acid residues on noncatalytic sites of the ACE. The results showed that chebulin derived from fruits of T. chebula Retz. is a potential ACE-peptide inhibitor that could be used as a functional food additive for the prevention of hypertension and as an alternative to ACE inhibitor drug. PMID:25410725

  1. Chinese medicinal formula Fufang Xueshuantong capsule could inhibit the activity of angiotensin converting enzyme

    PubMed Central

    Sheng, Shujing; Wang, Yonggang; Long, Chaofeng; Su, Weiwei; Rong, Xia

    2014-01-01

    Fufang Xueshuantong (FXST) capsule, a Chinese medicinal formula composed of four herbals – Panax notoginseng, Radix Astragali, Radix Salvia Miltiorrhizae and Radix Scrophulariaceae, has been used to treat cardiovascular diseases for many years, but the pharmacological mechanisms underlying its effects has not been clarified. This study investigates if a connection between FXST and angiotensin converting enzyme (ACE) might be an explanation for its pharmacological effects. ACE inhibition assay was performed on FXST capsule, 50% ethanol extracts from the four herbals and three selected saponins most abundant in P. notoginseng (Ginsenoside Rg1, Ginsenoside Rb1 and Notoginsenoside R1) using a biochemical test. Reversed-phase high-performance liquid chromatography of liberated hippuric acid from the ACE assay was conducted to determine the inhibitory effect. As a result, FXST and extracts from P. notoginseng showed a significant and dose-dependent inhibition on ACE activity with the IC50 values of 115 μg/ml and 179 μg/ml, respectively. But extracts from the other three herbals and the three selected saponins had no significant effect on ACE inhibition. Compared to other reported plant extracts, FXST could be considered as an effective ACE inhibitor. The inhibition of ACE activity supports the traditional use of FXST on blood circulation and the inhibitory property of FXST is mainly caused by P. notoginseng. PMID:26019516

  2. Influence of Angiotensin I-Converting Enzyme Gene Polymorphism on Hepatocellular Carcinoma Risk in China

    PubMed Central

    Yuan, Fang; Zhang, Lu-Shun; Li, Hong-Yu; Liao, Miao

    2013-01-01

    Growing evidence suggests that the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) genes are associated with risk in a wide range of cancers. The objective of this study was to examine whether two DNA polymorphisms at the ACE insertion/deletion (I/D) and the variable number of tandem repeats in NOS intron 4 (4a/4b) were linked to the risk of developing hepatocellular carcinoma (HCC) in a Chinese population. The polymorphisms at ACE I/D and eNOS 4a/4b were genotyped in 293 HCC patients and 384 healthy control subjects using polymerase chain reaction. The frequencies of the D allele (p=0.003, OR=0.72, 95% CI=0.58–0.90) in the ACE gene of HCC patients were significantly different from the healthy controls, and a significantly decreased HCC risk was associated with the DD genotype in both the recessive (p<0.001, OR=0.19, 95% CI=0.11–0.34) and codominant models (p<0.001, OR=0.26, 95% CI=0.14–0.48). This study provided evidence that the ACE I/D polymorphism is associated with HCC, indicating that the ACE I/D polymorphism contributes to HCC progression in the Chinese population. PMID:23570557

  3. Stability and cytotoxicity of angiotensin-I-converting enzyme inhibitory peptides derived from bovine casein*

    PubMed Central

    Wu, Wei; Yu, Pan-pan; Zhang, Feng-yang; Che, Hong-xia; Jiang, Zhan-mei

    2014-01-01

    This study investigated the effect of heat treatment combined with acid and alkali on the angiotensin-I-converting enzyme (ACE) inhibitory activity of peptides derived from bovine casein. The free amino group content, color, and cytotoxicity of the peptides were measured under different conditions. When heated at 100 °C in the pH range from 9.0 to 12.0, ACE inhibitory activity was reduced and the appearance of the peptides was significantly darkened. After thermal treatment in the presence of acid and alkali, the free amino group content of ACE inhibitory peptides decreased markedly. High temperature and prolonged heating also resulted in the loss of ACE inhibitory activity, the loss of free amino groups, and the darker coloration of bovine casein-derived peptides. However, ACE inhibitory peptides, within a concentration range of from 0.01 to 0.2 mg/ml, showed no cytotoxicity to Caco-2 and ECV-304 cell lines after heat treatment. This indicated that high temperature and alkaline heat treatment impaired the stability of bovine casein-derived ACE inhibitory peptides. PMID:24510707

  4. Radiation injury in rat lung: II. Angiotensin-converting enzyme activity

    SciTech Connect

    Ward, W.F.; Solliday, N.H.; Molteni, A.; Port, C.D.

    1983-11-01

    To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of /sup 60/Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90 to 150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.

  5. Identification of a new angiotensin-converting enzyme (ACE) inhibitor from Thai edible plants.

    PubMed

    Simaratanamongkol, Arunee; Umehara, Kaoru; Noguchi, Hiroshi; Panichayupakaranant, Pharkphoom

    2014-12-15

    Eight Thai edible plants were tested for their inhibitory activity against an angiotensin-converting enzyme (ACE) using an in vitro assay. The methanol extract of Apium graveolens exhibited significant ACE inhibitory activity with an IC50 value of 1.7 mg/ml, and was then subjected to an isolation procedure that resulted in identification of a pure active constituent, junipediol A 8-O-β-d-glucoside (1-β-d-glucosyloxy-2-(3-methoxy-4-hydroxyphenyl)-propane-1,3-diol) (1), which had good ACE inhibitory activity with an IC50 value of 76 μg/ml. Another eight known compounds, isofraxidin-β-d-glucoside (2), roseoside (3), apigenin-7-O-β-d-glucoside (4), luteolin-7-O-β-d-glucoside (5), icariside D2 (6), apiin (7), chrysoeriol-7-O-β-d-apiosylglucoside (8), and 11,21-dioxo-3 β,15 α,24-trihydroxyurs-12-ene-24-O-β-d-glucopyranoside (9) were also identified. Although each of these five constituents (2-6) isolated from the same fraction as 1 showed no activity at concentrations of 500 μM, together, when each was present at 300 μg/ml, they enhanced the inhibitory activity of 500 μM of 1 from 64% to 81%. PMID:25038653

  6. Angiotensin-converting enzyme gene polymorphisms and hypertension in occupational noise exposure in Egypt

    PubMed Central

    Zawilla, Nermin; Shaker, Dalia; Abdelaal, Amaal; Aref, Wael

    2014-01-01

    Background: The gene–environment interaction in the pathogenesis of hypertension has not been extensively studied in occupational noise. Objectives: The aim of this study was to determine the relationship between noise and hypertension in Egyptian workers, the interaction of angiotensin-converting enzyme (ACE) gene polymorphisms as modifiers, and the possible relationship between noise hearing impairment and hypertension. Methods: Study subjects were divided into two groups depending on noise exposure level. The control group (n = 161) was exposed to noise intensity <85 dB and the exposed group (n = 217) was exposed to noise intensity ≧85 dB. A polymerase chain reaction was used to differentiate the various genotypes of ACE insertion/deletion (I/D) and ACE G2350A. Results: Noise significantly increased the likelihood of hypertension. Carriers of the genotypes AG, GG, and DD were vulnerable to hypertension on noise exposure. No association between hypertension and hearing impairment or noise-induced hearing loss (NIHL) was found. Conclusion: Our results support the association between ACE gene polymorphisms and occurrence of hypertension in noise-exposed workers. PMID:25000107

  7. Impact of disease states on the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors.

    PubMed

    LeBlanc, Jaclyn M; Dasta, Joseph F; Pruchnicki, Maria C; Schentag, Jerome J

    2006-09-01

    The pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors (ACE) in elderly patients and patients with renal and hepatic impairment were examined, and a role for an AUC/EC50 ratio to guide dosing was evaluated. A Medline and International Pharmaceutical Abstracts search was used to identify human studies and abstracts. Relevant data were evaluated and summarized. Dosing regimens were compared using an AUC/EC50 ratio. Most studies evaluating ACE inhibitors in renal impairment report a strong linear correlation between creatine clearance and drug elimination. AUC and EC50 values for these drugs in elderly subjects appear similar to younger and hypertensive patients. There is increased AUC in some patients with hepatic impairment. Pharmacodynamic data are conflicting. Prolonged ACE inhibition is evident in renal impairment but not necessarily other disease states. ACE inhibitor dosing for hypertension is reasonable based on pharmacokinetics and EC50 values. Further individualization of therapy may improve outcomes, and using the threshold AUC/EC50 ratio may help guide appropriate dosing. PMID:16920891

  8. Smooth muscle cell conditioned medium elevates angiotensin-converting enzyme of bovine pulmonary artery endothelial cells.

    PubMed

    Yu, F S; Lee, S L; Fanburg, B L

    1989-11-01

    Conditioned medium obtained from bovine pulmonary artery smooth muscle cells (SMC) in culture was found to elevate angiotensin-I-converting enzyme (ACE) of bovine pulmonary artery endothelial cells (EC) by 2- to 3-fold upon incubation for 24 to 48 h. The elevation in ACE was time dependent and inhibited by 10(-6) M cycloheximide, making it likely that the elevation was related to new protein synthesis by EC. Conditioned medium from EC failed to produce the same effect. The stimulatory effect of SMC conditioned medium on EC ACE was uninfluenced by exposures to anoxia as compared with room air, either during conditioning of medium or while assaying the effect of conditioned medium on EC ACE. Inhibitors of prostaglandin metabolism and calcium transport failed to influence the stimulatory effect of SMC conditioned medium on EC ACE. The stimulatory effect on EC ACE by conditioned medium was additive to that produced by Ca2+ ionophore A23187 and 3-isobutyl-1-methylxanthine and, similar to baseline ACE, was inhibited by 3 x 10(-8) M ouabain. Thus, SMC produce a factor that regulates the level of EC ACE. PMID:2484059

  9. Treatment of Hypertension in Black Patients With Angiotensin-Converting Enzyme Inhibitors

    PubMed Central

    Shulman, Neil B.

    1988-01-01

    The prevalence of hypertension and the incidence of complications from uncontrolled elevated blood pressure in blacks is much greater than in the white population. In general, blacks have underlying differences in the factors relating to blood pressure level, including low plasma renin, and, in certain instances, a decreased ability to excrete sodium. The stepped-care approach in the management of the black hypertensive patient is similar to that taken with white patients, but racial differences in response to antihypertensive drugs exist that require careful consideration when choosing a treatment regimen. Thiazide diuretics are effective in blacks and are often used as initial therapy. Blacks tend to respond less well to β-blockers, but when combined with a diuretic, they are also effective. Encouraging data are available on the use of calcium channel blockers in blacks. When combined with a diuretic, the angiotensin-converting enzyme (ACE) inhibitors also provide an alternative to therapy for black patients. The use of low doses of ACE inhibitors has reduced the high incidence of adverse effects associated with this group of drugs in earlier studies. PMID:3280812

  10. Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships.

    PubMed

    Al Shukor, Nadin; Van Camp, John; Gonzales, Gerard Bryan; Staljanssens, Dorien; Struijs, Karin; Zotti, Moises J; Raes, Katleen; Smagghe, Guy

    2013-12-01

    In this study, 22 phenolic compounds were investigated to inhibit the angiotensin-converting enzyme (ACE). Tannic acid showed the highest activity (IC50 = 230 μM). The IC50 values obtained for phenolic acids and flavonoids ranged between 0.41 and 9.3 mM. QSAR analysis confirmed that the numbers of hydroxyl groups on the benzene ring play an important role for activity of phenolic compounds and that substitution of hydroxyl groups by methoxy groups decreased activity. Docking studies indicated that phenolic acids and flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. Other compounds, such as resveratrol and pyrogallol, may inhibit ACE via interactions with amino acids at the active site, thereby blocking the catalytic activity of ACE. These structure-function relationships are useful for designing new ACE inhibitors and potential blood-pressure-lowering compounds based on phenolic compounds. PMID:24219111

  11. [Psychotropic effects of angiotensin-converting enzyme inhibitors: what are the arguments?].

    PubMed

    Mesure, G; Fallet, A; Chevalier, J F

    1995-01-01

    The authors report a case of acute mania induced by perindopril (Coversyl) in a 57 year old man with no prior history of mental illness. This Angiotensin-Converting Enzyme Inhibitor (ACEI) had been introduced eight days prior to the first signs of excitation, in order to treat recently diagnosed arterial hypertension. Without proof of reintroduction, and on the basis of clinical observations, the attribution appears plausible. Similar observations have been made for other molecules in this class of medication, such as captopril (Lopril). A review of literature regroups recent data concerning psychotropic effects of ACEIs. Several reports claim that captopril clearly acts as an antidepressant. Studies on the mood or the quality of life of treated hypertensive patients show ACEIs to have an euphoric-type positive effect compared to other anti-hypertensive treatments. Captopril and perindopril also act like potential antidepressants in experimental models of antidepression. Furthermore, pharmacologic data confirm that the most lipophilic ACEIs penetrate the central nervous system and argue in favor of the role of these molecules in activating central opioides. As these data provide evidence of mood swing in some patients, but also of an overall benefit in hypertensive populations, the clinical importance of the antidepressant effect of ACEIs needs further investigations. PMID:8529571

  12. Serum Levels of Copper, Ceruloplasmin and Angiotensin Converting Enzyme among Silicotic and Non-Silicotic Workers

    PubMed Central

    Beshir, Safia; Aziz, Hisham; Shaheen, Weam; Eltahlawy, Eman

    2015-01-01

    BACKGROUND: Silicosis is the most frequently occurring pneumoconiosis. AIM: Measurement of serum levels of Angiotensin converting enzyme (ACE), Copper (Cu) and Ceruloplasmin (Cp) in cement workers occupationally exposed to silica dust as biomarkers of exposure rather than biomarkers of effect for silicosis. METHODS: Plain chest X-ray & pulmonary functions were done for 30 silicotic and 42 non-silicotic workers and 42 controls. CT scan was done for the exposed groups. Serum levels of Cu, Cp and ACE were estimated. RESULTS: The results showed a higher significant difference between the exposed groups and controls, and between the two exposed groups regarding the mean levels of all measured biochemical parameters. The pulmonary functions were significantly lower among silicotic workers than controls and non-silicotic groups. There was a significant positive correlation between duration of employment and serum ACE and Cu. CONCLUSION: Since respirable dust exposure-linked lung fibrosis disease is non-curable, the biochemical parameters (Cu, ACE and Cp) can be used as exposure biomarkers to silica dust, providing a better way for early diagnosis of this deadly disease. Down regulating the inflammatory responses could potentially reduce the adverse clinical pulmonary effects of air pollution. PMID:27275272

  13. Angiotensin I-Converting Enzyme Inhibitor Derived from Cross-Linked Oyster Protein

    PubMed Central

    Xie, Cheng-Liang; Kim, Jin-Soo; Ha, Jong-Myung; Choung, Se-Young

    2014-01-01

    Following cross-linking by microbial transglutaminase, modified oyster proteins were hydrolyzed to improve inhibitory activity against angiotensin-converting enzyme (ACE) inhibitory activity with the use of a single protease, or a combination of six proteases. The oyster hydrolysate with the lowest 50% ACE inhibitory concentration (IC50) of 0.40 mg/mL was obtained by two-step hydrolysis of the cross-linked oyster protein using Protamex and Neutrase. Five ACE inhibitory peptides were purified from the oyster hydrolysate using a multistep chromatographic procedure comprised of ion-exchange, size exclusion, and reversed-phase liquid chromatography. Their sequences were identified as TAY, VK, KY, FYN, and YA, using automated Edman degradation and mass spectrometry. These peptides were synthesized, and their IC50 values were measured to be 16.7, 29.0, 51.5, 68.2, and 93.9 μM, respectively. Toxicity of the peptides on the HepG2 cell line was not detected. The oyster hydrolysate also significantly decreased the systolic blood pressure of spontaneously hypertensive rats (SHR). The antihypertensive effect of the oyster hydrolysate on SHR was rapid and long-lasting, compared to commercially obtained sardine hydrolysate. These results suggest that the oyster hydrolysate could be a source of effective nutraceuticals against hypertension. PMID:25140307

  14. In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

    PubMed Central

    Muhammad, Syed Aun; Fatima, Nighat

    2015-01-01

    The purpose of this study was to analyze the inhibitory action of quercetin glycosides by computational docking studies. For this, natural metabolite quercetin glycosides isolated from buckwheat and onions were used as ligand for molecular interaction. The crystallographic structure of molecular target angiotensin-converting enzyme (ACE) (peptidyl-dipeptidase A) was obtained from PDB database (PDB ID: 1O86). Enalapril, a well-known brand of ACE inhibitor was taken as the standard for comparative analysis. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. The quercetin showed optimum binding affinity with a molecular target (angiotensin-converting-enzyme) with the binding energy of −8.5 kcal/mol as compared to the standard (−7.0 kcal/mol). These results indicated that quercetin glycosides could be one of the potential ligands to treat hypertension, myocardial infarction, and congestive heart failure. PMID:26109757

  15. Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane.

    PubMed Central

    Oppong, S Y; Hooper, N M

    1993-01-01

    Angiotensin-converting enzyme (ACE; EC 3.4.1.15.1) exists in both membrane-bound and soluble forms. Phase separation in Triton X-114 and a competitive e.l.i.s.a. have been employed to characterize the activity which post-translationally converts the amphipathic, membrane-bound form of ACE in pig kidney microvilli into a hydrophilic, soluble form. This secretase activity was enriched to a similar extent as other microvillar membrane proteins, was tightly membrane-associated, being resistant to extensive washing of the microvillar membranes with 0.5 M NaCl, and displayed a pH optimum of 8.4. The ACE secretase was not affected by inhibitors of serine-, thiol- or aspartic-proteases, nor by reducing agents or alpha 2-macroglobulin. The metal chelators, EDTA and 1,10-phenanthroline, inhibited the secretase activity, with, in the case of EDTA, an inhibitor concentration of 2.5 mM causing 50% inhibition. In contrast, EGTA inhibited the secretase by a maximum of 15% at a concentration of 10 mM. The inhibition of EDTA was reactivated substantially (83%) by Mg2+ ions, and partially (34% and 29%) by Zn2+ and Mn2+ ions respectively. This EDTA-sensitive secretase activity was also present in microsomal membranes prepared from pig lung and testis, and from human lung and placenta, but was absent from human kidney and human and pig intestinal brush-border membranes. The form of ACE released from the microvillar membrane by the secretase co-migrated on SDS/PAGE with ACE purified from pig plasma, thus the action and location of the secretase would be consistent with it possibly having a role in the post-translational proteolytic cleavage of membrane-bound ACE to generate the soluble form found in blood, amniotic fluid, seminal plasma and other body fluids. Images Figure 4 PMID:8389141

  16. Design of Peptide Substrate for Sensitively and Specifically Detecting Two Aβ-Degrading Enzymes: Neprilysin and Angiotensin-Converting Enzyme

    PubMed Central

    Chen, Po-Ting; Chen, Chao-Long; Lin, Lilian Tsai-Wei; Lo, Chun-Hsien; Hu, Chaur-Jong; Chen, Rita P.-Y.; Wang, Steven S.-S.

    2016-01-01

    Upregulation of neprilysin (NEP) to reduce Aβ accumulation in the brain is a promising strategy for the prevention of Alzheimer’s disease (AD). This report describes the design and synthesis of a quenched fluorogenic peptide substrate qf-Aβ(12–16)AAC (with the sequence VHHQKAAC), which has a fluorophore, Alexa-350, linked to the side-chain of its C-terminal cysteine and a quencher, Dabcyl, linked to its N-terminus. This peptide emitted strong fluorescence upon cleavage. Our results showed that qf-Aβ(12–16)AAC is more sensitive to NEP than the previously reported peptide substrates, so that concentrations of NEP as low as 0.03 nM could be detected at peptide concentration of 2 μM. Moreover, qf-Aβ(12–16)AAC had superior enzymatic specificity for both NEP and angiotensin-converting enzyme (ACE), but was inert with other Aβ-degrading enzymes. This peptide, used in conjunction with a previously reported peptide substrate qf-Aβ(1–7)C [which is sensitive to NEP and insulin-degrading enzyme (IDE)], could be used for high-throughput screening of compounds that only upregulate NEP. The experimental results of cell-based activity assays using both qf-Aβ(1–7)C and qf-Aβ(12–16)AAC as the substrates confirm that somatostatin treatment most likely upregulates IDE, but not NEP, in neuroblastoma cells. PMID:27096746

  17. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

    PubMed Central

    Kasi, Vijaykumar S.; Xiao, Hong D.; Shang, Lijuan L.; Iravanian, Shahriar; Langberg, Jonathan; Witham, Emily A.; Jiao, Zhe; Gallego, Carlos J.; Bernstein, Kenneth E.; Dudley, Samuel C.

    2011-01-01

    Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na+ channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca2+ channel, Kv4.2 K+ channel α-subunit, and Cx45 mRNA abundances and the peak ventricular Na+ current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as

  18. Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview.

    PubMed

    Zughaib, M E; Sun, J Z; Bolli, R

    1993-01-01

    the case of non-thiol-containing molecules). What is clear is that the enhanced recovery of function effected by these drugs is not due to hemodynamic effects, inhibition of the converting enzyme per se, or an "antischemic" action (since the drugs were effective when given at the time of reperfusion). The effects of ACE inhibitors on myocardial infarct size remain controversial. Further studies will be necessary to conclusively establish whether ACE inhibitors can protect against the detrimental effects of myocardial ischemia and reperfusion. Nevertheless, the evidence provided thus far is encouraging and warrants an in-depth assessment of the role of these drugs in attenuating myocardial ischemia/reperfusion injury. PMID:8357331

  19. Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.

    PubMed Central

    Telford, S E; Smith, A I; Lew, R A; Perich, R B; Madden, A C; Evans, R G

    1995-01-01

    1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7620708

  20. A Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibition for Skeletal Muscle Dysfunction in COPD

    PubMed Central

    Shrikrishna, Dinesh; Tanner, Rebecca J.; Lee, Jen Y.; Natanek, Amanda; Lewis, Amy; Murphy, Patrick B.; Hart, Nicholas; Moxham, John; Montgomery, Hugh E.; Kemp, Paul R.; Polkey, Michael I.

    2014-01-01

    BACKGROUND: Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD. METHODS: This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes. RESULTS: Eighty patients were enrolled (mean [SD], 65 [8] years, FEV1 43% [21%] predicted, 53% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (Δ−10.5 mm Hg; 95% CI, −19.9 to −1.1; P = .03) and serum ACE activity (Δ−20.4 IU/L; 95% CI, −31.0 to −9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (Δ0.5 s; 95% CI, −13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (Δ−0.03 arbitrary units; 95% CI, −0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: Δ1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: Δ3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51). CONCLUSIONS: This randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness. TRIAL REGISTRY: Current Controlled Trials; No.: ISRCTN05581879; URL: www

  1. Different reactivity to angiotensin II of peripheral and renal arteries in spontaneously hypertensive rats: effect of acute and chronic angiotensin converting enzyme inhibition

    NASA Technical Reports Server (NTRS)

    Guidi, E.; Hollenberg, N. K.

    1986-01-01

    We assessed renal blood flow and pressor responses to graded angiotensin II doses in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats ingesting a diet containing 1.6% sodium basally and after acute and chronic angiotensin converting enzyme (ACE) inhibition with captopril. In the basal state the pressor response to angiotensin II was enhanced (P<0.0005) and the renal vascular response was blunted (P<0.005) in SHR compared with WKY rats. After acute captopril administration the pressor response was enhanced in both strains, and the difference between them was maintained, while the renal vascular response was enhanced in both, but more in SHR, so that the renal vascular response in the SHR became larger than in WKY (P<0.0001). Chronic captopril treatment blunted both pressor and renal responses in WKY rats, but only the pressor response in SHR. The renal vessels of SHR seem to be different from those of WKY rats in reaction to exogenous angiotensin II, and in response to both acute administration of captopril (probably acting through blockade of angiotensin II production) and chronic administration of captopril (probably acting mainly through accumulation of kinin or production of prostaglandins).

  2. The pharmacological mechanism of angiotensin-converting enzyme inhibition by green tea, Rooibos and enalaprilat - a study on enzyme kinetics.

    PubMed

    Persson, Ingrid A-L

    2012-04-01

    Green tea (Camellia sinensis L.) and Rooibos (Aspalathus linearis Dahlg.) inhibit angiotensin-converting enzyme (ACE) in vitro and in vivo. The ACE inhibitor enalaprilat has been described previously as a competitive inhibitor and sometimes as a non-competitive inhibitor. The aim of this study was to investigate the pharmacological mechanism of ACE inhibition of green tea and Rooibos by enzyme kinetics, and to compare this with enalaprilat. A Michaelis-Menten kinetics and Lineweaver-Burk graph showed mean values of V(max)  = 3.73 µM and K(m)  = 0.71 µM for green tea, of V(max)  = 6.76 µM and K(m)  = 0.78 µM for Rooibos, of V(max)  = 12.54 µM and K(m)  = 2.77 µM for enalaprilat, and of V(max)  = 51.33 µM and K(m)  = 9.22 µM for the PBS control. Incubating serum with green tea or Rooibos saturated with zinc chloride did not change the inhibitory effect. Enalaprilat preincubated with zinc chloride showed a decrease in the inhibitory effect. In conclusion, green tea, Rooibos and enalaprilat seem to inhibit ACE activity using a mixed inhibitor mechanism. PMID:22095883

  3. Angiotensin-converting enzyme inhibitory and antioxidant activities of enzymatically synthesized phenolic and vitamin glycosides.

    PubMed

    Charles, Rajachristu Einstein; Ponrasu, Thangavel; Sivakumar, Ramaiah; Divakar, Soundar

    2009-03-01

    Amyloglucosidase from Rhizopus mould and beta-glucosidase from sweet almond were employed for the preparation of phenolic and vitamin glycosides of vanillin, N-vanillylnonanamide, DL-dopa, dopamine, curcumin, alpha-tocopherol (vitamin E), pyridoxine (vitamin B(6)), ergocalciferol (vitamin D(2)), thiamin (vitamin B(1)) and riboflavin (vitamin B(2)). Approx. 20 enzymatically prepared phenolic and vitamin glycosides were subjected to ACE (angiotensin-converting enzyme) inhibition activity measurements, and 14 glycosides were tested for antioxidant activities. Both phenolic and vitamin glycosides exhibited IC(50) values for ACE inhibition in the 0.52+/-0.03-3.33+/-0.17 mM range and antioxidant activities ranging from 0.8+/-0.04 to 1.18+/-0.06 mM. Comparable ACE inhibition values were observed between free phenols and vitamin glycosides. However, antioxidant activities of glycosides were, in general, lesser than those of free phenols. Best IC(50) value for ACE inhibition were observed for 11-O-(D-fructofuranosyl)thiamin (0.52+/-0.03 mM), 3-hydroxy-4-O-(6-D-sorbitol)phenylalanine (0.56+/-0.03 mM), 4-O-(beta-D-glucopyranosyl)vanillin (0.61+/-0.03 mM), 4-O-(D-galactopyranosyl)vanillin (0.61+/-0.03 mM) and pyridoxine-D-glucoside (0.84+/-0.04 mM). Similarly, best IC(50) values for antioxidant activity were observed for 1,7-O-(bis-beta-D-glucopyranosyl)curcumin (0.8+/-0.04 mM), 4-O-(beta-D-glucopyranosyl)vanillin (0.9+/-0.05 mM), 3-hydroxy-4-O-(beta-D-galactopyranosyl-(1'-->4)beta-D-glucopyranosyl)phenylalanine (0.9+/-0.05 mM), 20-O-(D-glucopyranosyl)ergocalciferol (0.9+/-0.05 mM) and dopamine-D-galactoside (0.93+/-0.05 mM). PMID:18547170

  4. Serum angiotensin-converting enzyme is elevated in association with underground coal mining

    SciTech Connect

    Thompson, A.B.; Cale, W.F.; Lapp, N.L. )

    1991-10-01

    Serum angiotensin-converting enzyme activity (SACE) and lysozyme activity were measured in a group of 40 underground coal miners and two control groups, 20 subjects with sarcoidosis and 15 normal non-dust-exposed volunteers. The miners were grouped first according to whether they had recent exposure (still actively mining or retired three years or less prior to measurement) or temporally more distant exposure (retired more than three years prior to measurement). Secondly, they were grouped as to whether or not they had coal workers' pneumoconiosis (CWP). The subjects with sarcoidosis were grouped according to disease activity. As expected, the subjects with active sarcoidosis had elevated SACE activity compared with normal subjects. The coal miners as a group did not have elevation of their SACE activity. However, the coal miners with recent exposure had elevated SACE activity (57.1 {plus minus} 3.9 U/ml) compared with normal controls (43.8 {plus minus} 1.5 U/ml, p = 0.007). The SACE activity in miners without recent exposure was not elevated (39.8 {plus minus} 1.3 U/ml) compared with the normal controls. No increase in SACE activity was found when the miners were grouped according to the presence or absence of CWP. In contrast, the miners' serum lysozyme activity was not elevated. Since alveolar macrophages are a potential source of SACE, elevation of SACE activity in underground coal miners may reflect alveolar macrophage activation caused by increased pulmonary mixed coal mine dust burden. Furthermore, since both SACE and serum lysozyme are elevated in association with silicosis, these findings may confirm that the macrophage responses to inhaled silica and coal dust differ.

  5. Angiotensin-Converting Enzyme Gene Polymophism in Adult Primary Focal Segmental Glomerulosclerosis

    PubMed Central

    Mohd, Rozita; Wahab, Zaimi Abdul; Cader, Rizna; Gafor, Halim A.; Radzi, Azizah Md; Shah, Shamsul Azhar; Tong, Norella Kong Chiew

    2014-01-01

    Background Primary focal segmental glomerulosclerosis (FSGS) accounts for a third of biopsy-proven primary glomerulonephritis in Malaysia. Pediatric studies have found the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to be associated with renal disease progression. The aim of this study was to determine the prevalence of the ACE (I/D) genotypes in adult primary FSGS and its association with renal outcome on follow-up. Methods Prospective observational study involving primary FSGS patients was conducted. Biochemical and urine tests at the time of study were compared to the time of the diagnosis and disease progression analyzed. ACE gene polymorphism was identified using polymerase chain reaction amplification technique and categorized into II, ID and DD genotypes. Results Forty-five patients with a median follow-up of 3.8 years (interquartile range: 1.8 - 5.6) were recruited. The commonest genotype was II (n = 23, 51.1%) followed by ID (n = 19, 42.2%) and DD (n = 3, 6.7%). The baseline characteristics were comparable between the II and non-II groups at diagnosis and at study recruitment except that the median urine protein-creatinine index was significantly lower in the II group compared to the non-II group (0.02 vs. 0.04 g/mmol (P = 0.03). Regardless of genotypes, all parameters of renal outcome improved after treatment. Conclusion The II followed by ID genotypes were the predominant ACE gene alleles in our FSGS. Although the D allele has been reported to have a negative impact on renal outcome, treatment appeared to be more important than genotype in preserving renal function in this cohort. PMID:24883149

  6. Pollen Count and Presentation of Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema

    PubMed Central

    Straka, Brittany; Nian, Hui; Sloan, Chantel; Byrd, James Brian; Woodard-Grice, Alencia; Yu, Chang; Stone, Elizabeth; Steven, Gary; Hartert, Tina; Teo, Koon K.; Pare, Guillaume; McCarty, Catherine A.; Brown, Nancy J.

    2014-01-01

    BACKGROUND The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. OBJECTIVE We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. METHODS Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. RESULTS At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ2 test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). CONCLUSIONS Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased. PMID:24565618

  7. Association of polymorphisms in angiotensin-converting enzyme gene with gestational diabetes mellitus in Indian women

    PubMed Central

    Aggarwal, Parul; Agarwal, Nutan; Das, Nibhriti; Dalal, Krishna

    2016-01-01

    Background: Numerous genes have been reported in relation with gestational diabetes mellitus (GDM), but the findings were not consistently replicated across populations, or there have been no detailed studies on them. Previous literatures suggested that, out of all angiotensin converting enzyme (ACE) gene polymorphisms, only ACE insertion/deletion (I/D) gene polymorphism has a strong association with GDM in Asian Indian women. Aim: This study was devoted to evaluate the association of four single nucleotide polymorphisms (SNPs) ACE A240T, C1237T, G2350A and I/D with GDM and Type 2 diabetes mellitus. Materials and Methods: This study recruited 105 GDM cases, 119 Type 2 diabetes mellitus subjects and 120 controls. PCR-RFLP was used for identifying genotypes of ACE A240T, C1237T and G2350A and PCR was performed in the case of ACE I/D. Results: Significant associations of ACE SNP's, C1237T, and G2350A with GDM were observed. Haplotype analysis revealed the remarkably significant evidence of association with SNP combination ACE A240T, C1237T, G2350A, and I/D with GDM patients (P = 0.024). Individuals possessing haplotype “TTAI” (frequency 30% in GDM and 0 in controls) derived from these SNPs had 185 fold increased risk of developing GDM (95% of confidence interval: 11.13–3102.15), which was highest when compared with other 15 haplotypes. Conclusion: Shorter-range haplotypes were also significant, but the only consistently associated alleles were found to be in ACE C1237T, G2350A, and I/D. These results suggested that the variant in close proximity to ACE C1237T, G2350A and/or I/D modulates susceptibility to GDM and noninsulin dependent diabetes mellitus in Indian women. PMID:26958520

  8. Activation of endogenous angiotensin converting enzyme 2 prevents early injuries induced by hyperglycemia in rat retina

    PubMed Central

    Foureaux, G.; Nogueira, B. S.; Coutinho, D. C. O.; Raizada, M. K.; Nogueira, J. C.; Ferreira, A. J.

    2015-01-01

    Diabetic retinopathy (DR) is a serious complication of diabetes mellitus that may result in blindness. We evaluated the effects of activation of endogenous angiotensin converting enzyme (ACE) 2 on the early stages of DR. Rats were administered an intravenous injection of streptozotocin to induce hyperglycemia. The ACE2 activator 1-[[2-(dimethylamino) ethyl] amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl) sulfonyl] oxy]-9H-xanthone 9 (XNT) was administered by daily gavage. The death of retinal ganglion cells (RGC) was evaluated in histological sections, and retinal ACE2, caspase-3, and vascular endothelial growth factor (VEGF) expressions were analyzed by immunohistochemistry. XNT treatment increased ACE2 expression in retinas of hyperglycemic (HG) rats (control: 13.81±2.71 area%; HG: 14.29±4.30 area%; HG+XNT: 26.87±1.86 area%; P<0.05). Importantly, ACE2 activation significantly increased the RCG number in comparison with HG animals (control: 553.5±14.29; HG: 530.8±10.3 cells; HG+XNT: 575.3±16.5 cells; P<0.05). This effect was accompanied by a reduction in the expression of caspase-3 in RGC of the HG+XNT group when compared with untreated HG rats (control: 18.74±1.59; HG: 38.39±3.39 area%; HG+XNT: 27.83±2.80 area%; P<0.05). Treatment with XNT did not alter the VEGF expression in HG animals (P>0.05). Altogether, these findings indicate that activation of ACE2 reduced the death of retinal ganglion cells by apoptosis in HG rats. PMID:26421871

  9. Inhibitory effects of kiwifruit extract on human platelet aggregation and plasma angiotensin-converting enzyme activity.

    PubMed

    Dizdarevic, Lili L; Biswas, Dipankar; Uddin, M D Main; Jørgenesen, Aud; Falch, Eva; Bastani, Nasser E; Duttaroy, Asim K

    2014-01-01

    Previous human studies suggest that supplementation with kiwifruits lowers several cardiovascular risk factors such as platelet hyperactivity, blood pressure and plasma lipids. The cardiovascular health benefit of fruit and vegetables is usually attributed to the complex mixture of phytochemicals therein; however, kiwifruit's cardioprotective factors are not well studied. In this study, we investigated the effects of kiwifruit extract on human blood platelet aggregation and plasma angiotensin-converting enzyme (ACE) activity. A sugar-free, heat-stable aqueous extract with molecular mass less than 1000 Da was prepared from kiwifruits. Typically, 100 g kiwifruits produced 66.3 ± 5.8 mg (1.2 ± 0.1 mg CE) of sugar-free kiwifruit extract (KFE). KFE inhibited both human platelet aggregation and plasma ACE activity in a dose-dependent manner. KFE inhibited platelet aggregation in response to ADP, collagen and arachidonic acid, and inhibitory action was mediated in part by reducing TxA2 synthesis. The IC50 for ADP-induced platelet aggregation was 1.6 ± 0.2 mg/ml (29.0 ± 3.0 μg CE/ml), whereas IC50 for serum ACE was 0.6 ± 0.1 mg/ml (11.0 ± 1.2 μg CE/ml). Consuming 500 mg of KFE (9.0 mg CE) in 10 g margarine inhibited ex vivo platelet aggregation by 12.7%, 2 h after consumption by healthy volunteers (n = 9). All these data indicate that kiwifruit contains very potent antiplatelet and anti-ACE components. Consuming kiwifruits might be beneficial as both preventive and therapeutic regime in cardiovascular disease. PMID:24219176

  10. DNA Methylation Analysis of the Angiotensin Converting Enzyme (ACE) Gene in Major Depression

    PubMed Central

    Zill, Peter; Baghai, Thomas C.; Schüle, Cornelius; Born, Christoph; Früstück, Clemens; Büttner, Andreas; Eisenmenger, Wolfgang; Varallo-Bedarida, Gabriella; Rupprecht, Rainer; Möller, Hans-Jürgen; Bondy, Brigitta

    2012-01-01

    Background The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ∼40%–50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. Materials and Methods The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. Results We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). Conclusion The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders. PMID:22808171

  11. Angiotensin I-Converting Enzyme Inhibitor Activity on Egg Albumen Fermentation

    PubMed Central

    Nahariah, N.; Legowo, A. M.; Abustam, E.; Hintono, A.

    2015-01-01

    Lactobacillus plantarum is used for fermentation of fish products, meat and milk. However, the utilization of these bacteria in egg processing has not been done. This study was designed to evaluate the potential of fermented egg albumen as a functional food that is rich in angiotensin I-converting enzyme inhibitors activity (ACE-inhibitor activity) and is antihypertensive. A completely randomized design was used in this study with six durations of fermentation (6, 12, 18, 24, 30, and 36 h) as treatments. Six hundred eggs obtained from the same chicken farm were used in the experiment as sources of egg albumen. Bacteria L. plantarum FNCC 0027 used in the fermentation was isolated from cow’s milk. The parameters measured were the total bacteria, dissolved protein, pH, total acid and the activity of ACE-inhibitors. The results showed that there were significant effects of fermentation time on the parameters tested. Total bacteria increased significantly during fermentation for 6, 12, 18, and 24 h and then decreased with the increasing time of fermentation to 30 and 36 h. Soluble protein increased significantly during fermentation to 18 h and then subsequently decreased during of fermentation to 24, 30, and 36 h. The pH value decreased markedly during fermentation. The activities of ACE-inhibitor in fermented egg albumen increased during fermentation to 18 h and then decreased with the increasing of the duration of fermentation to 24, 30, and 36 h. The egg albumen which was fermented for 18 h resulted in a functional food that was rich in ACE-inhibitor activity. PMID:25715689

  12. Angiotensin I Converting Enzyme Inhibitory Peptides Derived from Phycobiliproteins of Dulse Palmaria palmata

    PubMed Central

    Furuta, Tomoe; Miyabe, Yoshikatsu; Yasui, Hajime; Kinoshita, Yasunori; Kishimura, Hideki

    2016-01-01

    We examined the inhibitory activity of angiotensin I converting enzyme (ACE) in protein hydrolysates from dulse, Palmaria palmata. The proteins extracted from dulse were mainly composed of phycoerythrin (PE) followed by phycocyanin (PC) and allophycocyanin (APC). The dulse proteins showed slight ACE inhibitory activity, whereas the inhibitory activity was extremely enhanced by thermolysin hydrolysis. The ACE inhibitory activity of hydrolysates was hardly affected by additional pepsin, trypsin and chymotrypsin treatments. Nine ACE inhibitory peptides (YRD, AGGEY, VYRT, VDHY, IKGHY, LKNPG, LDY, LRY, FEQDWAS) were isolated from the hydrolysates by reversed-phase high-performance liquid chromatography (HPLC), and it was demonstrated that the synthetic peptide LRY (IC50: 0.044 μmol) has remarkably high ACE inhibitory activity. Then, we investigated the structural properties of dulse phycobiliproteins to discuss the origin of dulse ACE inhibitory peptides. Each dulse phycobiliprotein possesses α-subunit (Mw: 17,477–17,638) and β-subunit (Mw: 17,455–18,407). The sequences of YRD, AGGEY, VYRT, VDHY, LKNPG and LDY were detected in the primary structure of PE α-subunit, and the LDY also exists in the APC α- and β-subunits. In addition, the LRY sequence was found in the β-subunits of PE, PC and APC. From these results, it was suggested that the dulse ACE inhibitory peptides were derived from phycobiliproteins, especially PE. To make sure the deduction, we carried out additional experiment by using recombinant PE. We expressed the recombinant α- and β-subunits of PE (rPEα and rPEβ, respectively), and then prepared their peptides by thermolysin hydrolysis. As a result, these peptides showed high ACE inhibitory activities (rPEα: 94.4%; rPEβ: 87.0%). Therefore, we concluded that the original proteins of dulse ACE inhibitory peptides were phycobiliproteins. PMID:26861357

  13. Angiotensin I Converting Enzyme Inhibitory Peptides Derived from Phycobiliproteins of Dulse Palmaria palmata.

    PubMed

    Furuta, Tomoe; Miyabe, Yoshikatsu; Yasui, Hajime; Kinoshita, Yasunori; Kishimura, Hideki

    2016-02-01

    We examined the inhibitory activity of angiotensin I converting enzyme (ACE) in protein hydrolysates from dulse, Palmaria palmata. The proteins extracted from dulse were mainly composed of phycoerythrin (PE) followed by phycocyanin (PC) and allophycocyanin (APC). The dulse proteins showed slight ACE inhibitory activity, whereas the inhibitory activity was extremely enhanced by thermolysin hydrolysis. The ACE inhibitory activity of hydrolysates was hardly affected by additional pepsin, trypsin and chymotrypsin treatments. Nine ACE inhibitory peptides (YRD, AGGEY, VYRT, VDHY, IKGHY, LKNPG, LDY, LRY, FEQDWAS) were isolated from the hydrolysates by reversed-phase high-performance liquid chromatography (HPLC), and it was demonstrated that the synthetic peptide LRY (IC50: 0.044 μmol) has remarkably high ACE inhibitory activity. Then, we investigated the structural properties of dulse phycobiliproteins to discuss the origin of dulse ACE inhibitory peptides. Each dulse phycobiliprotein possesses α-subunit (Mw: 17,477-17,638) and β-subunit (Mw: 17,455-18,407). The sequences of YRD, AGGEY, VYRT, VDHY, LKNPG and LDY were detected in the primary structure of PE α-subunit, and the LDY also exists in the APC α- and β-subunits. In addition, the LRY sequence was found in the β-subunits of PE, PC and APC. From these results, it was suggested that the dulse ACE inhibitory peptides were derived from phycobiliproteins, especially PE. To make sure the deduction, we carried out additional experiment by using recombinant PE. We expressed the recombinant α- and β-subunits of PE (rPEα and rPEβ, respectively), and then prepared their peptides by thermolysin hydrolysis. As a result, these peptides showed high ACE inhibitory activities (rPEα: 94.4%; rPEβ: 87.0%). Therefore, we concluded that the original proteins of dulse ACE inhibitory peptides were phycobiliproteins. PMID:26861357

  14. Angiotensin-converting enzyme insertion/deletion polymorphism in heterozygous familial hypercholesterolemia patients

    SciTech Connect

    Maslen, C.L.; O`Malley, J.P.; Illingworth, D.R.

    1994-09-01

    The insertion/deletion polymorphism in angiotensin-converting enzyme (ACE/ID) has been shown to be an independent risk factor for myocardial infarction (MI). Patients with heterozygous familial hypercholesterolemia (FH) are known to be at greatly increased risk for heart disease because of their high levels of low density lipoprotein cholesterol. We obtained DNA samples from 105 unrelated FH patients and typed them for ACE/ID by PCR analysis. The frequencies of the DD, DI, and II genotypes were 0.381, 0.390, and 0.229, respectively. The allele frequencies were 0.576 for D and 0.423 for I. This is similar to the allele frequencies observed by Cambien et al. in a control population in Toulouse, France. The relative risk for MI or coronary artery disease (CAD) was assessed in patients who were aged 50 years or older. The criteria for CAD was history of coronary arterial bypass surgery. While the relative risk of having had a myocardial infarction was slightly increased from 0.14 (4/28) in the DI + II group to 0.16 (3/19) in the DD genotype, the differences were not statistically significant. The individual`s risk of CAD increased in the DD genotype, (0.579 of the DD population (n=19) compared to 0.321 of the DI + II population (n=28)). Therefore the ACE/ID polymorphism does appear to interact with FH in increasing a DD individual`s risk of heart disease by a factor of 1.8 relative to the DI and II genotypes.

  15. Angiotensin-I-converting enzyme-inhibitory peptides in commercial Wisconsin Cheddar cheeses of different ages.

    PubMed

    Lu, Y; Govindasamy-Lucey, S; Lucey, J A

    2016-01-01

    Bioactive peptides, including angiotensin-I-converting enzyme-inhibitory (ACEI) peptides, were investigated in commercially produced Wisconsin Cheddar cheeses that ranged in age from ≤ 6d to more than 2 yr. The ACEI activity of cheese was determined in water-soluble extracts (WSE) that were fractionated for components with molecular weight (MW) ≤ 3,000 Da, and peptides identified using HPLC and tandem mass spectrometry. The number of types of bioactive peptides increased with an increase in ripening time. Six of the identified ACEI peptides, Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP), Glu-Lys-Asp-Glu-Arg-Phe (EKDERF), Val-Arg-Tyr-Leu (VRYL), Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-Asn (YPFPGPIPN), and Phe-Phe-Val-Ala-Pro (FFVAP), with known high ACEI activity (low IC50 values, the concentration needed to inhibit ACE to 50% of its original activity) were synthesized and used to quantify the amounts of these peptides in various cheese extracts. The concentrations of these 6 ACEI peptides increased up to a certain stage of ripening. The maximum contents of IPP, VPP, and EKDERF were 2.8, 7.4, and 5.3mg/100 g of cheese, respectively, and these levels were found in a 1-yr-old Cheddar cheese sample. The maximum content of VRYL (7.5mg/100 g of cheese) was found in a 2-yr-old Cheddar cheese sample, whereas the maximum content of YPFPGPIPN (6.8 mg/100 g of cheese) was found in a 6-mo-old Cheddar cheese sample. Trace amounts of FFVAP were found in these cheeses. Aged Cheddar cheese was found to be a rich source of ACEI peptides even though large differences exist between cheeses from different manufacturers. PMID:26506550

  16. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    PubMed Central

    Guerrero, Ligia; Castillo, Julián; Quiñones, Mar; Garcia-Vallvé, Santiago; Arola, Lluis; Pujadas, Gerard; Muguerza, Begoña

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results. PMID:23185345

  17. Angiotensin-Converting Enzyme Inhibitors and Active Tuberculosis: A Population-Based Study.

    PubMed

    Wu, Jiunn-Yih; Lee, Meng-Tse Gabriel; Lee, Si-Huei; Lee, Shih-Hao; Tsai, Yi-Wen; Hsu, Shou-Chien; Chang, Shy-Shin; Lee, Chien-Chang

    2016-05-01

    Numerous epidemiological data suggest that the use of angiotensin-converting enzyme inhibitors (ACEis) can improve the clinical outcomes of pneumonia. Tuberculosis (TB) is an airborne bacteria like pneumonia, and we aimed to find out whether the use of ACEis can decrease the risk of active TB.We conducted a nested case-control analysis by using a 1 million longitudinally followed cohort, from Taiwan national health insurance research database. The rate ratios (RRs) for TB were estimated by conditional logistic regression, and adjusted using a TB-specific disease risk score (DRS) with 71 TB-related covariates.From January, 1997 to December, 2011, a total of 75,536 users of ACEis, and 7720 cases of new active TB were identified. Current use (DRS adjusted RR, 0.87 [95% CI, 0.78-0.97]), but not recent and past use of ACEis, was associated with a decrease in risk of active TB. Interestingly, it was found that chronic use (>90 days) of ACEis was associated with a further decrease in the risk of TB (aRR, 0.74, [95% CI, 0.66-0.83]). There was also a duration response effect, correlating decrease in TB risk with longer duration of ACEis use. The decrease in TB risk was also consistent across all patient subgroups (age, sex, heart failure, cerebrovascular diseases, myocardial infraction, renal diseases, and diabetes) and patients receiving other cardiovascular medicine.In this large population-based study, we found that subjects with recent and chronic use of ACEis were associated with decrease in TB risk. PMID:27175655

  18. Alterations in tissue glutathione and angiotensin converting enzyme due to inhalation of diesel engine exhaust

    SciTech Connect

    Chaudhari, A.; Dutta, S.

    1982-02-01

    Quantitative changes in reduced glutathione (GSH) and angiotensin converting enzyme (ACE) of lung and extrapulmonary tissues were determined following exposure of laboratory animals to diesel engine exhaust (DEE). Exposure of male rats and guinea pigs to DEE containing 750 ..mu..g particulates per cubic meter for 1 wk did not cause any changes in GSH levels of lung, liver, and heart compared to control values. Rats were then exposed for various time periods to 6 mg/m/sup 3/ DEE. Two weeks of exposure produced statistically significant increases of 21 and 7% in GSH levels of lung and liver, respectively, but no change in the heart. Following 4 wk of exposure, lung showed a 14% increase and heat an 11% increase in GSH level. Furthermore, rats exposed for 4 wk to DEE did not show any particular susceptibility toward the GSH-depleting effect of acetaminophen as compared to controls. A significant depletion (15%) of hepatic GSH was observed after 8 wk of exposure, while lung was still showing an increase of 18% in GSH and heart was unaffected. Time-dependent increases of 18 and 33% in serum ACE activity were noted after 4 and 8 wk of exposure. Pulmonary ACE activity did not decrease until after 8 wk, and then to a small extent (7%). The observed increases in GSH may have been related to the presence of NO/sub 2/ in the DEE. On the other hand, the depletion of hepatic GSH suggests production of electrophillic compounds due to an induction of metabolic activity of liver. The change in serum ACE activity may be due to time-requiring perturbations in the pulmonary endothelial cells.

  19. No association of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension.

    PubMed

    Benjafield, Adam V; Wang, William Y S; Morris, Brian J

    2004-07-01

    Recent intriguing findings from genetic linkage, knockout, and physiologic studies in mice and rats led us to conduct the first investigation of the novel angiotensin-converting enzyme 2 gene (ACE2) in human hypertension (HT). We genotyped four single nucleotide polymorphisms (SNP) (A-->G at nucleotide 1075 in intron 1, G-->A at nucleotide 8790 in intron 3, C-->G at nucleotide 28330 in intron 11, and G-->C at nucleotide 36787 in intron 16) in HT (n = 152) and normotensive (NT, n = 193) groups having inherently high biological power (>80%) due to our inclusion only of subjects whose parents had the same BP status as themselves. The SNPs were in linkage disequilibrium (D' = 54% to 100%, P =.05 to 0.0001). Because ACE2 is on the X chromosome, data for each sex were analyzed separately. Minor allele frequencies in HT versus NT were as follows: for the intron 1 variant 0.21 versus 0.17 in female subjects (P =.31) and 0.25 versus 0.29 in male subjects (P =.60); intron 3 variant 0.22 versus 0.18 in female subjects (P =.35) and 0.15 versus 0.20 in male subjects (P =.47); intron 11 variant 0.39 versus 0.46 in male subjects (P = 0.17) and 0.31 versus 0.30 in male subjects (P =.96); intron 16 variant 0.20 versus 0.19 in female subjects (P =.72) and 0.17 versus 0.17 in male subjects (P =.95). Haplotype analysis was also negative. These data provide little support for ACE2 in genetic predisposition to HT. PMID:15233982

  20. Effect of Jatropha curcas Peptide Fractions on the Angiotensin I-Converting Enzyme Inhibitory Activity

    PubMed Central

    Segura-Campos, Maira R.; Peralta-González, Fanny; Castellanos-Ruelas, Arturo; Chel-Guerrero, Luis A.; Betancur-Ancona, David A.

    2013-01-01

    Hypertension is one of the most common worldwide diseases in humans. Angiotensin I-converting enzyme (ACE) plays an important role in regulating blood pressure and hypertension. An evaluation was done on the effect of Alcalase hydrolysis of defatted Jatropha curcas kernel meal on ACE inhibitory activity in the resulting hydrolysate and its purified fractions. Alcalase exhibited broad specificity and produced a protein hydrolysate with a 21.35% degree of hydrolysis and 34.87% ACE inhibition. Ultrafiltration of the hydrolysate produced peptide fractions with increased biological activity (24.46–61.41%). Hydrophobic residues contributed substantially to the peptides' inhibitory potency. The 5–10 and <1 kDa fractions were selected for further fractionation by gel filtration chromatography. ACE inhibitory activity (%) ranged from 22.66 to 45.96% with the 5–10 kDa ultrafiltered fraction and from 36.91 to 55.83% with the <1 kDa ultrafiltered fraction. The highest ACE inhibitory activity was observed in F2 (IC50 = 6.7 μg/mL) from the 5–10 kDa fraction and F1 (IC50 = 4.78 μg/mL) from the <1 kDa fraction. ACE inhibitory fractions from Jatropha kernel have potential applications in alternative hypertension therapies, adding a new application for the Jatropha plant protein fraction and improving the financial viability and sustainability of a Jatropha-based biodiesel industry. PMID:24224169

  1. The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease

    PubMed Central

    2014-01-01

    Introduction Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau). Methods We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF. Results Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively. Conclusions These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD. PMID:24987467

  2. Adipocyte-derived lipids increase angiotensin-converting enzyme (ACE) expression and modulate macrophage phenotype.

    PubMed

    Kohlstedt, Karin; Trouvain, Caroline; Namgaladze, Dmitry; Fleming, Ingrid

    2011-03-01

    Human monocytes/macrophages express the angiotensin-converting enzyme (ACE) but nothing is known about its role under physiological conditions. As adipose tissue contains resident macrophages that have been implicated in the generation of insulin resistance in expanding fat mass, we determined whether adipocytes release factors that affect ACE expression and function in monocytes. Incubation of human monocyte-derived macrophages with conditioned medium from freshly isolated human adipocytes (BMI = 25.4 ± 0.96) resulted in a 4-fold increase in ACE expression. The effect was insensitive to denaturation and different proteases but abolished after lipid extraction. mRNA levels of the major histocompatibility complex class II protein increased in parallel with ACE, whereas the expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, and cyclooxygenase-2 decreased. As a consequence of the reduction in MCP-1, monocyte recruitment was also attenuated. Moreover, adipocyte-conditioned medium prevented the interferon (IFN)-γ induced formation of TNF-α, IL-6, and MCP-1, all markers of classically-activated (M1 type) macrophages. The decrease in cytokine expression in adipocyte-conditioned medium-treated macrophages was sensitive to ACE silencing by small interfering RNA (siRNA). Accordingly, ACE overexpression in THP-1 cells mimicked the effect of adipocyte-conditioned medium. In both cell types, ACE inhibition failed to affect the changes induced by adipocyte conditioned-medium treatment and ACE overexpression. Thus, the modulation of macrophage polarization by ACE appears to be mediated independently of enzyme activity, probably via intracellular signaling. Interestingly, human macrophage ACE expression was also upregulated by IL-4 and IL-13, which promote the "alternative" activation of macrophages and decreased by LPS and IFN-γ. Mechanistically, adipocyte-conditioned medium stimulated the phosphorylation of

  3. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    PubMed Central

    2012-01-01

    Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005), we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088) and in ARBs after price adjustments in 2001 (173.4%, p < 0.0001) and 2007 (146.3%, p < 0.0001). A significant long-term trend decrease in expenditures was observed for off-patent ACEIs after 2004 price adjustment (

  4. Pharmacology of a phosphorus-containing novel angiotensin converting enzyme inhibitor, SQ 29 852 in anesthetized dogs.

    PubMed

    Ohara, N; Yokota, S; Konishi, C; Shukunobe, K; Ono, H

    1991-12-01

    The effects of (S)-1[6-amino-2[[hydrozy(4- phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29 852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI), which is synthesized aiming an ACEI with long-lasting activity and with few side effects, were studied using anesthetized dogs. SQ 29 852 was equipotent with captopril to modify blood pressure response of the animals to angiotensin I (Ang I) and bradykinin (Bdk). An intravenous infusion of SQ 29 852 at 0.1 mg/kg/min for 30 min caused a remarkable hypotension without reflex tachycardia in open-chest dogs. In these animals cardiac contractility (dP/dtmax of left ventricular pressure) appeared to be reduced by SQ 29 852 without any changes in right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP) and aortic blood flow (AoF, cardiac output). In sodium-restricted dogs, the hypotension and renal vasodilation by SQ 29 852 (at 0.01, 0.1, and 1 mg/kg, i.v.) were slightly pronounced compared with animals fed with normal diet. It is demonstrated from these results that SQ 29 852 has comparable potency with captopril to inhibit angiotensin converting enzyme (ACE) activity and as common a pharmacological profile as ACEI. SQ 29 852 may be a favorable antihypertensive agent, if its long-lasting activity and few side effects are confirmed. PMID:1812274

  5. Differential regulation of angiotensin converting enzyme 2 and nuclear factor-κB by angiotensin II receptor subtypes in type 2 diabetic kidney.

    PubMed

    Pandey, Anuradha; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Gaikwad, Anil Bhanudas

    2015-11-01

    Angiotensin II (Ang II) acts through Angiotensin Converting Enzyme (ACE)/Ang II type 1 receptor (AT1R) axis to promote renal failure whereas the Ang II type 2 receptor (AT2R)/Angiotensin Converting Enzyme 2 (ACE2)/Ang1-7/Mas axis constitutes the protective arm of Renin Angiotensin System (RAS). Though Ang II has been known to activate the Nuclear Factor-κB (NF-κB) signalling pathway through different receptor subtype(s) in different tissues under various diseases, the subtype orchestrating this stimulation in type 2 diabetic kidney remains elusive. ACE2, a protective monocarboxypeptidase, responsible for conversion of Ang II to Ang1-7, opposes the deleterious effects of RAS pathway but how its expression is altered with blockade of AT1R and AT2R is not yet known. Hence, the present study was conceived to understand the regulation of NF-κB and ACE2 by using specific AT1 and AT2 receptor antagonists in non-genetic model of type 2 diabetic nephropathy. Our results show that the AT1R and AT2R antagonists lead to the repression and activation of NF-κB signalling pathway, respectively which suggests the role of AT1R in NF-κB activation. The blockade of AT2R led to an increase in ACE2 expression, which may be a compensatory response to the drastically increased inflammatory mediators and oxidative stress in the diabetic kidney. To the best of our knowledge, this is the first study showing the differential regulation of NF-κB and ACE2 by Ang II receptor subtypes and thus this study improves our understanding regarding regulation of inflammatory cascade and ACE2 by AT1R and AT2R in type 2 diabetic kidney, which may help in designing novel strategies to combat the disease in future. PMID:26271886

  6. Angiotensin-Converting Enzyme Genotype Affects Skeletal Muscle Strength In Elite Athletes

    PubMed Central

    Costa, Aldo Matos; Silva, António José; Garrido, Nuno; Louro, Hugo; Marinho, Daniel Almeida; Cardoso Marques, Mário; Breitenfeld, Luiza

    2009-01-01

    Previous studies have associated angiotensin-converting enzyme (ACE) D allele with variability in the skeletal muscle baseline strength, though conclusions have been inconsistent across investigations. The purpose of this study was to examine the possible association between ACE genotype and skeletal muscle baseline strength in elite male and female athletes involved in different event expertise. A group of 58 elite athletes, designated as Olympic candidates, were studied: 35 swimmers (19 males and 16 females, 18.8 ± 3.2 years) and 23 triathletes (15 males and 8 females, 18.7 ± 3.0 years). The athletes were classified as: short (≤ 200m) and middle (400m to 1500m) distance athletes, respectively. For each subject the grip strength in both hands was measure using an adjustable mechanical hand dynamometer. The maximum height in both squat jump (SJ) and counter movement jump (CMJ) were also assessed, using a trigonometric carpet (Ergojump Digitime 1000; Digitest, Jyvaskyla, Finland). DNA extraction was obtained with Chelex 100® and genotype determination by PCR-RFLP methods. Both males and females showed significantly higher right grip strength in D allele carriers compared to II homozygote’s. We found that allelic frequency differs significantly by event distance specialization in both genders (p < 0.05). In fact, sprinter D allele carriers showed the superior scores in nearly all strength measurements (p < 0.05), in both genders. Among endurance athletes, the results also demonstrated that female D allele carriers exhibited the higher performance right grip and CMJ scores (p < 0.05). In conclusion, the ACE D allele seems associated with skeletal muscle baseline strength in elite athletes, being easily identified in females. Key points DD homozygote’s and D allele carriers from both genders shows significantly higher right grip strength. Right grip strength remains significantly higher in the D allele carrier’s female endurance group. Female’s D allele

  7. Multifunctional gold nanoparticles for targeted imaging of angiotensin converting enzyme design, characterization, and application

    NASA Astrophysics Data System (ADS)

    Ghann, William Emmanuel

    Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the United States with approximately one in every three death being attributed to these diseases. The overarching problem with heart diseases is that once a person has suffered from an attack, there is a high likelihood of a recurrent attack. According to the American Heart Association, approximately 785,000 Americans per year suffer from heart attacks for the first time and about half of the aforementioned experience an ensuing attack. The second attack is often fatal, and therefore relapse prevention is crucial. One of the possible ways of averting the recurrence of such an attack is through the precise monitoring of the preceding biomarkers or risk indicators. This project encompasses the design, synthesis, characterization, and application of nanoparticle-based contrast agents that can potentially be used in the monitoring of the reemergence of a biomarker expressed after a person has suffered myocardial infarction. The overexpression of this biomarker, angiotensin converting enzyme (ACE), is also associated with development of cardiac and pulmonary fibrosis. To this end, highly concentrated gold nanoparticles have been synthesized and conjugated to Lisinopril, an ACE inhibitor, for the molecular imaging of ACE using X-ray CT. Various stabilities studies were conducted to verify the resistance of this gold nanoprobe in biological relevant media. They have also been successfully used in X-ray computed tomography to visualize tissue ACE and thus render them potentially versatile in the monitoring of cardiovascular diseases. An MRI tag was also conjugated to the gold nanoparticle affording the opportunity for bimodal imaging of ACE. This contrast agent could further be used for the quantification using K-edge CT of the relationship between the amount of the said marker and its role in predicting the possibility of a successive heart attack. The prepared nanoparticle-based contrast

  8. The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism

    PubMed Central

    Vaughan, David; Brogioli, Michael; Maier, Thomas; White, Andy; Waldron, Sarah; Rittweger, Jörn; Toigo, Marco; Wettstein, Jessica; Laczko, Endre; Flück, Martin

    2016-01-01

    Objective A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. Methods Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. Results Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and –3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. Conclusion The observations imply a genetically modulated role for ACE in control of

  9. Automated multi-step purification protocol for Angiotensin-I-Converting-Enzyme (ACE).

    PubMed

    Eisele, Thomas; Stressler, Timo; Kranz, Bertolt; Fischer, Lutz

    2012-12-12

    Highly purified proteins are essential for the investigation of the functional and biochemical properties of proteins. The purification of a protein requires several steps, which are often time-consuming. In our study, the Angiotensin-I-Converting-Enzyme (ACE; EC 3.4.15.1) was solubilised from pig lung without additional detergents, which are commonly used, under mild alkaline conditions in a Tris-HCl buffer (50mM, pH 9.0) for 48h. An automation of the ACE purification was performed using a multi-step protocol in less than 8h, resulting in a purified protein with a specific activity of 37Umg(-1) (purification factor 308) and a yield of 23.6%. The automated ACE purification used an ordinary fast-protein-liquid-chromatography (FPLC) system equipped with two additional switching valves. These switching valves were needed for the buffer stream inversion and for the connection of the Superloop™ used for the protein parking. Automated ACE purification was performed using four combined chromatography steps, including two desalting procedures. The purification methods contained two hydrophobic interaction chromatography steps, a Cibacron 3FG-A chromatography step and a strong anion exchange chromatography step. The purified ACE was characterised by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and native-PAGE. The estimated monomer size of the purified glycosylated ACE was determined to be ∼175kDa by SDS-PAGE, with the dimeric form at ∼330kDa as characterised by a native PAGE using a novel activity staining protocol. For the activity staining, the tripeptide l-Phe-Gly-Gly was used as the substrate. The ACE cleaved the dipeptide Gly-Gly, releasing the l-Phe to be oxidised with l-amino acid oxidase. Combined with peroxidase and o-dianisidine, the generated H(2)O(2) stained a brown coloured band. This automated purification protocol can be easily adapted to be used with other protein purification tasks. PMID:23217308

  10. Lymphocyte-suppressing action of angiotensin-converting enzyme inhibitors in coronary artery disease patients with normal blood pressure.

    PubMed

    Krysiak, Robert; Okopień, Bogusław

    2011-01-01

    The clinical effectiveness of angiotensin-converting enzyme (ACE) in the prevention and treatment of cardiovascular disorders partially results from its anti-inflammatory action. No previous study has investigated the effect of any ACE inhibitor on lymphocyte cytokine release. In this study, we compared the effects of serum- and tissue-type angiotensin-converting enzyme inhibitors on systemic inflammation and lymphocyte secretory function in normotensive patients with stable coronary artery disease. The study included 134 patients with coronary artery disease who were randomized into one of three groups and treated with enalapril (20 mg/d, n = 47), perindopril (4 mg/d, n = 45) or placebo (n = 42), respectively. The control group included 40 age-, sex- and weight-matched healthy subjects. The plasma lipid profile, glucose metabolism markers, hsCRP and lymphocyte cytokine release were examined at the beginning of the study and after 30 and 90 days of treatment. Phytohemagglutinin-stimulated T cells released significantly more interleukin-2, interferon-γ and TNFα than the lymphocytes of control subjects. Neither enalapril nor perindopril treatment was associated with any significant changes in blood pressure. Perindopril treatment inhibited lymphocyte cytokine release and systemic inflammation, while the effect of enalapril was insignificant. Perindopril, and, to a lesser extent, enalapril, strongly reduced lymphocyte cytokine release in insulin-resistant but not insulin-sensitive subjects. Our results indicate that perindopril is superior to enalapril in producing lymphocyte-suppressing and systemic anti-inflammatory effects in normotensive coronary artery disease patients. These effects may contribute to a reduction in the vascular risk of this group of patients, particularly in those subjects who are resistant to insulin, when these patients are treated with tissue-type angiotensin-converting enzyme inhibitors. PMID:22180357

  11. New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

    PubMed Central

    Ferreira, Anderson J.; Murça, Tatiane M.; Fraga-Silva, Rodrigo A.; Castro, Carlos Henrique; Raizada, Mohan K.; Santos, Robson A. S.

    2012-01-01

    Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT1 receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis. PMID:22319643

  12. Angiotensin-converting enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus.

    PubMed

    Mizuiri, S; Hemmi, H; Inoue, A; Yoshikawa, H; Tanegashima, M; Fushimi, T; Ishigami, M; Amagasaki, Y; Ohara, T; Shimatake, H

    1995-01-01

    We determined the distribution frequency of angiotensin-converting enzyme insertion/deletion (I/D) polymorphism in 111 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) of at least 10 years duration (80 patients with diabetic nephropathy and 31 patients without nephropathy) and 76 healthy Japanese controls. Patients with diabetic nephropathy showed an excess of the ID genotype compared with patients without nephropathy (p < 0.02) and less of the II genotype compared with healthy controls (p < 0.01) and patients without nephropathy (p < 0.01). NIDDM patients with the II genotype have a decreased risk for the development of diabetic nephropathy. PMID:7477652

  13. Significant correlation of angiotensin converting enzyme and glycoprotein IIIa genes polymorphisms with unexplained recurrent pregnancy loss in north of Iran

    PubMed Central

    Fazelnia, Shokoufeh; Farazmandfar,, Touraj; Hashemi-Soteh, Seyed Mohammad Bagher

    2016-01-01

    Background: Spontaneous abortion is considered as the most complex problem during pregnancy. Thrombophilia is resumed as a cause of recurrent pregnancy loss (RPL). Glycoprotein IIIa (GPIIIa) gene is involved in thrombosis and abortion. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II and is involved in thrombosis. The most common polymorphism in this gene is the insertion/deletion (I/D). Objective: In this study, we analyzed the association between ACE I/D and GPIIIa c.98C >T polymorphisms in women with unexplained RPL from the north of Iran. Materials and Methods: Sample population consisted of 100 women with unexplained RPL and 100 controls. The ACE I/D and GPIIIa c.98C>T polymorphisms were genotyped by TETRA-ARMS PCR. The association between genotypes frequency and RPL were analyzed using χ2 and exact fisher tests. Associated risk with double genotype combinations was also investigated by binary logistic regression. Results: There was significant association between ACE DD genotype and RPL (OR=2.04; 95% CI=0.94-4.44; p=0.036). ACE D Allele was also significantly associated with the RPL (OR=1.59; 95% CI=1.05-2.41; p=0.013). No significant association was observed between GPIIIa c.98C>T polymorphism and RPL. Conclusion: ACE I/D polymorphism may probably be a prognostic factor in female family members of women with the history of recurrent abortion. PMID:27326417

  14. Molecular evidence for the expression of angiotensin converting enzyme in hemocytes of Locusta migratoria: stimulation by bacterial lipopolysaccharide challenge.

    PubMed

    Macours, N; Hens, K; Francis, C; De Loof, A; Huybrechts, R

    2003-08-01

    The presence of angiotensin converting enzyme (ACE) in insects has been reported many times, but numerous questions about the functional role of this enzyme in insects remain. Here we show by RT-PCR experiments that ACE has a wide tissue distribution in Locusta migratoria, suggesting diverse roles for this enzyme in the locust. Immune challenge through injection of bacterial lipopolysaccharides resulted in a tenfold increase of ACE gene transcripts in the hemocytes and is suggestive for a role of ACE in the cellular defense of the locust. However, phenotypic knockout experiments with the ACE inhibitor captopril showed that ACE is not essential for the efficient clearance of injected E. coli bacteria. PMID:12880654

  15. Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

    PubMed

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. PMID:26612192

  16. Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice.

    PubMed

    Dominguez, James M; Hu, Ping; Caballero, Sergio; Moldovan, Leni; Verma, Amrisha; Oudit, Gavin Y; Li, Qiuhong; Grant, Maria B

    2016-06-01

    Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP(+) cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm(2)) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm(2)) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80(+)) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm(2); reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm(2)). In both study cohorts, intracapillary bone marrow-derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system. PMID:27178803

  17. Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Oxidant Activities of Sea Cucumber (Actinopyga lecanora) Hydrolysates.

    PubMed

    Ghanbari, Raheleh; Zarei, Mohammad; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid

    2015-01-01

    In recent years, food protein-derived hydrolysates have received considerable attention because of their numerous health benefits. Amongst the hydrolysates, those with anti-hypertensive and anti-oxidative activities are receiving special attention as both activities can play significant roles in preventing cardiovascular diseases. The present study investigated the angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities of Actinopyga lecanora (A. lecanora) hydrolysates, which had been prepared by alcalase, papain, bromelain, flavourzyme, pepsin, and trypsin under their optimum conditions. The alcalase hydrolysate showed the highest ACE inhibitory activity (69.8%) after 8 h of hydrolysis while the highest anti-oxidative activities measured by 2,2-diphenyl 1-1-picrylhydrazyl radical scavenging (DPPH) (56.00%) and ferrous ion-chelating (FIC) (59.00%) methods were exhibited after 24 h and 8 h of hydrolysis, respectively. The ACE-inhibitory and anti-oxidative activities displayed dose-dependent trends, and increased with increasing protein hydrolysate concentrations. Moreover, strong positive correlations between angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities were also observed. This study indicates that A. lecanora hydrolysate can be exploited as a source of functional food owing to its anti-oxidant as well as anti-hypertension functions. PMID:26690117

  18. Angiotensin-I Converting Enzyme (ACE) Inhibitory and Anti-Oxidant Activities of Sea Cucumber (Actinopyga lecanora) Hydrolysates

    PubMed Central

    Ghanbari, Raheleh; Zarei, Mohammad; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid

    2015-01-01

    In recent years, food protein-derived hydrolysates have received considerable attention because of their numerous health benefits. Amongst the hydrolysates, those with anti-hypertensive and anti-oxidative activities are receiving special attention as both activities can play significant roles in preventing cardiovascular diseases. The present study investigated the angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities of Actinopyga lecanora (A. lecanora) hydrolysates, which had been prepared by alcalase, papain, bromelain, flavourzyme, pepsin, and trypsin under their optimum conditions. The alcalase hydrolysate showed the highest ACE inhibitory activity (69.8%) after 8 h of hydrolysis while the highest anti-oxidative activities measured by 2,2-diphenyl 1-1-picrylhydrazyl radical scavenging (DPPH) (56.00%) and ferrous ion-chelating (FIC) (59.00%) methods were exhibited after 24 h and 8 h of hydrolysis, respectively. The ACE-inhibitory and anti-oxidative activities displayed dose-dependent trends, and increased with increasing protein hydrolysate concentrations. Moreover, strong positive correlations between angiotensin-I converting enzyme (ACE) inhibitory and anti-oxidative activities were also observed. This study indicates that A. lecanora hydrolysate can be exploited as a source of functional food owing to its anti-oxidant as well as anti-hypertension functions. PMID:26690117

  19. Radioimmunoimaging of lung vessels: An approach using indium-111-labeled monoclonal antibody to angiotensin-converting enzyme

    SciTech Connect

    Danilov, S.M.; Martynov, A.V.; Klibanov, A.L.; Slinkin, M.A.; Sakharov, I.Yu.; Malov, A.G.; Sergienko, V.B.; Vedernikov, A.Yu.; Muzykantov, V.R.; Torchilin, V.P.

    1989-10-01

    A murine monoclonal antibody against human angiotensin-converting enzyme was radiolabeled with {sup 111}In via diethylenetriaminepentaacetic acid without substantial loss of antigen-binding capacity. This monoclonal antibody designated 9B9 cross-reacted with rat and monkey angiotensin-converting enzyme. Indium-111-labeled 9B9 selectively accumulated 10-20 times greater in the lung than in blood or other organs following intravenous administration in rats. Kinetics of lung accumulation and blood clearance were studied for {sup 111}In-9B9-antibody and compared to that of {sup 125}I-labeled 9B9 in rat. Highly specific accumulation of {sup 111}In-9B9-antibody in the lung of Macaca Rhesus monkeys after intravenous injection was monitored by gamma-imaging. Images of {sup 111}In-labeled antibody 9B9 biodistribution in monkey lung noticeably differ from the images of biodistribution of {sup 99m}Tc-labeled albumin microspheres. This difference may provide information concerning the state of the endothelium of lung capillaries, which is different from the blood flow characteristics determined with routine microsphere technique.

  20. Increase of migration of cultured endothelial cells by angiotensin-converting enzyme inhibitor derived from tuna muscle.

    PubMed

    Kohama, Y; Oka, H; Murayama, N; Iida, K; Itoh, M; Itoh, M; Ying, X; Mimura, T

    1992-05-01

    The influence of angiotensin-converting enzyme (ACE) inhibitory octapeptide derived from tuna muscle (tuna AI) on the bovine aorta endothelial cell (BAEC) migration was investigated, as compared with captopril. BAEC migration was quantitated 6 d after release from contact inhibition by a teflon fence assay. The culture grown in the presence of tuna AI (1 and 10 microM) clearly exhibited an increase in migration, compared with the control. The media collected from tuna AI (1 and 10 microM)-stimulated BAECs significantly exhibited the interleukin (IL) -1 activity that was detected by the thymocyte costimulation assay with phytohemagglutinin. Although tuna AI was a weaker ACE inhibitor than captopril, the increasing effect of tuna AI on the migration and the IL-1 generation in BAECs was slightly greater than that of captopril. In quiescent BAECs, tuna AI (1 microM) apparently induced c-myc and platelet derived growth factor (PDGF) A-chain messenger ribonucleic acid (mRNA) expressions within 30 min, which persisted for 6 h. In contrast, captopril induced a very low expression of c-myc mRNA, and had no relation to PDGF A-chain mRNA expression. These results suggest that the increase of BAEC migration by tuna AI, unlike captopril, is likely related to the induction or activation of IL-1, and c-myc and PDGF mRNAs, in addition to the inhibition of the conversion of endogenous angiotensin I to angiotensin II. PMID:1527698

  1. Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways

    PubMed Central

    Chappell, Mark C.; Marshall, Allyson C.; Alzayadneh, Ebaa M.; Shaltout, Hossam A.; Diz, Debra I.

    2013-01-01

    The renin-angiotensin-system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. Indeed, dysregulation of the RAS may lead to the development of cardiovascular pathologies including kidney injury. Moreover, the blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS that the system is comprised of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the non-classical RAS composed of the ACE2-Ang-(1–7)-Mas receptor axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and oxidative stress. Thus, a reduced tone of the Ang-(1–7) system may contribute to these pathologies as well. Moreover, the non-classical RAS components may contribute to the effects of therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury. The review considers recent studies on the ACE2-Ang-(1–7)-Mas receptor axis regarding the precursor for Ang-(1–7), the intracellular expression and sex differences of this system, as well as an emerging role of the Ang1-(1–7) pathway in fetal programing events and cardiovascular dysfunction. PMID:24409169

  2. Angiotensin-converting enzyme gene 2350 G/A polymorphism and susceptibility to atrial fibrillation in Han Chinese patients with essential hypertension

    PubMed Central

    Jiang, Min-Hui; Su, Ya-Min; Tang, Jian-Zhong; Shen, Yan-Bo; Deng, Xin-Tao; Yuan, Ding-Shan; Wu, Jie; Pan, Min; Huang, Zhong-Wei

    2013-01-01

    OBJECTIVE: The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension. METHODS: A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies. RESULTS: The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively). CONCLUSIONS: The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension. PMID:24270955

  3. Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review

    PubMed Central

    Gard, Paul R

    2010-01-01

    This review considers the 250+ papers concerning the association of the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (rs1799752) and various disease conditions published in 2009. The deletion allele occurs in approximately 55% of the population and is associated with increased activity of the ACE enzyme. It might be predicted that the D allele, therefore, might be associated with pathologies involving increased activity of the renin-angiotensin system. The D allele was seen to be associated with an increased risk of hypertension, pre-eclampsia, heart failure, cerebral infarct, diabetic nephropathy, encephalopathy, asthma, severe hypoglycaemia in diabetes, gastric cancer (in Caucasians) and poor prognosis following kidney transplant. On the positive side, the D allele appears to offer protection against schizophrenia and chronic periodontitis and confers greater up-per-body strength in old age. The I allele, meanwhile, offers improved endurance/athletic performance and aerobic capacity as determined by lung function tests, although it does increase the risk of oral squamous cell carcinoma and obstructive sleep apnoea in hypertensives. PMID:21537387

  4. Regulation of cardiac angiotensin-converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene-disrupted mice

    PubMed Central

    Pandey, Kailash N; Vellaichamy, Elangovan

    2015-01-01

    SUMMARY Understanding of the regulatory mechanisms of gene expression in the control of blood pressure and fluid volume is a key issue in cardiovascular medicine. Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signalling antagonizes the physiological and pathophysiological effects mediated by the renin–angiotensin–aldosterone system (RAAS) in the regulation of cardiovascular homeostasis.The targeted-disruption of the Npr1 gene (coding for GC-A/PRA) leads to activation of the cardiac RAAS involved in the hypertrophic remodelling process, which influences cardiac size, expression of pro-inflammatory cytokine genes and the behaviour of various hypertrophy marker genes. The Npr1 gene-knockout (Npr1−/−) mice exhibit 35–40 mmHg higher systolic blood pressure and a significantly greater heart weight to bodyweight ratio than wild-type (Npr1+/+) mice.The expression of both angiotensin-converting enzyme (ACE) and angiotensin II AT1a receptors are significantly increased in hearts from Npr1−/− mice compared with hearts from Npr1+/+ mice. In parallel, the expression of interleukin-6 and tumour necrosis factor-α is also markedly increased in hearts from Npr1−/− mice.These findings indicate that disruption of NPRA/cGMP signalling leads to augmented expression of the cardiac RAAS in conjunction with pro-inflammatory cytokines in Npr1-null mutant mice, which promotes the development of cardiac hypertrophy and remodelling. PMID:19843097

  5. Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

    PubMed

    Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

    2015-12-01

    For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors. PMID:26105590

  6. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.

    PubMed

    Raimondi, Sara; Botteri, Edoardo; Munzone, Elisabetta; Cipolla, Carlo; Rotmensz, Nicole; DeCensi, Andrea; Gandini, Sara

    2016-07-01

    Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2)  = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted. PMID:26916107

  7. Diabetes and CVD risk during angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment in hypertension: a study of 15 990 patients

    PubMed Central

    Hasvold, L P; Bodegård, J; Thuresson, M; Stålhammar, J; Hammar, N; Sundström, J; Russell, D; Kjeldsen, S E

    2014-01-01

    Differences in clinical effectiveness between angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in the primary treatment of hypertension are unknown. The aim of this retrospective cohort study was to assess the prevention of type 2 diabetes and cardiovascular disease (CVD) in patients treated with ARBs or ACEis. Patients initiated on enalapril or candesartan treatment in 71 Swedish primary care centers between 1999 and 2007 were included. Medical records data were extracted and linked with nationwide hospital discharge and cause of death registers. The 11 725 patients initiated on enalapril and 4265 on candesartan had similar baseline characteristics. During a mean follow-up of 1.84 years, 36 482 patient-years, the risk of new diabetes onset was lower in the candesartan group (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69–0.96, P=0.01) compared with the enalapril group. No difference between the groups was observed in CVD risk (HR 0.99, 95% CI 0.87–1.13, P=0.86). More patients discontinued treatment in the enalapril group (38.1%) vs the candesartan group (27.2%). In a clinical setting, patients initiated on candesartan treatment had a lower risk of new-onset type 2 diabetes and lower rates of drug discontinuation compared with patients initiated on enalapril. No differences in CVD risk were observed. PMID:25211055

  8. Catalytic properties of recombinant dipeptidyl carboxypeptidase from Escherichia coli: a comparative study with angiotensin I-converting enzyme.

    PubMed

    Cunha, Carlos Eduardo L; Magliarelli, Helena de Fátima; Paschoalin, Thaysa; Nchinda, Aloysius T; Lima, Jackson C; Juliano, Maria A; Paiva, Paulo B; Sturrock, Edward D; Travassos, Luiz R; Carmona, Adriana K

    2009-09-01

    Dipeptidyl carboxypeptidase from Escherichia coli (EcDcp) is a zinc metallopeptidase with catalytic properties closely resembling those of angiotensin I-converting enzyme (ACE). However, EcDcp and ACE are classified in different enzyme families (M3 and M2, respectively) due to differences in their primary sequences. We cloned and expressed EcDcp and studied in detail the enzyme's S(3) to S(1)' substrate specificity using positional-scanning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides. These peptides contain ortho-aminobenzoic acid (Abz) and 2,4-dinitrophenyl (Dnp) as donor/acceptor pair. In addition, using FRET substrates developed for ACE [Abz-FRK(Dnp)P-OH, Abz-SDK(Dnp)P-OH and Abz-LFK(Dnp)-OH] as well as natural ACE substrates (angiotensin I, bradykinin, and Ac-SDKP-OH), we show that EcDcp has catalytic properties very similar to human testis ACE. EcDcp inhibition studies were performed with the ACE inhibitors captopril (K(i)=3 nM) and lisinopril (K(i)=4.4 microM) and with two C-domain-selective ACE inhibitors, 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-tryptophan (kAW; K(i)=22.0 microM) and lisinopril-Trp (K(i)=0.8 nM). Molecular modeling was used to provide the basis for the differences found in the inhibitors potency. The phylogenetic relationship of EcDcp and related enzymes belonging to the M3 and M2 families was also investigated and the results corroborate the distinct origins of EcDcp and ACE. PMID:19558329

  9. Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin-angiotensin system

    PubMed Central

    Garcia, P; Schwenzer, S; Slotta, JE; Scheuer, C; Tami, AE; Holstein, JH; Histing, T; Burkhardt, M; Pohlemann, T; Menger, MD

    2010-01-01

    Background and purpose: The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, ‘local’ tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. Experimental approach: In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. Key results: ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Conclusions: Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling. PMID:20233225

  10. Effects of nabumetone, celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors.

    PubMed

    Palmer, Robert; Weiss, Robert; Zusman, Randall M; Haig, Ann; Flavin, Susan; MacDonald, Brian

    2003-02-01

    Nonsteroidal anti-inflammatory drugs interfere with certain antihypertensive therapies. In a double-blind study, 385 hypertensive patients stabilized on an angiotensin converting enzyme inhibitor were treated with nabumetone, celecoxib, ibuprofen, or placebo for 4 weeks. Ibuprofen caused significantly greater increases in systolic (P < .001) and diastolic (P < .01) blood pressures (BPs) compared to placebo, but not nabumetone or celecoxib. The proportion of patients with systolic BP increases of clinical concern at end point was significantly higher (P < .001) for the ibuprofen group (16.7%; 15 of 90), but not for the nabumetone group (5.5%; 5 of 91) or the celecoxib group (4.6%; 4 of 87) compared to the placebo group (1.1%; 1 of 91). PMID:12559680

  11. Synthesis and biological studies of highly concentrated lisinopril-capped gold nanoparticles for CT tracking of angiotensin converting enzyme (ACE)

    NASA Astrophysics Data System (ADS)

    Ghann, William E.; Aras, Omer; Fleiter, Thorsten; Daniel, Marie-Christine

    2011-05-01

    For patients with a history of heart attack or stroke, the prevention of another cardiovascular or cerebrovascular event is crucial. The development of cardiac and pulmonary fibrosis has been associated with overexpression of tissue angiotensin-converting enzyme (ACE). Recently, gold nanoparticles (GNPs) have shown great potential as X-ray computed tomography (CT) contrast agents. Since lisinopril is an ACE inhibitor, it has been used as coating on GNPs for targeted imaging of tissue ACE in prevention of fibrosis. Herein, lisinopril-capped gold nanoparticles (LIS-GNPs) were synthesized up to a concentration of 55 mgAu/mL. Their contrast was measured using CT and the results were compared to Omnipaque, a commonly used iodine-based contrast agent. The targeting ability of these LIS-GNPs was also assessed.

  12. An Unusual Case of Angiotensin-Converting-Enzyme Inhibitor-Related Penile Angioedema with Evolution to the Oropharynx

    PubMed Central

    Wagner, Jonathan G.; Bench, Elias M.; Plantmason, Lee

    2015-01-01

    A 52-year-old African American male with a long history of poorly controlled hypertension presented to the emergency department (ED) with two days of genital edema and pain. During ED work-up, the patient developed sudden onset of non-pitting, non-pruritic, and non-urticarial upper lip edema. Review of his antihypertensive medication list revealed that he normally took benazepril, highly suggestive of a diagnosis of angiotensin-converting-enzyme inhibitor-related angioedema (ACEI-RA). We present the first reported case of penile ACEI-RA that progressed to involve the oropharynx. The ED management of the condition and some of the newer treatment options available for ACEI-RA is also briefly discussed. PMID:26759679

  13. The angiotensin-converting enzyme gene insertion–deletion polymorphism in a white British patient cohort with obstetric cholestasis

    PubMed Central

    Müllenbach, Roman; Tetlow, Natasha; Bennett, Amanda; Pipkin, Fiona Broughton; Morgan, Linda; Williamson, Catherine

    2009-01-01

    The DD genotype of the angiotensin-converting enzyme (ACE) gene is over-represented in Finnish patients with obstetric cholestasis (OC). The purpose of this study was to establish whether this genotype is associated with cholestasis in UK cases. In a retrospective case-control study, we determined the ACE insertion/deletion frequencies in 166 British cases and 100 control women by polymerase chain reaction analysis. No significant difference in allele frequencies was found between these groups, but allele frequencies differed significantly between Finnish and UK OC cases (P = 0.0005). The prevalence of the DD genotype is lower in UK cases than in controls (χ2 [1 d.f.] = 4.32, P = 0.05) and the odds ratio for OC associated with the DD genotypeis 0.54, 95% confidence interval 0.30–0.97. In contrast to Finnish OC cases, the DD genotype of the ACE is not increased in UK cases.

  14. Predictors of angiotensin-converting enzyme inhibitor-induced reduction of urinary albumin excretion in nondiabetic patients.

    PubMed

    van de Wal, Ruud M A; Gansevoort, Ron T; van der Harst, Pim; Boomsma, Frans; Thijs Plokker, H W; van Veldhuisen, Dirk J; de Jong, Paul E; van Gilst, Wiek H; Voors, Adriaan A

    2006-11-01

    Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1+/-11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (beta(standardized)=0.161; P=0.006), urinary sodium excretion (beta(standardized)=0.154; P=0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months (P<0.001). Fosinopril use and blood pressure reduction independently predicted the change in urinary albumin excretion. Baseline urinary albumin excretion independently predicted the antialbuminuric effect of fosinopril (beta(standardized)=-0.303; P<0.001). In conclusion, at baseline, sodium intake and blood pressure were positively associated with urinary albumin excretion. Fosinopril reduced albuminuria more than might be expected from its blood pressure-lowering effect alone, and this effect was more outspoken in subjects with higher baseline albumin excretion. Based on our data, we hypothesize that angiotensin-converting enzyme inhibition may result in superior cardiovascular protection when compared with other blood pressure-lowering agents in subjects with higher baseline levels of albuminuria. PMID:17000930

  15. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    PubMed

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  16. Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk?

    PubMed

    Chaumont, Martin; Pourcelet, Aline; van Nuffelen, Marc; Racapé, Judith; Leeman, Marc; Hougardy, Jean-Michel

    2016-06-01

    In contrast to angiotensin receptor blockers (ARBs), mainly excreted by the liver, the dosage of angiotensin-converting enzyme (ACE) inhibitors, cleared by the kidney, must be adapted to account for renal clearance in patients with chronic kidney disease (CKD) to avoid acute kidney injury (AKI). Community-acquired AKI and the use of ACE inhibitors or ARBs in the emergency department were retrospectively assessed in 324 patients with baseline stage 3 or higher CKD. After stepwise regression analysis, the use of ACE inhibitors (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1; P=.02) and the presence of dehydration (OR, 30.8; 95% CI, 3.9-239.1) were associated with AKI. A total of 45% of patients using ACE inhibitors experienced overdosing, which causes most of the excess risk of AKI. These results suggest that dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI. Moreover, ACE inhibitors and ARBs should be stopped in cases of dehydration. PMID:27080620

  17. Determination of angiotensin I-converting enzyme activity in cell culture using fluorescence resonance energy transfer peptides.

    PubMed

    Sabatini, R A; Bersanetti, P A; Farias, S L; Juliano, L; Juliano, M A; Casarini, D E; Carmona, A K; Paiva, A C M; Pesquero, J B

    2007-04-15

    An assay using fluorescence resonance energy transfer peptides was developed to assess angiotensin I-converting enzyme (ACE) activity directly on the membrane of transfected Chinese hamster ovary cells (CHO) stably expressing the full-length somatic form of the enzyme. The advantage of the new method is the possibility of using selective substrates for the two active sites of the enzyme, namely Abz-FRK(Dnp)P-OH for somatic ACE, Abz-SDK(Dnp)P-OH for the N domain, and Abz-LFK(Dnp)-OH for the C domain. Hydrolysis of a peptide bond between the donor/acceptor pair (Abz/Dnp) generates detectable fluorescence, allowing quantitative measurement of the enzymatic activity. The kinetic parameter K(m) for the hydrolysis of the three substrates by ACE in this system was also determined and the values are comparable to those obtained using the purified enzyme in solution. The specificity of the activity was demonstrated by the complete inhibition of the hydrolysis by the ACE inhibitor lisinopril. Therefore, the results presented in this work show for the first time that determination of ACE activity directly on the surface of intact CHO cells is feasible and that the method is reliable and sensitive. In conclusion, we describe a methodology that may represent a new tool for the assessment of ACE activity which will open the possibility to study protein interactions in cells in culture. PMID:17320031

  18. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal

    PubMed Central

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-01-01

    Key Clinical Message C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine. PMID:25767713

  19. Short communication: Measuring the angiotensin-converting enzyme inhibitory activity of an 8-amino acid (8mer) fragment of the C12 antihypertensive peptide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An eight amino acid fragment (PFPEVFGK) of a known milk protein-derived antihypertensive peptide was synthesized by microwave-assisted solid phase peptide synthesis and purified by reverse phase HPLC. Its ability to inhibit the angiotensin-converting enzyme was assessed and compared to that of the ...

  20. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal.

    PubMed

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-02-01

    C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine. PMID:25767713

  1. Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study

    PubMed Central

    Nelveg-Kristensen, Karl Emil; Busk Madsen, Majbritt; Torp-Pedersen, Christian; Køber, Lars; Egfjord, Martin; Berg Rasmussen, Henrik; Riis Hansen, Peter

    2015-01-01

    Background Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). Methods Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of ≤1, 2 and ≥3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses. Results We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A ≤1 vs. 2 (HR 1.03 [95% CI 0.79–1.34] and HR 1.11 [95% CI 0.88–1.42]), score A ≤1 vs. ≥3 (HR 0.80 [95% CI 0.59–1.08] and HR 0.91 [95% CI 0.70–1.20]), score B ≤1 vs. 2 (HR 1.02 [95% CI 0.78–1.32] and HR 0.98 [95% CI 0.77–1.24]), and score B ≤1 vs. ≥3 (HR 1.03 [95% CI 0.75–1.41] and HR 1.05 [95% CI 0.79–1.40]), respectively. Conclusions We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI

  2. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects the function of pancreatic β cells by improving the function of islet microvascular endothelial cells.

    PubMed

    Lu, Chun-Li; Wang, Ying; Yuan, Li; Li, Yang; Li, Xiao-Ya

    2014-11-01

    In the diabetic state, the local rennin-angiotensin system (RAS) is activated in the pancreas, and is strongly associated with islet dysfunction. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis is a protective, negative regulator of the classical renin-angiotensin system. In this study, we assessed the role of the ACE2/Ang(1‑7)/Mas axis in pancreatic β cell survival and function. ACE2 knockout and wild-type mice were fed a high-fat diet for 16 weeks. We then performed terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and determined the expression levels of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) in the pancreatic islets. The effects of Ang(1-7) or Mas receptor silencing on endothelial function were assessed in MS-1 cells. MIN6 cells were then co-cultured with the MS-1 cells to evaluate the effects of ACE2 on insulin secretion. The ACE2 knockout mice were more susceptible than the wild-type mice to high-fat diet-induced β cell dysfunction. The TUNEL-positive area of the pancreatic islets and the expression levels of IL-1β and iNOS were markedly increased in the ACE2 knockout mice compared with their wild-type littermates. The Mas-silenced MS-1 cells were more sensitive to palmitate-induced dysfunction and apoptosis in vitro. Ang(1-7) increased the activity of the Akt/endothelial NOS/nitric oxide (NO) pathway in the MS-1 cells, protected MIN6 cells against palmitate-induced apoptosis, and improved MIN6 insulin secretory function in the co-culture system. In conclusion, this study demonstrates that the ACE2/Ang(1-7)/Mas axis is a potential target for protecting the funcion of β cells by improving the function of islet microvascular endothelial cells. PMID:25175177

  3. Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food.

    PubMed

    Murakami, Keiko; Yamanaka, Naoki; Ohnishi, Katsunori; Fukayama, Minoru; Yoshino, Masataka

    2012-06-01

    Angiotensin I converting enzyme (ACE) was inhibited by the culture medium of Bacillus subtilis subsp. natto, which ferments boiled soy beans to natto, a Japanese traditional food. Subtilisin NAT (nattokinase) produced by B. subtilis also inhibited ACE, and the inhibition was markedly stimulated by heat treatment of subtilisin at 120 °C for 15 min. Inhibition of ACE by subtilisin was of a mixed type: the decrease in V(max) and the increase in K(m) value. SDS-polyacrylamide gel electrophoresis showed that heat treatment of subtilisin caused inactivation with fragmentation of the enzyme protein into small peptides. The inhibitory action of subtilisin was not due to an enzymatic action of protease, but may be ascribed to the potent ACE-inhibitory peptides such as LY and FY, amino acid sequences in subtilisin. HPLC-MS analysis of heat-inactivated subtilisin confirmed that LY and FY were liberated by fragmentation of the enzyme. Inhibition of ACE by subtilisin and its degradation peptides such as LY and FY may participate in the suppression of blood pressure by ingestion of natto. PMID:22453301

  4. Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

    PubMed Central

    Ni, He; Li, Lin; Liu, Guang; Hu, Song-Qing

    2012-01-01

    Angiotensin I-converting enzyme (ACE) has an important function in blood pressure regulation. ACE-inhibitory peptides can lower blood pressure by inhibiting ACE activity. Based on the sequence of an ACE-inhibitory hexapeptide (TPTQQS) purified from yeast, enzyme kinetics experiments, isothermal titration calorimetry (ITC), and a docking simulation were performed. The hexapeptide was found to inhibit ACE in a non-competitive manner, as supported by the structural model. The hexapeptide bound to ACE via interactions of the N-terminal Thr1, Thr3, and Gln4 residues with the residues on the lid structure of ACE, and the C-terminal Ser6 attracted the zinc ion, which is vital for ACE catalysis. The displacement of the zinc ion from the active site resulted in the inhibition of ACE activity. The structural model based on the docking simulation was supported by experiments in which the peptide was modified. This study provides a new inhibitory mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets. PMID:22606330

  5. Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: Role of the angiotensin-(1-7)/Mas receptor axis.

    PubMed

    Souza, Luan Kelves M; Nicolau, Lucas A D; Sousa, Nayara A; Araújo, Thiago S L; Sousa, Francisca Beatriz M; Costa, Douglas S; Souza, Fabiana M; Pacífico, Dvison M; Martins, Conceição S; Silva, Renan O; Souza, Marcellus H L P; Cerqueira, Gilberto S; Medeiros, Jand Venes R

    2016-07-15

    The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent. PMID:27241079

  6. Gallium 67 citrate scanning and serum angiotensin converting enzyme levels in sarcoidosis

    SciTech Connect

    Gupta, R.G.; Bekerman, C.; Sicilian, L.; Oparil, S.; Pinsky, S.M.; Szidon, J.P.

    1982-09-01

    Gallium 67 citrate scans and serum angiotension converting enzyme (ACE) levels were obtained in 54 patients with sarcoidosis and analyzed in relation to clinical manifestation. /sup 67/Ga scans were abnormal in 97% of patients with clinically active disease (n = 30) and in 71% of patients with inactive disease (n = 24). Serum ACE levels were abnormally high (2 standard deviations above the control mean) in 73% of patients with clinically active disease and in 54% of patients with inactive disease. Serum ACE levels correlated significantly with /sup 67/Ga uptake score (r = .436; p < .005). The frequency of abnormal /sup 67/Ga scans and elevated serum ACE levels suggests that inflammatory activity with little or no clinical expression is common in sarcoidosis. Abnormal /sup 67/Ga scans were highly sensitive (97%) but had poor specificity (29%) to clinical disease activity. The accuracy of negative prediction of clinical activity by normal scans (87%) was better than the accuracy of positive prediction of clinical activity by abnormal scans (63%). /sup 67/Ga scans can be used to support the clinical identification of inactive sarcoidosis.

  7. Association of angiotensin converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries.

    PubMed Central

    Hamon, M.; Amant, C.; Bauters, C.; Richard, F.; Helbecque, N.; McFadden, E.; Lablanche, J. M.; Bertrand, M.; Amouyel, P.

    1997-01-01

    OBJECTIVE: To analyse the potential association of the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) gene polymorphisms on left ventricular function and mass in patients with normal coronary arteries. DESIGN: Consecutive sample. SETTING: University hospital. SUBJECTS: 141 consecutive white patients referred for coronary angiography and with angiographically normal coronary arteries. Patients with valvar diseases, cardiomyopathies, or a history of myocardial infarction were excluded. MAIN OUTCOME MEASURES: Left ventricular variables were measured for all patients. The ACE and AT1R genotypes were determined with a polymerase chain reaction based protocol using DNA prepared from white blood cells. A general linear model was used to compare data according to the ACE and to the AT1R genotypes. RESULTS: A strong association was observed between left ventricular mass and systemic hypertension (mean (SD) hypertension: 114 (31) g/m2; no hypertension 98 (23) g/m2; P < 0.003). However, no influence of ACE and AT1R polymorphisms on left ventricular mass was found, regardless of systemic hypertension. The subjects homozygous for the AT1R CC mutation had a significantly lower ejection fraction than those with allele A (AC+AA) (mean (SD) 62(12)% and 68(10)%, respectively, P < 0.05). No synergistic interaction of ACE and AT1R gene polymorphisms on left ventricular function and mass was found. CONCLUSIONS: These data do not support an association of the ACE and AT1R genotypes on left ventricular hypertrophy in white patients with normal coronary arteries. PMID:9227291

  8. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Terms of Major Cardiovascular Disease Outcomes in Elderly Patients

    PubMed Central

    Chien, Shu-Chen; Ou, Shuo-Ming; Shih, Chia-Jen; Chao, Pei-Wen; Li, Szu-Yuan; Lee, Yi-Jung; Kuo, Shu-Chen; Wang, Shuu-Jiun; Chen, Tzeng-Ji; Tarng, Der-Cherng; Chu, Hsi; Chen, Yung-Tai

    2015-01-01

    Abstract Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive. In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted. In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis. Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations. PMID:26512568

  9. Effects of angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist combination on nitric oxide bioavailability and atherosclerotic change in Watanabe heritable hyperlipidemic rabbits.

    PubMed

    Imanishi, Toshio; Kuroi, Akio; Ikejima, Hideyuki; Kobayashi, Katsunobu; Muragaki, Yasuteru; Mochizuki, Seiichi; Goto, Masami; Yoshida, Kiyoshi; Akasaka, Takashi

    2008-03-01

    We investigated the effects of co-administration of an angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. Plasma NO was measured using the new NO sensor in the abdominal aorta of anesthetized Watanabe heritable hyperlipidemic (WHHL) rabbits. Acetylcholine (ACh)-stimulated (20 microg in 5 min into the aortic arch) NO production was recorded after an 8 week per os pretreatment with 1) vehicle (control), 2) the ACEI enalapril (E: 3 mg/kg/day), 3) the ARB losartan (L: 30 mg/kg/day) and 4) enalapril (1.5 mg/kg/day)+losartan (15 mg/kg/day) (E+L). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all the drug treatments than with the control. E increased ACh-induced NO significantly more than L (by 6.9 nmol/L, and 4.7 nmol/L, respectively). E+L increased ACh-induced NO by 9.5 nmol/L, significantly more than either E or L. Plasma peroxynitrite concentration was 1.2 pmol/mg protein in the control group and significantly less than in the E- and L-group. The lowest peroxynitrite concentration was observed in the E+L group (0.5 pmol/mg protein), which was significantly lower than in the E-group and the L-group. Optical coherence tomography and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy (p<0.01). In conclusion, the combined treatment with an ACEI and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change. PMID:18497479

  10. Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study

    PubMed Central

    Sørensen, Gitte Vrelits; Ganz, Patricia A.; Cole, Steven W.; Pedersen, Lars A.; Toft Sørensen, Henrik; Cronin-Fenton, Deirdre P.; Peter Garne, Jens; Christiansen, Peer M.; Lash, Timothy L.; Ahern, Thomas P.

    2013-01-01

    Purpose To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. Patients and Methods We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. Results Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). Conclusion Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk. PMID:23650417

  11. Optimized determination of angiotensin I-converting enzyme activity with hippuryl-L-histidyl-L-leucine as substrate.

    PubMed

    Schnaith, E; Beyrau, R; Bückner, B; Klein, R M; Rick, W

    1994-06-01

    The determination of the angiotensin I-converting enzyme activity (ACE, kininase II, peptidyldipeptide hydrolase, EC 3.4.15.1) is necessary to control the course and the treatment of sarcoidosis, as well as to monitor the therapeutic use of enzyme inhibitors such as captopril in hypertension or congestive heart failure. Numerous synthetic substrates are known with which to measure the enzyme activity. A discontinuous method using hippuryl-L-histidyl-L-leucine was tested and improved. The cleavage product, hippurate, reacts with cyanuric chloride to give a yellow complex which can be measured at 405 nm using a spectral line photometer. Enzyme activity, kinetic constants and activation energy are dependent on the chloride ion concentration. Optimal test concentrations are 1.1 mol/l potassium chloride and 3.0 mmol/l hippuryl-L-histidyl-L-leucine at pH 8.3. Higher substrate concentrations effect an inhibition of the enzyme reaction. A Michaelis constant of 0.9 mmol/l was found with serum as enzyme source. An activation energy of 57 kJ/mol was obtained from the relation between the logarithm of velocity of enzyme reaction and reciprocal value of absolute temperature. Furthermore, a linear dependence on chloride ion concentration was observed. The histogram of the enzyme activities in sera from 146 healthy volunteers shows a non-gaussian distribution. The reference interval at 25 degrees C is characterized by a median of 24 units/l with the 2.5th and the 97.5th percentiles at 13 units/l and 42 units/l, respectively. The corresponding values at 37 degrees C are 27 units/l and 86 units/l with a median of 48 units/l. No significant sex and age dependence could be found. A potent ACE inhibitor such as captopril leads to a rapid decrease of the enzyme activity within 60 min after oral administration. In the following hours, the enzyme activity slowly increases. PMID:7955411

  12. Antihypertensive effect of angiotensin i converting enzyme-inhibitory peptide from hydrolysates of Bigeye tuna dark muscle, Thunnus obesus.

    PubMed

    Qian, Zhong-Ji; Je, Jae-Young; Kim, Se-Kwon

    2007-10-17

    Angiotensin I converting enzyme (ACE) inhibitory peptide was isolated from tuna dark muscle hydrolysate prepared by alcalase, neutrase, pepsin, papain, alpha-chymotrypsin, and trypsin, respectively. Among hydrolysates, the pepsin-derived hydrolysate exhibited the highest ACE I inhibitory activity versus those of other enzyme hydrolysates. The structure of the peptide was identified to be Trp-Pro-Glu-Ala-Ala-Glu-Leu-Met-Met-Glu-Val-Asp-Pro (molecular weight 1581 Da) by time of flight mass spectrometry/mass spectrometry analysis, and the IC 50 value of the peptide was 21.6 microM. The Lineweaver-Burk plots revealed that the peptide acts as a noncompetitive inhibitor, and the inhibitor constant ( K i) was calculated as 26.6 microM using the secondary plots. The peptide had an antihypertensive effect according to the time-course measurement after oral administration to spontaneously hypertensive rats. Maximal reduction was detected 3 h after oral administration at a dose of 10 mg/kg of body weight. These results suggest that the peptide derived from tuna dark muscle would be a beneficial ingredient for functional food or pharmaceuticals against hypertension and its related diseases. PMID:17894458

  13. A new high-resolution crystal structure of the Drosophila melanogaster angiotensin converting enzyme homologue, AnCE.

    PubMed

    Harrison, Charlotte; Acharya, K Ravi

    2015-01-01

    Angiotensin converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase with an essential role in blood pressure homeostasis in mammals. ACE has long been targeted in the treatment of hypertension through ACE inhibitors, however current inhibitors are known to cause severe side effects. Therefore, there is a requirement for a new generation of ACE inhibitors and structural information will be invaluable in their development. ACE is a challenging enzyme to work with due to its extensive glycosylation. As such, the Drosophila melanogaster ACE homologue, AnCE, which shares ∼60% sequence similarity with human ACE, can be used as a model for studying inhibitor binding. The presence of ligands originating from the crystallisation condition at the AnCE active site has proved an obstacle to studying the binding of new inhibitor precursors. Here we present the crystal structure of AnCE (in a new crystal form) at 1.85 Å resolution, using crystals grown under different conditions. This new structure may be more suitable for studying the binding of new compounds, with the potential of developing a new generation of improved ACE inhibitors. PMID:26380810

  14. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy.

    PubMed

    Forbes, Josephine M; Thorpe, Suzanne R; Thallas-Bonke, Vicki; Pete, Josefa; Thomas, Merlin C; Deemer, Elizabeth R; Bassal, Sahar; El-Osta, Assam; Long, David M; Panagiotopoulos, Sianna; Jerums, George; Osicka, Tanya M; Cooper, Mark E

    2005-08-01

    Recent studies have identified that first-line renoprotective agents that interrupt the renin-angiotensin system not only reduce BP but also can attenuate advanced glycation end product (AGE) accumulation. This study used in vitro, preclinical, and human approaches to explore the potential effects of these agents on the modulation of the receptor for AGE (RAGE). Bovine aortic endothelial cells that were exposed to the angiotensin-converting enzyme inhibitor (ACEi) ramiprilat in the presence of high glucose demonstrated a significant increase in soluble RAGE (sRAGE) secreted into the medium. In streptozotocin-induced diabetic rats, ramipril treatment (ACEi) at 3 mg/L for 24 wk reduced the accumulation of skin collagen-linked carboxymethyllysine and pentosidine, as well as circulating and renal AGE. Renal gene upregulation of total RAGE (all three splice variants) was observed in ACEi-treated animals. There was a specific increase in the gene expression of the splice variant C-truncated RAGE (sRAGE). There were also increases in sRAGE protein identified within renal cells with ACEi treatment, which showed AGE-binding ability. This was associated with decreases in renal full-length RAGE protein from ACEi-treated rats. Decreases in plasma soluble RAGE that were significantly increased by ACEi treatment were also identified in diabetic rats. Similarly, there was a significant increase in plasma sRAGE in patients who had type 1 diabetes and were treated with the ACEi perindopril. Complexes between sRAGE and carboxymethyllysine were identified in human and rodent diabetic plasma. It is postulated that ACE inhibition reduces the accumulation of AGE in diabetes partly by increasing the production and secretion of sRAGE into plasma. PMID:15930093

  15. Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice

    PubMed Central

    2013-01-01

    Background Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling. Methods 10-week-old ACE2 knockout (ACE2KO; Ace2-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively. Results Compared with the Ace2+/y mice, cardiac expression of PPARα and PPARγ were reduced in Ace2-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2-/y mice linked with enhancement of plasma Ang-(1–7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III

  16. Angiotensin I–Converting Enzyme Type 2 (ACE2) Gene Therapy Improves Glycemic Control in Diabetic Mice

    PubMed Central

    Bindom, Sharell M.; Hans, Chetan P.; Xia, Huijing; Boulares, A. Hamid; Lazartigues, Eric

    2010-01-01

    OBJECTIVE Several clinical studies have shown the benefits of renin-angiotensin system (RAS) blockade in the development of diabetes, and a local RAS has been identified in pancreatic islets. Angiotensin I–converting enzyme (ACE)2, a new component of the RAS, has been identified in the pancreas, but its role in β-cell function remains unknown. Using 8- and 16-week-old obese db/db mice, we examined the ability of ACE2 to alter pancreatic β-cell function and thereby modulate hyperglycemia. RESEARCH DESIGN AND METHODS Both db/db and nondiabetic lean control (db/m) mice were infected with an adenovirus expressing human ACE2 (Ad-hACE2-eGFP) or the control virus (Ad-eGFP) via injection into the pancreas. Glycemia and β-cell function were assessed 1 week later at the peak of viral expression. RESULTS In 8-week-old db/db mice, Ad-hACE2-eGFP significantly improved fasting glycemia, enhanced intraperitoneal glucose tolerance, increased islet insulin content and β-cell proliferation, and reduced β-cell apoptosis compared with Ad-eGFP. ACE2 overexpression had no effect on insulin sensitivity in comparison with Ad-eGFP treatment in diabetic mice. Angiotensin-(1–7) receptor blockade by d-Ala7–Ang-(1-7) prevented the ACE2-mediated improvements in intraperitoneal glucose tolerance, glycemia, and islet function and also impaired insulin sensitivity in both Ad-hACE2-eGFP– and Ad-eGFP–treated db/db mice. d-Ala7–Ang-(1-7) had no effect on db/m mice. In 16-week-old diabetic mice, Ad-hACE2-eGFP treatment improved fasting blood glucose but had no effect on any of the other parameters. CONCLUSIONS These findings identify ACE2 as a novel target for the prevention of β-cell dysfunction and apoptosis occurring in type 2 diabetes. PMID:20660625

  17. Protein Kinase C-δ Mediates Shedding of Angiotensin-Converting Enzyme 2 from Proximal Tubular Cells

    PubMed Central

    Xiao, Fengxia; Zimpelmann, Joseph; Burger, Dylan; Kennedy, Christopher; Hébert, Richard L.; Burns, Kevin D.

    2016-01-01

    Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin (Ang) II to Ang-(1–7), and protects against diabetic renal injury. Soluble ACE2 fragments are shed from the proximal tubule, and appear at high levels in the urine with diabetes. High glucose-induced shedding of ACE2 from proximal tubular cells is mediated by the enzyme “a disintegrin and metalloproteinase-17″ (ADAM17). Here, we investigated the mechanism for constitutive shedding of ACE2. Mouse proximal tubular cells were cultured and ACE2 shedding into the media was assessed by enzyme activity assay and immunoblot analysis. Cells were incubated with pharmacologic inhibitors, or transfected with silencing (si) RNA. Incubation of proximal tubular cells with increasing concentrations of D-glucose stimulated ACE2 shedding, which peaked at 16 mM, while L-glucose (osmotic control) had no effect on shedding. In cells maintained in 7.8 mM D-glucose, ACE2 shedding was significantly inhibited by the pan-protein kinase C (PKC) competitive inhibitor sotrastaurin, but not by an inhibitor of ADAM17. Incubation of cells with the PKC-α and -β1-specific inhibitor Go6976, the PKC β1 and β2-specific inhibitor ruboxistaurin, inhibitors of matrix metalloproteinases-2,-8, and -9, or an inhibitor of ADAM10 (GI250423X) had no effect on basal ACE2 shedding. By contrast, the PKC-δ inhibitor rottlerin significantly inhibited both constitutive and high glucose-induced ACE2 shedding. Transfection of cells with siRNA directed against PKC-δ reduced ACE2 shedding by 20%, while knockdown of PKC-ε was without effect. These results indicate that constitutive shedding of ACE2 from proximal tubular cells is mediated by PKC-δ, which is also linked to high glucose-induced shedding. Targeting PKC-δ may preserve membrane-bound ACE2 in proximal tubule in disease states and diminish Ang II-stimulated adverse signaling. PMID:27313531

  18. Association of angiotensin converting enzyme gene insertion/deletion polymorphism and familial hypercholesterolemia in the Saudi population

    PubMed Central

    2013-01-01

    Background The study of the association between genotype and phenotype is of great importance for the prediction of multiple diseases and pathophysiological conditions. The relationship between angiotensin converting enzyme (ACE) Insertion/Deletion (I/D) polymorphism and Familial Hypercholesterolemia (FH) has been not fully investigated in all the ethnicities. In this study we sought to determine the frequency of I/D polymorphism genotypes of ACE gene in Saudi patients with FH. Results This is a case–control study carried out purely in Saudi population. Genomic DNA was isolated from 128 subjects who have participated in this study. ACE gene I/D polymorphism was analyzed by polymerase chain reaction in 64 FH cases and 64 healthy controls. There was no statistically significant difference between the groups with respect to genotype distribution. Furthermore, we did not find any significant difference in the frequency of ACE I/D polymorphism in FH subjects when stratified by gender (p = 0.43). Conclusion Our data suggest that ACE gene I/D polymorphism examined in this study has no role in predicting the occurrence and diagnosis of FH. PMID:24289455

  19. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats.

    PubMed

    Jawaid, Talha; Jahan, Shah; Kamal, Mehnaz

    2015-01-01

    The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.]), perindopril (0.1 mg/kg b.w., [i.p.]), enalapril (0.1 mg/kg b.w., [i.p.]), and ramipril (0.1 mg/kg b.w., [i.p.]) were administered in different group of animals for 5 days. On 5(th) day, scopolamine (1 mg/kg b.w., i.p.) was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM) test and pole climbing test (PCT). Biochemical estimations like glutathione (GSH), malondialdehyde (MDA), and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril. PMID:26317078

  20. Sleep-related movement disorder symptoms in SHR are attenuated by physical exercise and an angiotensin-converting enzyme inhibitor.

    PubMed

    Frank, Miriam Kannebley; de Mello, Marco Tulio; Lee, Kil Sun; Daubian-Nosé, Paulo; Tufik, Sergio; Esteves, Andrea Maculano

    2016-02-01

    The relationship between hypertension and sleep-related movement disorders has been hypothesized for humans, but the causes and mechanisms have not been elucidated. We investigated whether an alteration in blood pressure (BP) induced by physical exercise and/or an angiotensin-converting enzyme inhibitor (enalapril) could affect locomotor activity in spontaneously hypertensive rats, with emphasis on the dopaminergic system. We used SHR and normotensive Wistar rats distributed into 4 groups for each strain: control, physical exercise, enalapril and physical exercise+enalapril. Physical exercise was performed on a treadmill, and enalapril was administered by gavage, both for 8weeks. During this period, locomotor activity was evaluated in an open field test, and BP was evaluated by tail plethysmography. Dopaminergic receptors, dopamine transporter and tyrosine hydroxylase levels at the striatum were evaluated by Western blotting. The control group of spontaneously hypertensive rats showed higher BP, increased activity in the open field test and lower levels of D2 receptors and tyrosine hydroxylase compared with all other groups throughout the experimental period. In general, physical exercise and enalapril attenuated these alterations. This study suggested the existence of comorbidity between hypertension and sleep-related movement disorders in spontaneously hypertensive rats. Physical exercise and enalapril conferred protection for both hypertension and the observed behavioral changes. In addition, these treatments led to changes in dopaminergic signaling in the striatal region (i.e., D2 receptor, TH and DAT). PMID:26650246

  1. Sardine peptide with angiotensin I-converting enzyme inhibitory activity improves glucose tolerance in stroke-prone spontaneously hypertensive rats.

    PubMed

    Otani, Lila; Ninomiya, Toshio; Murakami, Megumi; Osajima, Katsuhiro; Kato, Hisanori; Murakami, Tetsuo

    2009-10-01

    An enzymatic hydrolysate of sardine protein (sardine peptide, SP) derived from sardine muscle possesses angiotensin I-converting enzyme (ACE) inhibitory activity. In the present study, we investigated the effect of SP on the blood glucose levels in stroke-prone spontaneously hypertensive rats (SHRSPs). Ten-week-old SHRSPs were assigned to three groups. The control group was given tap water for 4 weeks, while the experimental groups were given water containing SP (1 g/kg/d) or an ACE inhibitor, captopril (8 mg/kg/d). Treatment with SP and captopril decreased ACE activity in the kidney, aorta, and mesentery. There were no differences in fasting blood glucose levels among the three groups, whereas SP and captopril administration significantly suppressed the increase in blood glucose after glucose loading in the control SHRSPs. No difference was observed in plasma insulin levels among the three groups. Thus treatment with captopril and ACE-inhibitory sardine peptides ameliorated the glucose tolerance of this rat strain. PMID:19809178

  2. An angiotensin I-converting enzyme insertion/deletion polymorphism is associated with Pakistani asthmatic cases and controls.

    PubMed

    Saba, Nusrat; Yusuf, Osman; Rehman, Sadia; Munir, Saeeda; Ahmad, Sheeraz; Mansoor, Atika; Raja, Ghazala K

    2016-09-01

    Asthma is a chronic disease due to inflammation of the airways of lungs that is clinically characterized by variable symptoms including wheezing, coughing and shortness of breath. Angiotensin I-converting enzyme (ACE) plays a major role in fibrous tissue formation and is highly expressed in lungs. The main aim of this research work was to study the role of ACE insertion/deletion (I/D) polymorphism, rs4646994, in asthma in Pakistani patients. A total of 854 subjects, including 333 asthma patients and 521 ethnically matched controls, were studied. The ACE (I/D) polymorphism was genotyped using polymerase chain reaction (PCR). Chi-square, Fisher's exact and Hardy-Weinberg equilibrium tests were used to compare groups. Homozygous insertion genotype II (p less than 0.0001, OR=3.38) and insertion allele (I) was significantly more frequent in Pakistani asthmatics than in healthy controls (p=0.0007, OR=1.40). The ID genotype (p less than 0.0001, OR=0.43) and the deletion allele (D) were associated with protection of disease in Pakistani patients (p=0.0007, OR=0.71). These data suggest the involvement of ACE I/D polymorphism in asthma risk in the Pakistani population. This marker may be an important indication in the molecular mechanism of asthma and can become a useful tool in risk assessment and help in designing strategy to combat disease. PMID:27581935

  3. Preoperative angiotensin converting enzyme inhibitor usage in patients with chronic subdural hematoma: Associations with initial presentation and clinical outcome.

    PubMed

    Neidert, Marian C; Schmidt, Tobias; Mitova, Tatyana; Fierstra, Jorn; Bellut, David; Regli, Luca; Burkhardt, Jan-Karl; Bozinov, Oliver

    2016-06-01

    The aim of this study is to analyze the association of preoperative usage of angiotensin converting enzyme (ACE) inhibitors with the initial presentation and clinical outcome of patients with chronic subdural hematoma (cSDH). Patients treated for cSDH between 2009 and 2013 at our institution were included in this retrospective case-control study. Medical charts were reviewed retrospectively and data were analyzed using descriptive and inferential statistics. Out of 203 patients (58 females, mean age 73.2years), 53 (26%) patients were on ACE inhibitors before their presentation with cSDH. Median initial hematoma volume in individuals with ACE inhibitors (179.2±standard error of the mean [SEM] 13.0ml) was significantly higher compared to patients without ACE inhibitors (140.4±SEM 6.2ml; p=0.007). There was an increased probability of surgical reintervention in the ACE inhibitor group (12/53, 23% versus 19/153, 12%; p=0.079), especially in patients older than 80years (6/23, 26% versus 3/45, 7%; p=0.026). ACE inhibitors are associated with higher hematoma volume in patients with cSDH and with a higher frequency of recurrences requiring surgery (especially in the very old). We hypothesize that these effects are due to ACE inhibitor induced bradykinin elevation causing increased vascular permeability of the highly vascularized neomembranes in cSDH. PMID:26898577

  4. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats

    PubMed Central

    Jawaid, Talha; Jahan, Shah; Kamal, Mehnaz

    2015-01-01

    The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.]), perindopril (0.1 mg/kg b.w., [i.p.]), enalapril (0.1 mg/kg b.w., [i.p.]), and ramipril (0.1 mg/kg b.w., [i.p.]) were administered in different group of animals for 5 days. On 5th day, scopolamine (1 mg/kg b.w., i.p.) was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM) test and pole climbing test (PCT). Biochemical estimations like glutathione (GSH), malondialdehyde (MDA), and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril. PMID:26317078

  5. Angiotensin I-converting enzyme inhibitory activity and bioconversion of isoflavones by probiotics in soymilk supplemented with prebiotics.

    PubMed

    Yeo, Siok-Koon; Liong, Min-Tze

    2010-03-01

    Lactobacillus sp. FTDC 2113, L. acidophilus FTDC 8033, L. acidophilus ATCC 4356, L. casei ATCC 393, Bifidobacterium FTDC 8943 and B. longum FTDC 8643 were incorporated into soymilk supplemented with fructooligosaccharides (FOS), inulin, mannitol, maltodextrin and pectin. The objective of the present study was to evaluate the effects of prebiotics on the bioactivity of probiotic-fermented soymilk. Proteolytic activity was increased in the presence of FOS, while the supplementation of inulin and pectin increased the angiotensin I-converting enzyme inhibitory activity accompanied by lower IC(50) values. The beta-glucosidase activity was also enhanced in the presence of pectin. This led to higher bioconversion of glucosides to aglycones by probiotics, especially genistin and malonyl genistin to genistein. Results from this study indicated that the supplementation of prebiotics enhanced the in-vitro antihypertensive effect and production of bioactive aglycones in probiotic-fermented soymilk. Therefore, this soymilk could potentially be used as a dietary therapy to reduce the risks of hypertension and hormone-dependent diseases such as breast cancer, prostate cancer and osteoporosis. PMID:20085504

  6. Segregation and linkage analysis of serum angiotensin I-converting enzyme levels: Evidence for two quantitative-trait loci

    SciTech Connect

    McKenzie, C.A.; Keavney, B.; Farrall, M.

    1995-12-01

    Human serum angiotensin I-converting enzyme (ACE) levels vary substantially between individuals and are highly heritable. Segregation analysis in European families has shown that more than half of the total variability in ACE levels is influenced by quantitative-trait loci (QTL). One of these QTLs is located within or close to the ACE locus itself. Combined segregation/linkage analysis in a series of African Caribbean families from Jamaica shows that the ACE insertion-deletion polymorphism is in moderate linkage disequilibrium with an ACE-linked QTL. Linkage analysis with a highly informative polymorphism at the neighboring growth hormone gene (GH) shows surprisingly little support for linkage (LOD score [Z] = 0.12). An extended analysis with a two-QTL model, where an ACE-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACE-linked QTL and GH polymorphism (Z = 5.0). We conclude that two QTLs jointly influence serum ACE levels in this population. One QTL is located within or close to the ACE locus and explains 27% of the total variability; the second QTL is unlinked to the ACE locus and explains 52% of the variability. The identification of the molecular mechanisms underlying both QTLs is necessary in order to interpret the role of ACE in cardiovascular disease. 44 refs., 7 tabs.

  7. Angiotensin-converting enzyme insertion/deletion polymorphism and risk of restenosis after directional coronary atherectomy followed by stent implantation.

    PubMed

    Canosi, Umberto; Angelica Merlini, Piera; Bernardi, Francesco; Repetto, Alessandra; Bramucci, Ezio; Ferrario, Maurizio; Angoli, Luigi; Gnecchi, Massimiliano; Ferraresi, Paolo; Marchetti, Giovanna; Tavazzi, Luigi; Ardissino, Diego

    2004-04-01

    The D allele of the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is associated with higher plasma and tissue ACE levels, which enhance the stimulus for neo-intimal hyperplasia. Plaque debulking before stenting reduces the plaque-related determinants of in-stent restenosis and provides an ideal clinical model for studying neointimal hyperplasia. We prospectively studied 113 consecutive patients undergoing elective DCA followed by stent implantation. The presence of I/D in ACE genome DNA was analysed by means of polymerase chain reaction. Follow-up coronary angiography was performed 6-12 months after DCA, and all of the angiograms were quantitatively analysed. The baseline clinical and angiographic characteristics of the patients with a D/D (33%), I/D (52%) and I/I (15%) genotype were well balanced. There were no significant differences in minimal lumen diameter before and after the procedure or at follow-up, and no significant differences in acute gain, late loss or the loss index. Our results indicate that ACE I/D polymorphism does not influence the risk of developing angiographic restenosis in patients undergoing DCA followed by stent implantation. PMID:15045142

  8. Angiotensin I Converting Enzyme Inhibitory Peptides Obtained after In Vitro Hydrolysis of Pea (Pisum sativum var. Bajka) Globulins

    PubMed Central

    Baraniak, Barbara

    2014-01-01

    Pea seeds represent a valuable source of active compounds that may positively influence health. In this study, the pea globulins were digested in vitro under gastrointestinal condition and potentially bioaccessible angiotensin I converting enzyme (ACE) inhibitory peptides were identified. The degree of hydrolysis after pepsin, 14.42%, and pancreatin, 30.65%, were noted. The peptides with the highest ACE inhibitory properties were separated using ion exchange chromatography on DEAE-cellulose. Thirteen peptides fractions were obtained but only four showed potential antihypertensive properties. The highest inhibitory activity was determined for the fraction F8 (IC50 = 0.0014 mg/mL). This fraction was separated on Sephadex G10 and two peptide fractions were obtained. The peptides fraction (B) with the highest ACE inhibitory activity (IC50 = 0.073 mg/mL) was identified by ESI-MS/MS. The sequences of ACE inhibitory peptides were GGSGNY, DLKLP, GSSDNR, MRDLK, and HNTPSR. Based on Lineweaver-Burk plots for the fraction B, the kinetic parameters as Km, Vmax, and Ki and mode of inhibition were determined. This fraction belongs to uncompetitive inhibitor of ACE activity. The seeds of pea are the source of precursor protein, which releases the ACE inhibitory peptides as a result of enzymatic hydrolysis. PMID:25250321

  9. Gallium-67 in the evaluation of sarcoidosis: correlations with serum angiotensin-converting enzyme and bronchoalveolar lavage.

    PubMed Central

    Beaumont, D; Herry, J Y; Sapene, M; Bourguet, P; Larzul, J J; de Labarthe, B

    1982-01-01

    Gallium-67 (67Ga) scanning was assessed for its usefulness in the evaluation and follow-up of 54 patients with sarcoidosis, both treated and untreated. Scans were repeated in 23 subjects. Serum levels of angiotensin-converting enzyme (ACE) were determined concurrently in all 54 patients and bronchoalveolar lavage was performed in 29 patients. Gallium-67 scan was effective in the detection and assessment of lesions not revealed by traditional methods of investigation, particularly those affecting the mediastinum, spleen, and salivary glands. The scan also enabled fibrotic lesions, which do not show uptake, to be distinguished from granulomatous lesions, which do--an advantage of prognostic interest particularly in patients with pulmonary lesions. Another merit of 67Ga scanning was that it offered a means of following disease progression in each site. In patients showing spontaneous clearing of disease or receiving treatment the scintigraphic method was more sensitive than serum ACE determination. Scan findings showed a rough correlation with serum ACE but not with bronchoalveolar lavage findings. This suggests that the three markers probably reflect different stages of the granulomatous process. On the strength of this study the indications for gallium scanning in sarcoid patients can be defined more clearly than has previously been possible. Images PMID:6280330

  10. Antioxidant capacity and angiotensin I converting enzyme inhibitory activity of a melon concentrate rich in superoxide dismutase.

    PubMed

    Carillon, Julie; Del Rio, Daniele; Teissèdre, Pierre-Louis; Cristol, Jean-Paul; Lacan, Dominique; Rouanet, Jean-Max

    2012-12-01

    Antioxidant capacity and angiotensin 1-converting enzyme (ACE) inhibitory activity of a melon concentrate rich in superoxide dismutase (SOD-MC) were investigated in vitro. The total antioxidant capacity (TAC) was measured by the Trolox equivalent antioxidant capacity assay (TEAC), the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay, and the ferric reducing antioxidant power assay (FRAP). The ability of the extract to scavenge three specific reactive oxygen species (superoxide radical anion (O(2)(-)), hydroxyl radical (HO()) and hydrogen peroxide (H(2)O(2))) was also investigated in order to better evaluate its antioxidant properties. Even if the measures of TAC were relatively low, results clearly established an antioxidant potential of SOD-MC that exhibited the highest radical-scavenging activity towards O(2)(-), with a IC(50) 12-fold lower than that of H(2)O(2) or HO(). This lets hypothesis that the antioxidant potential of SOD-MC could be mainly due to its high level of SOD. Moreover, for the first time, an ACE inhibitory activity of SOD-MC (IC(50)=2.4±0.1mg/mL) was demonstrated, showing that its use as a functional food ingredient with potential preventive benefits in the context of hypertension may have important public health implications and should be carefully considered. PMID:22953857

  11. Early genes induction in spontaneously hypertensive rats left ventricle with angiotensin-converting enzyme inhibitors but not hydralazine

    SciTech Connect

    Susic, D.; Aristizabal, D.J.; Prakash, O.; Nunez, E.; Frohlich, E.D.

    1995-12-01

    Spontaneously hypertensive rats were given an angiotensin-converting enzyme (ACE) inhibitor (benazepril or quinapril) or hydralazine and were left for up to 6 hr. To examine whether administration of antihypertensive agents affects expression of immediate early genes in left ventricular myocardium, groups of rats were sacrificed at 1, 3, and 6 hr after dosing; total RNA was extracted from left ventricular tissue and analyzed by blot hybridization technique using labeled probes for c-myc, c-fos, and GAPDH mRNA. All three antihypertensive agents reduced pressure similarly, and treatment with the two ACE inhibitors increased c-fos and c-myc mRNA expression in left ventriculum. By contrast, hydralazine did not increase steady-state mRNA expression of either proto-oncogene. Thus, in parallel with the pressure fall, acute administration of the ACE inhibitors induced expression of c-fos and c-myc mRNAs in the left ventricle. Since the equidepressor dose of hyralazine did not affect expression of these proto-oncogenes, this effect of ACE inhibitors is independent of their hemodynamic action. 27 refs., 1 fig., 2 tabs.

  12. Retroviruses Pseudotyped with the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Efficiently Infect Cells Expressing Angiotensin-Converting Enzyme 2

    PubMed Central

    Moore, Michael J.; Dorfman, Tatyana; Li, Wenhui; Wong, Swee Kee; Li, Yanhan; Kuhn, Jens H.; Coderre, James; Vasilieva, Natalya; Han, Zhongchao; Greenough, Thomas C.; Farzan, Michael; Choe, Hyeryun

    2004-01-01

    Infection of receptor-bearing cells by coronaviruses is mediated by their spike (S) proteins. The coronavirus (SARS-CoV) that causes severe acute respiratory syndrome (SARS) infects cells expressing the receptor angiotensin-converting enzyme 2 (ACE2). Here we show that codon optimization of the SARS-CoV S-protein gene substantially enhanced S-protein expression. We also found that two retroviruses, simian immunodeficiency virus (SIV) and murine leukemia virus, both expressing green fluorescent protein and pseudotyped with SARS-CoV S protein or S-protein variants, efficiently infected HEK293T cells stably expressing ACE2. Infection mediated by an S-protein variant whose cytoplasmic domain had been truncated and altered to include a fragment of the cytoplasmic tail of the human immunodeficiency virus type 1 envelope glycoprotein was, in both cases, substantially more efficient than that mediated by wild-type S protein. Using S-protein-pseudotyped SIV, we found that the enzymatic activity of ACE2 made no contribution to S-protein-mediated infection. Finally, we show that a soluble and catalytically inactive form of ACE2 potently blocked infection by S-protein-pseudotyped retrovirus and by SARS-CoV. These results permit studies of SARS-CoV entry inhibitors without the use of live virus and suggest a candidate therapy for SARS. PMID:15367630

  13. Efficient Replication of Severe Acute Respiratory Syndrome Coronavirus in Mouse Cells Is Limited by Murine Angiotensin-Converting Enzyme 2

    PubMed Central

    Li, Wenhui; Greenough, Thomas C.; Moore, Michael J.; Vasilieva, Natalya; Somasundaran, Mohan; Sullivan, John L.; Farzan, Michael; Choe, Hyeryun

    2004-01-01

    Replication of viruses in species other than their natural hosts is frequently limited by entry and postentry barriers. The coronavirus that causes severe acute respiratory syndrome (SARS-CoV) utilizes the receptor angiotensin-converting enzyme 2 (ACE2) to infect cells. Here we compare human, mouse, and rat ACE2 molecules for their ability to serve as receptors for SARS-CoV. We found that, compared to human ACE2, murine ACE2 less efficiently bound the S1 domain of SARS-CoV and supported less-efficient S protein-mediated infection. Rat ACE2 was even less efficient, at near background levels for both activities. Murine 3T3 cells expressing human ACE2 supported SARS-CoV replication, whereas replication was less than 10% as efficient in the same cells expressing murine ACE2. These data imply that a mouse transgenically expressing human ACE2 may be a useful animal model of SARS. PMID:15452268

  14. Angiotensin-converting enzyme inhibitory activity and antioxidant properties of Nepeta crassifolia Boiss & Buhse and Nepeta binaludensis Jamzad.

    PubMed

    Tundis, Rosa; Nadjafi, Farsad; Menichini, Francesco

    2013-04-01

    This article reports phytochemical and biological studies on Nepeta binaludensis and Nepeta crassifolia. Both species were investigated for their angiotensin-converting enzyme (ACE) inhibitory activity and antioxidant properties through three in vitro models [2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP) assay]. Aerial parts were extracted with methanol and partitioned between water and subsequently n-hexane, ethyl acetate and n-butanol. N. binaludensis methanol extract exerted significantly higher reducing power (1.9 μM Fe(II)/g) than did the positive control butylhydroxytoluene (63.2 μM Fe(II)/g) in FRAP assay. The highest DPPH radical scavenging activity was found for N. crassifolia, with IC50 values of 9.6 and 12.1 µg/mL for ethyl acetate and n-butanol fractions, respectively. n-Butanol fraction of both species showed the highest ACE inhibitory activity, with IC50 values of 59.3 and 81.7 µg/mL for N. binaludensis and N. crassifolia, respectively. Phytochemical investigations resulted in the isolation of ursolic acid, oleanolic acid, apigenin, luteolin and ixoroside. Apigenin-7-O-glucoside, 8-hydroxycirsimaritin and cirsimaritin were furthermore identified in N. crassifolia ethyl acetate-soluble fraction. Nepetanudoside B was isolated from the n-butanol fraction of N. binaludensis. PMID:22693035

  15. Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.

    PubMed Central

    Oike, Y; Hata, A; Ogata, Y; Numata, Y; Shido, K; Kondo, K

    1995-01-01

    It has been reported that individuals with the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene are at greater risk for myocardial infarction (MI), especially among subjects normally considered to be at low risk. However, little is known about the mechanism by which the ACE polymorphism affects the risk of MI. Coronary artery spasm (CAS) is considered to be one possible mechanism for developing MI. We therefore examined the ACE polymorphism relation to CAS to determine if this was the mechanism by which the DD genotype influences MI. We studied 150 angiographically assessed Japanese males, all more than 60 yr old. CASs were detected using intracoronary injection of ergonovine maleate. Subjects were divided into three groups: those with CAS (group 1), those without CAS, but with fixed organic stenosis (group 2); and those without CAS and no organic stenosis (group 3). DD subjects were significantly represented in group 1 when compared with groups 2 (P = 0.002) and 3 (P = 0.026). These results suggest that the DD genotype relates to the greater risk for MI in the patients with CAS. PMID:8675669

  16. Fine-Mapping Angiotensin-Converting Enzyme Gene: Separate QTLs Identified for Hypertension and for ACE Activity

    PubMed Central

    Chung, Chia-Min; Wang, Ruey-Yun; Fann, Cathy S. J.; Chen, Jaw-Wen; Jong, Yuh-Shiun; Jou, Yuh-Shan; Yang, Hsin-Chou; Kang, Chih-Sen; Chen, Chien-Chung; Chang, Huan-Cheng; Pan, Wen-Harn

    2013-01-01

    Angiotensin-converting enzyme (ACE) has been implicated in multiple biological system, particularly cardiovascular diseases. However, findings associating ACE insertion/deletion polymorphism with hypertension or other related traits are inconsistent. Therefore, in a two-stage approach, we aimed to fine-map ACE in order to narrow-down the function-specific locations. We genotyped 31 single nucleotide polymorphisms (SNPs) of ACE from 1168 individuals from 305 young-onset (age ≤40) hypertension pedigrees, and found four linkage disequilibrium (LD) blocks. A tag-SNP, rs1800764 on LD block 2, upstream of and near the ACE promoter, was significantly associated with young-onset hypertension (p = 0.04). Tag-SNPs on all LD blocks were significantly associated with ACE activity (p-value: 10–16 to <10–33). The two regions most associated with ACE activity were found between exon13 and intron18 and between intron 20 and 3′UTR, as revealed by measured haplotype analysis. These two major QTLs of ACE activity and the moderate effect variant upstream of ACE promoter for young-onset hypertension were replicated by another independent association study with 842 subjects. PMID:23469169

  17. Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats

    PubMed Central

    Wang, Yang-Kai; Shen, Du; Hao, Qiang; Yu, Qiang; Wu, Zhao-Tang; Deng, Yu; Chen, Yan-Fang; Yuan, Wen-Jun; Hu, Qi-Kuan; Su, Ding-Feng

    2014-01-01

    The rostral ventrolateral medulla (RVLM) plays a key role in cardiovascular regulation. It has been reported that tonically active glutamatergic input to the RVLM is increased in hypertensive rats, whereas angiotensin-converting enzyme 2 (ACE2) in the brain has been suggested to be beneficial to hypertension. This study was designed to determine the effect of ACE2 gene transfer into the RVLM on tonically active glutamatergic input in spontaneously hypertensive rats (SHRs). Lentiviral particles containing enhanced green fluorescent protein (lenti-GFP) or ACE2 (lenti-ACE2) were injected bilaterally into the RVLM. Both protein expression and activity of ACE2 in the RVLM were increased in SHRs after overexpression of ACE2. A significant reduction in blood pressure and heart rate in SHRs was observed 6 wk after lenti-ACE2 injected into the RVLM. The concentration of glutamate in microdialysis fluid from the RVLM was significantly reduced by an average of 61% in SHRs with lenti-ACE2 compared with lenti-GFP. ACE2 overexpression significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity evoked by bilateral injection of the glutamate receptor antagonist kynurenic acid (2.7 nmol in 100 nl) into the RVLM in SHRs. Therefore, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced tonically active glutamatergic input in SHRs, which may be an important mechanism underlying the beneficial effect of central ACE2 to hypertension. PMID:24838502

  18. Identification of Angiotensin I-Converting Enzyme Inhibitory Peptides Derived from Enzymatic Hydrolysates of Razor Clam Sinonovacula constricta

    PubMed Central

    Li, Yun; Sadiq, Faizan A.; Fu, Li; Zhu, Hui; Zhong, Minghua; Sohail, Muhammad

    2016-01-01

    Angiotensin I-converting enzyme (ACE) inhibitory activity of razor clam hydrolysates produced using five proteases, namely, pepsin, trypsin, alcalase, flavourzyme and proteases from Actinomucor elegans T3 was investigated. Flavourzyme hydrolysate showed the highest level of degree of hydrolysis (DH) (45.87%) followed by A. elegans T3 proteases hydrolysate (37.84%) and alcalase (30.55%). The A. elegans T3 proteases was observed to be more effective in generating small peptides with ACE-inhibitory activity. The 3 kDa membrane permeate of A. elegans T3 proteases hydrolysate showed the highest ACE-inhibitory activity with an IC50 of 0.79 mg/mL. After chromatographic separation by Sephadex G-15 gel filtration and reverse phase-high performance liquid chromatography, the potent fraction was subjected to MALDI/TOF-TOF MS/MS for identification. A novel ACE-inhibitory peptide (VQY) was identified exhibiting an IC50 of 9.8 μM. The inhibitory kinetics investigation by Lineweaver-Burk plots demonstrated that the peptide acts as a competitive ACE inhibitor. The razor clam hydrolysate obtained by A. elegans T3 proteases could serve as a source of functional peptides with ACE-inhibitory activity for physiological benefits. PMID:27271639

  19. Interactions between carnosine and captopril on free radical scavenging activity and angiotensin-converting enzyme activity in vitro.

    PubMed

    Nakagawa, Kazuo; Ueno, Akemi; Nishikawa, Yukari

    2006-01-01

    Interactions between carnosine (beta-alanyl-L-histidine), being plentiful in skeletal muscles and neuronal tissues, and captopril, a widely used angiotensin-converting enzyme (ACE) inhibitor, were examined concerning free radical scavenging activity and ACE activity in vitro. Not only captopril, but also carnosine, at concentrations less than those ordinarily found in muscles and neuronal tissues, significantly scavenged 2,2'-azinobis (3-ethylbenzothiazoline-6-sulphonate) (ABTS) radical cations, and inhibited ACE activity. Cupric ions reversed the ABTS scavenging activity of carnosine and captopril, whereas cupric ions strengthened the inhibitory action of carnosine on ACE activity. In contrast, cupric ions antagonized the inhibition of ACE activity induced by ethylenediaminetetraacetic acid, indicating that the inhibitory effect of carnosine on ACE activity is not related to the chelating action of carnosine. On the other hand, carnosine and captopril synergistically enhanced the free radical scavenging activity, but not the inhibitory effect on the ACE activity. These data suggest that carnosine in its concurrent use with captopril could act as a beneficial free radical scavenger, with less danger of overdose, in the inhibition of ACE activity. PMID:16394648

  20. Reduction of microalbuminuria in type-2 diabetes mellitus with angiotensin-converting enzyme inhibitor alone and with cilnidipine

    PubMed Central

    Singh, V. K.; Mishra, A.; Gupta, K. K.; Misra, R.; Patel, M. L.; Shilpa

    2015-01-01

    The aim of our study was to find out the antiproteinuric effect of enalapril angiotensin-converting enzyme (ACE inhibitor) alone or in combination with cilnidipine in patients with type-2 diabetes mellitus. The study was conducted on 71 patients with type-2 diabetes mellitus patients with hypertension and microalbuminuria. They were divided into two groups randomly as follows: Group I (enalaprilalone, n = 36) and Group II (enalapril with cilnidipine, n = 35). In both the groups, baseline 24 h urinary albumin was estimated and was repeated every 3 months upto 1-year. After 1-year follow-up, reduction in microalbuminuria was found to be greater in Group II. In Group I microalbuminuria came down by 25.68 ± 21.40 while in Group II it reduced by 54.88 ± 13.84 (P < 0.001). We conclude that in diabetic population, cilnidipine has an additive effect in microalbuminuria reduction over and above the well-proven effect of ACE inhibitors. PMID:26664207

  1. Angiotensin I converting enzyme-inhibitory activity of bovine, ovine, and caprine kappa-casein macropeptides and their tryptic hydrolysates.

    PubMed

    Manso, M A; López-Fandiño, R

    2003-09-01

    This work evaluated the angiotensin-converting enzyme (ACE)-inhibitory activities of bovine, ovine, and caprine kappa-casein macropeptides (CMPs) and their tryptic hydrolysates. The results obtained indicate that bovine, ovine, and caprine CMPs exhibited moderate in vitro ACE-inhibitory activities that increased considerably after digestion under simulated gastrointestinal conditions. Active peptides could also be produced from CMPs via proteolysis with trypsin, with tryptic hydrolysates exhibiting a more extensive ACE-inhibitory activity than intact CMPs during simulated gastrointestinal digestion. Two active fractions were chromatographically separated from the tryptic hydrolysate of the bovine CMP, but their complexity hampered the assignment of the ACE-inhibitory activity to specific peptide sequences. Evidence for the release of the strong ACE-inhibitory tripeptide IPP was found upon simulation of the gastrointestinal digestion of peptides released by trypsin from the CMP sequence. These findings might help to promote further exploitation of cheese whey in the preparation of nutraceuticals for inclusion in the composition of functional food products with high added values. PMID:14503726

  2. β-blockers and Angiotensin Converting Enzyme Inhibitors: Comparison of Effects on Aortic Growth in Pediatric Patients with Marfan Syndrome

    PubMed Central

    Phomakay, Venusa; Huett, Wilson G.; Gossett, Jeffrey M.; Tang, Xinyu; Bornemeier, Renee A.; Collins, R. Thomas

    2015-01-01

    Objectives Angiotensin converting enzyme inhibitors (ACEI) have been shown to decrease AGV in Marfan syndrome (MFS). We sought to compare the effect of β-blockers and ACEI on aortic growth velocity (AGV) in MFS. Study design We reviewed retrospectively all data from all patients with MFS seen at Arkansas Children’s Hospital between January 1, 1976 and January 1, 2013. Generalized least squares were used to evaluate AGV over time as a function of age, medication group, and the interaction between the two. A mixed model was used to compare AGV between medication groups as a function of age, medication group (none, β-blocker, ACEI), and the interaction between the two. Results A total of 67 patients with confirmed MFS were identified (34/67, 51% female). Mean age at first encounter was 13 ± 10 years, with mean follow-up of 7.6 ± 5.8 years. There were 839 patient encounters with a median of 10 (range 2–42) encounters per patient. AGV was nearly normal in the β-blocker group, and was less than either the ACEI or untreated groups. The AGV was higher than normal in ACEI and untreated groups (p<0.001 for both). Conclusions β-blocker therapy results in near-normalization of AGV in MFS. ACEI did not decrease AGV in a clinically significant manner. PMID:25109242

  3. A Tricholoma matsutake Peptide with Angiotensin Converting Enzyme Inhibitory and Antioxidative Activities and Antihypertensive Effects in Spontaneously Hypertensive Rats

    PubMed Central

    Geng, Xueran; Tian, Guoting; Zhang, Weiwei; Zhao, Yongchang; Zhao, Liyan; Wang, Hexiang; Ng, Tzi Bun

    2016-01-01

    Hypertension is a major risk factor for cardiovascular disease. A crude water extract of the fruiting bodies of a highly prized mushroom Tricholoma matsutakei exerted an antihypertensive action on spontaneously hypertensive rats (SHRs) at a dosage of 400 mg/kg. An angiotensin converting enzyme (ACE) inhibitory peptide with an IC50 of 0.40 μM was purified from the extract and designated as TMP. Its amino acid sequence was elucidated to be WALKGYK through LC-MS/MS analysis. The Lineweaver-Burk plot suggested that TMP was a non-competitive inhibitor of ACE. A short-term assay of antihypertensive activity demonstrated that TMP at the dosage of 25 mg/kg could significantly lower the systolic blood pressure (SBP) of SHRs. TMP exhibited remarkable stability over a wide range of temperatures and pH values. It also demonstrated 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. The aforementioned activities of TMP were corroborated by utilizing the synthetic peptide. Hence T. matsutake can be used as a functional food to help prevent hypertension- associated diseases. PMID:27052674

  4. Identification of Angiotensin I-Converting Enzyme Inhibitory Peptides Derived from Enzymatic Hydrolysates of Razor Clam Sinonovacula constricta.

    PubMed

    Li, Yun; Sadiq, Faizan A; Fu, Li; Zhu, Hui; Zhong, Minghua; Sohail, Muhammad

    2016-01-01

    Angiotensin I-converting enzyme (ACE) inhibitory activity of razor clam hydrolysates produced using five proteases, namely, pepsin, trypsin, alcalase, flavourzyme and proteases from Actinomucor elegans T3 was investigated. Flavourzyme hydrolysate showed the highest level of degree of hydrolysis (DH) (45.87%) followed by A. elegans T3 proteases hydrolysate (37.84%) and alcalase (30.55%). The A. elegans T3 proteases was observed to be more effective in generating small peptides with ACE-inhibitory activity. The 3 kDa membrane permeate of A. elegans T3 proteases hydrolysate showed the highest ACE-inhibitory activity with an IC50 of 0.79 mg/mL. After chromatographic separation by Sephadex G-15 gel filtration and reverse phase-high performance liquid chromatography, the potent fraction was subjected to MALDI/TOF-TOF MS/MS for identification. A novel ACE-inhibitory peptide (VQY) was identified exhibiting an IC50 of 9.8 μM. The inhibitory kinetics investigation by Lineweaver-Burk plots demonstrated that the peptide acts as a competitive ACE inhibitor. The razor clam hydrolysate obtained by A. elegans T3 proteases could serve as a source of functional peptides with ACE-inhibitory activity for physiological benefits. PMID:27271639

  5. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats.

    PubMed

    Husková, Zuzana; Kopkan, Libor; Červenková, Lenka; Doleželová, Šárka; Vaňourková, Zdeňka; Škaroupková, Petra; Nishiyama, Akira; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kramer, Herbert J; Červenka, Luděk

    2016-04-01

    The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis. PMID:26833491

  6. Hypotensive and Angiotensin-Converting Enzyme Inhibitory Activities of Eisenia fetida Extract in Spontaneously Hypertensive Rats

    PubMed Central

    Mao, Shumei; Li, Chengde

    2015-01-01

    Objectives. This study aimed to investigate the antihypertensive effects of an Eisenia fetida extract (EFE) and its possible mechanisms in spontaneously hypertensive rats (SHR rats). Methods. Sixteen-week-old SHR rats and Wistar-Kyoto rats (WKY rats) were used in this study. Rats were, respectively, given EFE (EFE group), captopril (captopril group), or phosphate-buffered saline (PBS) (normal control group and SHR group) for 4 weeks. ACE inhibitory activity of EFE in vitro was determined. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using a Rat Tail-Cuff Blood Pressure System. Levels of angiotensin II (Ang II), aldosterone (Ald), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1α) in plasma were determined by radioimmunoassay, and serum nitric oxide (NO) concentration was measured by Griess reagent systems. Results. EFE had marked ACE inhibitory activity in vitro (IC50 = 2.5 mg/mL). After the 4-week drug management, SHR rats in EFE group and in captopril group had lower SBP and DBP, lower levels of Ang II and Ald, and higher levels of 6-keto-PGF1α and NO than the SHR rats in SHR group. Conclusion. These results indicate that EFE has hypotensive effects in SHR rats and its effects might be associated with its ACE inhibitory activity. PMID:26798397

  7. [The role of angiotensin-converting enzyme gene I/D polymorphism in development of metabolic disorders in patients with cardiovascular pathology].

    PubMed

    Vynohradova, S V

    2005-01-01

    The role of angiotensin-converting enzyme (ACE) gene I/D polymorphism in development of cardiovascular pathology (CVP), metabolic syndrom and insulin-independent diabet associated with such metabolic disorders as glucose intolerance and hyperglicemia, intolerance to insulin and hyperinsulinemia, dyslipiproteinemia (DLP) and obesity is discussed. Most of authors consider D-allel and DD genotype to be assosiated with development of DLP and such CVP as ishemic heart disease and myocardial infarction. PMID:16018179

  8. Top-down Targeted Metabolomics Reveals a Sulfur-Containing Metabolite with Inhibitory Activity against Angiotensin-Converting Enzyme in Asparagus officinalis.

    PubMed

    Nakabayashi, Ryo; Yang, Zhigang; Nishizawa, Tomoko; Mori, Tetsuya; Saito, Kazuki

    2015-05-22

    The discovery of bioactive natural compounds containing sulfur, which is crucial for inhibitory activity against angiotensin-converting enzyme (ACE), is a challenging task in metabolomics. Herein, a new S-containing metabolite, asparaptine (1), was discovered in the spears of Asparagus officinalis by targeted metabolomics using mass spectrometry for S-containing metabolites. The contribution ratio (2.2%) to the IC50 value in the crude extract showed that asparaptine (1) is a new ACE inhibitor. PMID:25922884

  9. Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model.

    PubMed

    Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan

    2016-09-01

    Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. PMID:27343405

  10. Altered activities of kininase II, an angiotensin converting enzyme, prekallikrein, and nitric oxide in Kuwaiti patients with type 2 diabetes.

    PubMed

    Sharma, J N; Al-Shoumer, Kas; Matar, K M; Madathil, N V; Al-Moalem, Amk

    2015-06-01

    The current investigation was conducted to examine kininase II or angiotensin converting enzyme (ACE), plasma prekallikrein (PK), and nitric oxide (NO) concentrations in healthy Kuwaiti subjects and newly diagnosed Kuwaiti type 2 diabetic patients before and after treatment for 6 weeks with metformin hydrochloride 500 mg twice daily after meal. With the consent of volunteers, blood and urine samples were collected after an overnight fasting. Samples were collected from the diabetic patients before and after treatment for 6 weeks. Enzyme linked immunosorbent assay (ELISA) was carried out on the aliquoted samples to measure the concentration of kininase II. NO was detected via colorimetry. Plasma Kininase II or ACE levels were significantly (P <0.01) increased by 18% in untreated diabetics when compared with healthy volunteers. However, after treatment there was a significant decrease of 20% in their ACE levels. Plasma prekallikrein levels were raised significantly (P <0.01) by 28% in diabetic patients in contrast with the control subjects and the levels were significantly reduced (P <0.0001) by 44% after treatment with metformin hydrochloride. NO levels were found to be significantly decreased in plasma by 56% and in urine by 62% in untreated diabetic patients as compared with the healthy subjects. However, when the treated diabetic patients were compared with untreated diabetics, there was an increase of 50% in plasma and 37% in urine samples. The high levels of kininase II, prekallikrein, and reduced NO may be partly responsible for the induction of renal, cardiac, and hypertensive complications associated with type 2 diabetes. Reduced NO level is an indication of endothelial dysfunction resulting in increased blood pressure. Oral anti-diabetic treatment is associated with protective effects through the reduction of kininase II (ACE), prekallikrein, and elevation of NO levels. PMID:25964383

  11. Monocrotaline pyrrole-induced changes in angiotensin-converting enzyme activity of cultured pulmonary artery endothelial cells.

    PubMed Central

    Hoorn, C. M.; Roth, R. A.

    1993-01-01

    1. Changes in the structural and functional integrity of endothelium have been recognized as relatively early features of delayed and progressive pulmonary vascular injury caused by the pyrrolizidine alkaloid, monocrotaline (MCT). Although a number of investigators have evaluated angiotensin-converting enzyme (ACE) activity in the lungs of rats treated with MCT, the exact nature of changes in activity of this enzyme and the role they may play in MCT pneumotoxicity remain controversial. 2. We examined the direct effects of monocrotaline pyrrole (MCTP), a toxic metabolite of MCT, on cultured endothelial cell ACE activity. Post-confluent monolayers of porcine or bovine pulmonary artery endothelial cells (PECs or BECs, respectively) were treated with a single administration of MCTP at time 0; then they were examined for their ability to degrade the synthetic peptide, [3H]-benzoyl-Phe-Ala-Pro. 3. In PECs, which are relatively insensitive to the direct cytolytic effects of MCTP, monolayer ACE activity was unchanged initially but gradually decreased within 4 days after treatment with a high concentration of MCTP (150 microM). This decrease was transient, and PEC monolayer ACE activity returned to the control value by 10 days post treatment. 4. BEC monolayer ACE activity was also unchanged initially but rapidly declined within 4 days after MCTP treatment and remained depressed throughout the post treatment period. BECs were quite sensitive to the cytolytic effects of MCTP and the decline in ACE activity occurred coincident with the decrease in monolayer cellularity and appearance of marked cytotoxicity. 5. We conclude that high concentrations of MCTP decrease endothelial ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8242234

  12. Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy

    PubMed Central

    Shih, Chia-Jen; Chen, Hung-Ta; Kuo, Shu-Chen; Li, Szu-Yuan; Lai, Pi-Hsiang; Chen, Shu-Chen; Ou, Shuo-Ming; Chen, Yung-Tai

    2016-01-01

    Background: Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. Methods: We conducted a propensity score–matched cohort study using Taiwan’s National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. Results: We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87–1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87–1.04), including myocardial infarction (HR 1.03, 95% CI 0.88–1.20), ischemic stroke (HR 0.94, 95% CI 0.85–1.04) and cardiovascular death (HR 1.01, 95% CI 0.88–1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91–1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86–1.18). Results were similar in as-treated analyses. Interpretation: Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy. PMID:27001739

  13. Angiotensin-converting enzyme inhibition increases glucose-induced insulin secretion in response to acute restraint.

    PubMed

    Schweizer, Júnia R O L; Miranda, Paulo A C; Fóscolo, Rodrigo B; Lemos, Joao P M; Paula, Luciano F; Silveira, Warley C; Santos, Robson A S; Pinheiro, Sérgio V B; Coimbra, Candido C; Ribeiro-Oliveira, Antônio

    2012-12-01

    There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint. PMID:23734984

  14. Angiotensin I Converting enzyme inhibitory peptides from commercial wet- and dry-milled corn germ

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bioprocesses were developed to enhance the value of proteins from de-oiled corn germ. Proteins were hydrolyzed with trypsin, GC106, Flavourzyme or thermolysin in order to free the bioactive peptide sequences. Protein hydrolysis, at an enzyme to substrate ratio of 1:250, was greater for wet- than d...

  15. Acute hemodynamic effects of angiotensin- converting enzyme inhibition after prolonged cardiac arrest with Bretschneider's solution.

    PubMed

    Hoyer, Alexandro; Kempfert, Jörg; Pritzwald-Stegmann, Patrick; Mohr, Friedrich-Wilhelm; Dhein, Stefan

    2014-12-01

    angiotensin-II receptor type 1 (AT1-R) or ETa receptor (ETa-R). PMID:25308324

  16. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

    SciTech Connect

    Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade; Xiang Qun; Gore, Elizabeth

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or

  17. Analysis of novel angiotensin-I-converting enzyme inhibitory peptides from protease-hydrolyzed marine shrimp Acetes chinensis.

    PubMed

    Hai-Lun, He; Xiu-Lan, Chen; Cai-Yun, Sun; Yu-Zhong, Zhang; Bai-Cheng, Zhou

    2006-11-01

    Acetes chinensis is an underutilized shrimp species thriving in the Bo Hai Gulf of China. In a previous study, we had used the protease from Bacillus sp. SM98011 to digest this kind of shrimp and found that the oligopeptide-enriched hydrolysate possessed antioxidant activity and high angiotensin I-converting enzyme (ACE) inhibitory activity with an IC50 value of 0.97 mg/ml. In this paper, by ultrafiltration, gel permeation chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC), five peptides with high ACE inhibitory activity were purified from the shrimp hydrolysates and their sequences were identified by amino acid composition analysis and molecular weight (MW) analysis. Three of them, FCVLRP (a), IFVPAF (f) and KPPETV (j), were novel ACE inhibitory peptides. Their IC50 values were 12.3 microM, 3.4 microM and 24.1 microM, respectively, and their recoveries were 30 mg/100 g (solid basis of shrimp), 19 mg/100 g and 33 mg/100 g, respectively. Lineweaver-Burk plots for the three novel peptides showed that they are all competitive inhibitors. To test the ACE inhibitory activity of peptide a, f, j after they were digested by digestive enzymes in vivo, 12 derived peptides from FCVLRP and IFVPAF were synthesized based on their amino acid sequences and the cleavage sites of digestive enzymes. No digestive enzyme cleavage site was found in KPPETV. The IC50 values of the derived peptides were determined and the result showed that except for VPAF, FC and FCVL, the ACE inhibitory activity of the other nine derived peptides did not significantly change when compared with their original peptides. Surprisingly, five peptides had lower IC50 values than their original peptides, particularly for RP (IC50 value = 0.39 microM), which is about 30 times lower than its original peptide and almost the lowest IC50 value for ACE inhibitory peptides reported. Therefore, the novel peptides identified from A. chinensis hydrolysates probably still maintain a high ACE

  18. Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver.

    PubMed

    Reza, Hasan Mahmud; Tabassum, Nabila; Sagor, Md Abu Taher; Chowdhury, Mohammed Riaz Hasan; Rahman, Mahbubur; Jain, Preeti; Alam, Md Ashraful

    2016-01-01

    Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats. PMID:26862777

  19. Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats

    PubMed Central

    Lopes, P.R.; Moreira, M.C.S.; Marques, S.M.; Pinto, I.S.J.; Macedo, L.M.; Silva, C.C.; Freiria-Oliveira, A.H.; Rebelo, A.C.S.; Reis, A.A.S.; Rosa, D.A.; Ferreira-Neto, M.L.; Castro, C.H.; Pedrino, G.R.

    2016-01-01

    The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280–350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50–60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation. PMID:27533767

  20. Convergent evidences from human and animal studies implicate angiotensin I-converting enzyme activity in cognitive performance in schizophrenia.

    PubMed

    Gadelha, A; Vendramini, A M; Yonamine, C M; Nering, M; Berberian, A; Suiama, M A; Oliveira, V; Lima-Landman, M T; Breen, G; Bressan, R A; Abílio, V; Hayashi, M A F

    2015-01-01

    In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations. PMID:26645626

  1. Segregation and linkage analysis of serum angiotensin I-converting enzyme levels: evidence for two quantitative-trait loci.

    PubMed Central

    McKenzie, C A; Julier, C; Forrester, T; McFarlane-Anderson, N; Keavney, B; Lathrop, G M; Ratcliffe, P J; Farrall, M

    1995-01-01

    Human serum angiotensin I-converting enzyme (ACE) levels vary substantially between individuals and are highly heritable. Segregation analysis in European families has shown that more than half of the total variability in ACE levels is influenced by quantitative-trait loci (QTL). One of these QTLs is located within or close to the ACE locus itself. Combined segregation/linkage analysis in a series of African Caribbean families from Jamaica shows that the ACE insertion-deletion polymorphism is in moderate linkage disequilibrium with an ACE-linked QTL. Linkage analysis with a highly informative polymorphism at the neighboring growth-hormone gene (GH) shows surprisingly little support for linkage (LOD score [Z] = 0.12). An extended analysis with a two-QTL model, where an ACE-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACe-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACe-linked QTL and GH polymorphism (Z = 5.0). We conclude that two QTLs jointly influence serum ACE levels in this population. One QTL is located within or close to the ACE locus and explains 27% of the total variability; the second QTL is unlinked to the ACE locus and explains 52% of the variability. The identification of the molecular mechanisms underlying both QTLs is necessary in order to interpret the role of ACE in cardiovascular disease. PMID:8533773

  2. Effect of angiotensin I-converting enzyme and α-actinin-3 gene polymorphisms on sport performance.

    PubMed

    Gunel, Tuba; Gumusoglu, Ece; Hosseini, Mohammad Kazem; Yilmazyildirim, Eda; Dolekcap, Ismail; Aydinli, Kilic

    2014-04-01

    Genetic polymorphism is considered to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) and the α-actinin-3 gene (ACTN3) R577X polymorphisms have been widely investigated for such associations, and functional ACE I/D and ACTN3 R577X polymorphisms have been associated with sprinter performance. The aim of this study was to determine the effect of these polymorphisms on sport performance among 37 elite athletes and 37 healthy controls. The ACE II genotype was identified in 32.43% of the control group and 8.11% of elite athletes, the DD genotype in 37.84% of the control group and 51.35% of the elite athletes, and the ID genotype in 29.73% of the control group and 40.54% of the elite athletes. With regard to the ACTN3 gene, the XX genotype, which confers an advantage for endurance activities, was identified in 10.81% of the control group and 35.14% of the elite athletes. The XX genotype was observed more frequently than the RR genotype (advantageous for sprinting), which was identified in 2.70% of the control group and 10.81% of elite athletes. The RX genotype (observed in 86.48% of the control group and in 54.05% of the elite athletes) was the most common genotype of the individuals in the present study. The study showed that ACTN3 and ACE gene polymorphisms have an effect on muscle power; however, larger studies are required. PMID:24566537

  3. Furosemide- sup 131 I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension

    SciTech Connect

    Erbsloeh-Moeller, B.Du.; Dumas, A.; Roth, D.; Sfakianakis, G.N.; Bourgoignie, J.J. )

    1991-01-01

    We have previously demonstrated the greater sensitivity of 131I-hippuran renography than 99mTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-131I-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. All patients were investigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function and 22 had renal insufficiency. Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 micrograms/kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 131I-hippuran. The residual cortical activity (RCA) of 131I-hippuran was measured at 20 minutes. RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely, RVH was present when 131I-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and 100%, RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition, RVH was likely; whereas, intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20).

  4. Polymorphisms in the angiotensin-converting enzyme gene region predict coping styles in healthy adults and depressed patients.

    PubMed

    Heck, Angela; Lieb, Roselind; Ellgas, Andrea; Pfister, Hildegard; Lucae, Susanne; Erhardt, Angelika; Himmerich, Hubertus; Horstmann, Sonja; Kloiber, Stefan; Ripke, Stephan; Müller-Myhsok, Bertram; Bettecken, Thomas; Uhr, Manfred; Holsboer, Florian; Ising, Marcus

    2009-01-01

    Dispositional coping styles are important moderators of the stress reaction and are altered in stress-related disorders like cardiovascular diseases and affective disorders. Heritability studies suggest a considerable genetic contribution to the interindividual variability in coping styles. Since the angiotensin-converting enzyme (ACE) gene has been described to be associated with the vulnerability for stress-related disorders and with altered stress hormone regulation, we investigated the ACE gene as potential candidate gene for coping styles. Five hundred forty one mentally healthy subjects and 194 patients suffering from depression participating in the Munich Antidepressant Response Signature (MARS) project were examined. Coping styles were assessed with a self-report questionnaire (German Stress Coping Questionnaire SVF78) measuring the individual coping style pattern in response to stressful situations. We genotyped 15 single nucleotide polymorphisms (SNPs) and the insertion/Deletion (I/D)-polymorphism in the ACE gene region and investigated their associations with coping styles. In healthy subjects, the highest association was observed between rs8066276, an intronic SNP of the ACE gene, and the coping factor Distraction. A further intronic SNP rs4305, not in linkage disequilibrium with rs8066276, showed an association with Devaluation/Defense. All associated copying styles can be categorized as potentially stress reducing factors (positive coping). Both SNPs were also found to be associated with positive coping styles in the patient sample; rs8066276 was associated with Devaluation/Defense, and rs4305 showed associations with Control. These results suggest that the ACE gene is involved in the development of coping strategies. PMID:18484085

  5. Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women

    PubMed Central

    Shakarami, Fatemeh; Akbari, Mohammad Taghi; Zare Karizi, Shohreh

    2015-01-01

    Background: Recurrent pregnancy loss (RPL) defined by two or more failed pregnancies before 20 weeks of gestation. Several factors play a role in RPL including thrombophilic conditions which can be influenced by gene polymorphisms. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) genes are closely related to fibrinolytic process, embryonic development and pregnancy success. Objective: The aim of this study was to investigate the relationship between RPL and common polymorphisms in ACE and PAI-1 genes. Materials and Methods: In this case control study, 100 women with recurrent abortions (at least two) were selected as cases and 100 healthy women with two or more normal term deliveries without a history of abortion as controls. Total genomic DNA was isolated from blood leukocytes. The status of the PAI-1 4G/5G and ACE (D/I) polymorphism was determined by PCR-RFLP. Results: Homozygosity for PAI-1 4G polymorphism was seen in 17 cases (17%), and 5 controls (5%) (p=0.006) so patients with homozygote 4G mutation were significantly more prone to RPL in contrast to control group (OR: 4.63, % 95 CI: 1.55-13.84). In addition, 7 patients (7 %), and no one from the control group, were homozygote (I/I) for ACE polymorphism (p=0.034), suggesting no significant associations between ACE D allele or DD genotype and RPL. Conclusion: Considering these results, because 4G/4G polymorphism for PAI-1 gene could be a thrombophilic variant leading to abortion, analysis of this mutation and other susceptibility factors are recommended in patients with RPL. PMID:26644791

  6. Association of apolipoprotein E and angiotensin converting enzyme gene polymorphisms with the multidimensional impairment in older patients.

    PubMed

    Pilotto, Alberto; Matera, Maria G; Ferrucci, Luigi; Sancarlo, Daniele; Leandro, Gioacchino; D'Onofrio, Grazia; Seripa, Davide; Addante, Filomena; Franceschi, Marilisa; Dallapiccola, Bruno

    2009-08-01

    The role of the apolipoprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy-Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of epsilon4 allele and the ACE D/D genotype was observed. The APOE epsilon4(+) and ACE D/D genotypes were associated with severe MPI grade (APOE epsilon4(+), odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20-2.67; ACE D/D, OR = 1.42, 95% CI 1.05-1.92). The combined APOE epsilon4(+) and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75-4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive. PMID:19653879

  7. Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats.

    PubMed

    Lopes, P R; Moreira, M C S; Marques, S M; Pinto, I S J; Macedo, L M; Silva, C C; Freiria-Oliveira, A H; Rebelo, A C S; Reis, A A S; Rosa, D A; Ferreira-Neto, M L; Castro, C H; Pedrino, G R

    2016-01-01

    The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280-350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50-60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation. PMID:27533767

  8. Association of Apolipoprotein E and Angiotensin Converting Enzyme Gene Polymorphisms with the Multidimensional Impairment in Older Patients

    PubMed Central

    Matera, Maria G.; Ferrucci, Luigi; Sancarlo, Daniele; Leandro, Gioacchino; D'Onofrio, Grazia; Seripa, Davide; Addante, Filomena; Franceschi, Marilisa; Dallapiccola, Bruno

    2009-01-01

    Abstract The role of the apoliprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy–Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of ɛ4 allele and the ACE D/D genotype was observed. The APOE ɛ4+ and ACE D/D genotypes were associated with severe MPI grade (APOE ɛ4+, odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20–2.67; ACE D/D, OR = 1.42, 95% CI 1.05–1.92). The combined APOE ɛ4+ and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75–4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive. PMID:19653879

  9. Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway.

    PubMed

    Silvestre, J S; Bergaya, S; Tamarat, R; Duriez, M; Boulanger, C M; Levy, B I

    2001-10-12

    Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B(2) receptor-deficient mice (B(2)(-/-)) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B(2)(-/-) mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0.87+/-0.07 versus 0.59+/-0.05, respectively, P<0.01). Activation of the angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B(2)(-/-) mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B(2)-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression. PMID:11597990

  10. Association of angiotensin-converting enzyme gene polymorphisms with Crohn’s disease in a Chinese Han population

    PubMed Central

    Zhou, Jie; Zheng, Sichang; Wang, Zhengting; Fan, Rong; Yuan, Jielu; Zhong, Jie

    2015-01-01

    Objective: To investigate whether Angiotensin-converting enzyme (ACE) gene polymorphisms alter the susceptibility of a Chinese Han population to Crohn’s disease (CD). Methods: Blood samples were collected from patients with CD and from healthy control subjects for analyzing SNP rs4291 (promoter, A262T), SNP rs4343 (exon 16, A11860G), and rs4646994 (intron 16, Alu insertion/deletion). Allele and genotype frequencies were compared, and pairwise linkage disequilibrium and haplotypes were analyzed in patients with CD. Results: Both rs4343 A/G and rs4646994 I/D allele frequencies differed significantly between patients with CD and control subjects (rs4343: OR=1.438, 95% CI=1.099-1.882, P=0.008; rs4646994: OR=1.559, 95% CI=1.191-2.039, P=0.001). There were also significant associations between the risk of CD and both rs4343 AA/(AG+GG) and rs4646994 II/(ID+DD) genotype frequencies (P=0.039 and P=0.019). The frequency of the G-D haplotype was significantly lower in patients with CD than control subjects (31.7% vs. 40.4%, P=0.010). Conclusions: The results suggest that ACE rs4343G and rs4646994D alleles protect against CD, while rs4343AA and the I allele in the dominant genetic model are risk alleles for CD. The association between the G-D haplotype and CD was significant, suggesting a protective role in the pathogenesis of CD. PMID:26823847

  11. Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry

    NASA Technical Reports Server (NTRS)

    McElmurray, J. H. 3rd; Mukherjee, R.; New, R. B.; Sampson, A. C.; King, M. K.; Hendrick, J. W.; Goldberg, A.; Peterson, T. J.; Hallak, H.; Zile, M. R.; Spinale, F. G.

    1999-01-01

    The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.

  12. Hypotensive, Angiotensin Converting Enzyme (ACE) Inhibitory and Diuretic Activities of the Aqueous-methanol Extract of Ipomoea reniformis

    PubMed Central

    Jabeen, Qaiser; Aslam, Naveed

    2013-01-01

    Ipomoea reniformis Roxb. (Convolvulaceae) is a small, weedy herb used for the management of cardiac problems in traditional systems of medicine in India and Pakistan. Objective of the present study was to investigate the hypotensive, diuretic and angiotensin converting enzyme (ACE) inhibitory activities of the aqueous-methanol (30:70) crude extract of the dried aerial parts of I. reniformis (Ir.Cr.) in rats. To record blood pressure lowering effects of the Ir.Cr, different doses of the extract were administered through jugular vein to the ketamine-diazepam anesthetized normotensive rats and blood pressure was recorded via carotid artery. ACE inhibitory activity of the extract was studied in-vitro; using hippuryl-l-histidyl-l-leucine as substrate, the product hippurate was quantified spectrophotometrically after reacting with cyanuric chloride/dioxane reagent. Effects of intraperitoneal administration of the extract on urine and urinary electrolyte excretion were also investigated in rats. The extract (Ir.Cr.) produced 21.51 ± 3.41, 28.99 ± 2.30, 53.34 ± 0.88 and 61.71 ± 3.37% fall in mean arterial blood pressure of the anesthetized rats at the doses of 0.1, 0.3, 1.0 and 3.0 mg/Kg, respectively. Ir.Cr. was found to have serum ACE inhibitory activity, with IC50 value of 422 ± 21.16 μg/mL. The extract also increased urine volume and urinary Na+ excretion significantly at the doses of 30 and 50 mg/Kg in rats. The study concludes that the crude extract of Ipomoea reniformis (Ir.Cr.) has hypotensive, ACE inhibitory and diuretic activities, which provide the scientific justification for the traditional uses of the plant as cardioprotective, antihypertensive and diuretic remedy. PMID:24523757

  13. Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors.

    PubMed

    Douglas, Ross G; Sharma, Rajni K; Masuyer, Geoffrey; Lubbe, Lizelle; Zamora, Ismael; Acharya, K Ravi; Chibale, Kelly; Sturrock, Edward D

    2014-02-01

    ACE (angiotensin-1-converting enzyme) is a zinc metallopeptidase that plays a prominent role in blood pressure regulation and electrolyte homeostasis. ACE consists of two homologous domains that despite similarities of sequence and topology display differences in substrate processing and inhibitor binding. The design of inhibitors that selectively inhibit the N-domain (N-selective) could be useful in treating conditions of tissue injury and fibrosis due to build-up of N-domain-specific substrate Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro). Using a receptor-based SHOP (scaffold hopping) approach with N-selective inhibitor RXP407, a shortlist of scaffolds that consisted of modified RXP407 backbones with novel chemotypes was generated. These scaffolds were selected on the basis of enhanced predicted interaction energies with N-domain residues that differed from their C-domain counterparts. One scaffold was synthesized and inhibitory binding tested using a fluorogenic ACE assay. A molecule incorporating a tetrazole moiety in the P2 position (compound 33RE) displayed potent inhibition (K(i)=11.21±0.74 nM) and was 927-fold more selective for the N-domain than the C-domain. A crystal structure of compound 33RE in complex with the N-domain revealed its mode of binding through aromatic stacking with His388 and a direct hydrogen bond with the hydroxy group of the N-domain specific Tyr369. This work further elucidates the molecular basis for N-domain-selective inhibition and assists in the design of novel N-selective ACE inhibitors that could be employed in treatment of fibrosis disorders. PMID:24015848

  14. Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review and an algorithm for airway management.

    PubMed

    Chiu, A G; Newkirk, K A; Davidson, B J; Burningham, A R; Krowiak, E J; Deeb, Z E

    2001-09-01

    Angioedema is a nonpitting edema of which the presentation ranges from benign facial swelling to airway obstruction managed by intubation or tracheotomy. The presentation of this disease is reviewed, and a treatment algorithm based on initial signs and symptoms is proposed for proper airway management. We performed a retrospective review of 108 patients treated in 2 tertiary care centers in the Washington, DC, area over a 5-year period. Ninety-eight patients (90.7%) were African-American, and 81 (75%) were female. Seventy-four patients (68.5%) were taking angiotensin-converting enzyme inhibitors (ACEIs). A classification system was developed based on the location of the edema at initial presentation: 1) isolated facial swelling and oral cavity edema, excluding the floor of the mouth; 2) floor of mouth and/or oropharyngeal edema, and 3) oropharyngeal edema with glottic and/or supraglottic involvement. Fourteen patients (13%) needed airway intervention, 2 of whom underwent a cricothyrotomy after a failed intubation attempt. Eleven (78.6%) were taking ACEIs. The indication for each intubation was massive tongue and floor of mouth edema. The patients were extubated 48 to 72 hours later. No patient demonstrated symptom progression after medical treatment was initiated. Therapy included discontinuation of the ACEI or other inciting agent, a high-humidity face tent, an initial dose of intravenous antihistamines, and a continued course of intravenous steroids. Within 48 hours, most patients had a resolution of their edema. Only cases of significant tongue and oropharyngeal edema took longer than 48 hours to resolve. The ACEIs are a common cause of angioedema. Left untreated, angioedema may progress to involve the oropharynx and supraglottis, resulting in a life-threatening airway compromise. Marked floor of mouth and tongue edema are the indications for airway intervention. An algorithm based on the initial presentation is essential for proper airway and patient management

  15. Chronic endothelin-A receptor antagonism is as protective as angiotensin converting enzyme inhibition against cardiac dysfunction in diabetic rats

    PubMed Central

    Wölkart, G; Pang, X; Stessel, H; Kirchengast, M; Brunner, F

    2007-01-01

    Background and purpose: Diabetes mellitus is associated with a specific cardiomyopathy. We compared the cardioprotective effects of an endothelin-A receptor blocker (ETA-RB) with those of an angiotensin-converting enzyme inhibitor (ACE-I) in rats with streptozotocin (STZ)-induced diabetes. Experimental approach: Diabetic rats were left untreated or received either the ETA-RB atrasentan or the ACE-I ramipril (each 3 mg kg−1 per day) orally for 8 weeks. Isolated isovolumic heart function was studied during normoxia and in response to ischaemia-reperfusion. Cardiac fibrosis, tissue oxidative stress and tissue nitric oxide synthase (NOS) activity were determined. Key results: Basal left ventricular systolic contractility was lower in diabetic compared to nondiabetic hearts and ETA-RB or ACE-I treatment significantly antagonised the decline. Following 15 min of no-flow ischaemia, reperfusion systolic function was depressed and left-ventricular end-diastolic pressure (LVEDP) was elevated in diabetic hearts. ETA-RB or ACE-I treatment significantly improved recovery of reperfusion systolic and diastolic function, without differences between groups. Hydroxyproline (an index of tissue fibrosis) and malondialdehyde (a measure of tissue oxidative stress) were elevated at the end of reperfusion in diabetic, compared to nondiabetic hearts. Either treatment reduced hydroxyproline and malondialdehyde to control level. Constitutive NOS activity was similar in nondiabetic and diabetic hearts and unaffected by ETA-RB or ACE-I treatment. Conclusions and implications: These results suggest that in experimental type 1 diabetes ETA-RB is as effective as an ACE-I in ameliorating myocardial functions during normoxia and ischaemia-reperfusion. Combining the two treatments neither afforded additive effects, nor diminished any protection effect seen with either drug. PMID:17572700

  16. Angiotensin-converting enzyme and progression of white matter lesions and brain atrophy--the SMART-MR study.

    PubMed

    Jochemsen, Hadassa M; Geerlings, Mirjam I; Grool, Anne M; Vincken, Koen L; Mali, Willem Ptm; van der Graaf, Yolanda; Muller, Majon

    2012-01-01

    High levels of angiotensin-converting-enzyme (ACE) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease. However, high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy. Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average (range) 3.9 (3.0-5.8) years of follow-up in 682 persons (mean age 58 ± 10 years). Brain segmentation was used to quantify total, deep, and periventricular white matter lesion (WML) volume, and total brain, cortical gray matter and ventricular volume (%ICV). Lacunar infarcts were rated visually. Regression analyses were used to examine the prospective associations between serum ACE and brain measures. Patients with the highest serum ACE levels (>43.3 U/L) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels (<21.8 U/L); mean difference (95% CI) in change was 0.20 (-0.02; 0.43) %ICV. On the contrary, patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels; mean difference (95% CI) in change was 0.78 (0.21; 1.36) %ICV. Serum ACE was not associated with subcortical atrophy, periventricular WML, or lacunar infarcts. Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume, but with less progression of cortical brain atrophy. This suggests both detrimental and beneficial effects of high ACE levels on the brain. PMID:22214784

  17. The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late-onset Pompe patients receiving alglucosidase alfa.

    PubMed

    Baek, Rena C; Palmer, Rachel; Pomponio, Robert J; Lu, Yuefeng; Ma, Xiwen; McVie-Wylie, Alison J

    2016-09-01

    Correlations between angiotensin-converting enzyme (ACE) genotype (I/I, I/D, D/D), disease severity at baseline and response to enzyme replacement therapy (ERT) were assessed in the Pompe disease Late-Onset Treatment Study (LOTS). No correlations were observed between ACE genotype and disease severity at baseline. However, D/D patients appeared to have a reduced response to alglucosidase alfa treatment than I/I or I/D patients, suggesting that ACE polymorphisms may influence the response to alglucosidase alfa treatment and warrants further investigation. PMID:27489778

  18. Casein Fermentate of Lactobacillus animalis DPC6134 Contains a Range of Novel Propeptide Angiotensin-Converting Enzyme Inhibitors▿

    PubMed Central

    Hayes, M.; Stanton, C.; Slattery, H.; O'Sullivan, O.; Hill, C.; Fitzgerald, G. F.; Ross, R. P.

    2007-01-01

    This work evaluated the angiotensin-converting-enzyme (ACE)-inhibitory activities of a bovine sodium caseinate fermentate generated using the proteolytic capabilities of the porcine small intestinal isolate Lactobacillus animalis DPC6134 (NCIMB deposit 41355). The crude 10-kDa L. animalis DPC6134 fermentate exhibited ACE-inhibitory activity of 85.51% (±15%) and had a 50% inhibitory concentration (IC50) of 0.8 mg protein/ml compared to captopril, which had an IC50 value of 0.005 mg/ml. Fractionation of the crude L. animalis DPC6134 fermentate by membrane filtration and reversed-phase high-performance liquid chromatography (HPLC) generated three bioactive fractions from a total of 72 fractions. Fractions 10, 19, and 43 displayed ACE-inhibitory activity percentages of 67.53 (±15), 83.71 (±19), and 42.36 (±11), respectively, where ACE inhibition was determined with 80 μl of the fractions with protein concentrations of 0.5 mg/ml. HPLC and mass spectrometry analysis identified 25 distinct peptide sequences derived from α-, β-, and κ-caseins. In silico predictions, based on the C-terminal tetrapeptide sequences, suggested that peptide NIPPLTQTPVVVPPFIQ, corresponding to β-casein f(73-89); peptide IGSENSEKTTMP, corresponding to αs1-casein f(201212); peptide SQSKVLPVPQ, corresponding to β-casein f(166-175); peptide MPFPKYPVEP, corresponding to β-casein f(124133); and peptide EPVLGPVRGPFP, corresponding to β-casein f(210-221), contained ACE-inhibitory activities. These peptides were chosen for chemical synthesis to confirm the ACE-inhibitory activity of the fractions. Chemically synthesized peptides displayed IC50 values in the range of 92 μM to 790 μM. Additionally, a simulated gastrointestinal digestion confirmed that the ACE-inhibitory 10-kDa L. animalis DPC6134 fermentation was resistant to a cocktail of digestive enzymes found in the gastrointestinal tract. PMID:17483275

  19. Angiotensin I-Converting Enzyme (ACE) Inhibitory Activity and ACE Inhibitory Peptides of Salmon (Salmo salar) Protein Hydrolysates Obtained by Human and Porcine Gastrointestinal Enzymes

    PubMed Central

    Darewicz, Małgorzata; Borawska, Justyna; Vegarud, Gerd E.; Minkiewicz, Piotr; Iwaniak, Anna

    2014-01-01

    The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and ex vivo digestion (with human gastrointestinal enzymes). Secondly, to evaluate the ACE inhibitory activity of generated hydrolysates. A two-step ex vivo and in vitro model digestion was performed to simulate the human digestion process. Salmon proteins were degraded more efficiently by porcine enzymes than by human gastrointestinal juices and sarcoplasmic proteins were digested/hydrolyzed more easily than myofibrillar proteins. The ex vivo digested myofibrillar and sarcoplasmic duodenal samples showed IC50 values (concentration required to decrease the ACE activity by 50%) of 1.06 and 2.16 mg/mL, respectively. The in vitro hydrolyzed myofibrillar and sarcoplasmic samples showed IC50 values of 0.91 and 1.04 mg/mL, respectively. Based on the results of in silico studies, it was possible to identify 9 peptides of the ex vivo hydrolysates and 7 peptides of the in vitro hydrolysates of salmon proteins of 11 selected peptides. In both types of salmon hydrolysates, ACE-inhibitory peptides IW, IY, TVY and VW were identified. In the in vitro salmon protein hydrolysates an ACE-inhibitory peptides VPW and VY were also detected, while ACE-inhibitory peptides ALPHA, IVY and IWHHT were identified in the hydrolysates generated with ex vivo digestion. In our studies, we documented ACE inhibitory in vitro effects of salmon protein hydrolysates obtained by human and as well as porcine gastrointestinal enzymes. PMID:25123137

  20. Angiotensin-converting enzyme gene insertion/deletion, not bradykinin B2 receptor -58T/C gene polymorphism, associated with angiotensin-converting enzyme inhibitor-related cough in Chinese female patients with non-insulin-dependent diabetes mellitus.

    PubMed

    Lee, Y J; Tsai, J C

    2001-11-01

    To investigate the genetic susceptibility associated with cough related to angiotensin-converting enzyme inhibitor (ACEI) therapy in patients with type 2 diabetes, 189 non-insulin-dependent diabetes mellitus (NIDDM) patients with proteinuria or hypertension treated with perindopril were studied. Cough was considered to be present if the patients had been bothered by a cough during treatment and if they had had related symptoms for at least 2 weeks without an identifiable cause. Polymerase chain reaction (PCR) coupled with single-strand conformation polymorphism (SSCP) was used to detect polymorphisms of ACE and bradykinin B2-receptor genes. After 8 weeks of treatment, 49.2% (93 of 189) of our NIDDM patients were found to be suffering from ACEI-related cough. ACEI-related cough was mainly associated with female patients, with 71.7% (76 of 106) of female and only 20.5% (17 of 83) of male patients experiencing cough after ACEI treatment. There was a significant association of ACE II genotype with ACEI-related cough. The genotype frequencies were 58.2% for II, 47.8% for ID, and 16.7% for DD in patients with ACEI-associated cough and 41.8% for II, 52.2% for ID, and 83.3% for DD in subjects without ACEI-associated cough (chi(2) = 10.268; df = 2, P =.006). As female patients made up the majority of the subjects suffering from ACEI-related cough, we further analyzed the association of ACE I/D genotype with ACEI-related cough separately by sex. Male patients with ACEI-related cough were not associated with ACE I/D genotype distribution, while female patients were strongly associated with ACE I/D genotype polymorphism (chi(2) = 16.12; df = 2; P <.001). There was no association between the bradykinin B2 receptor gene -58T/C polymorphism with ACEI-related cough. In conclusion, our results indicate that Chinese diabetic female subjects are susceptible to ACEI-related cough, and this susceptibility may be genetically predetermined. PMID:11699055

  1. Necessity of angiotensin-converting enzyme-related gene for cardiac functions and longevity of Drosophila melanogaster assessed by optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Liao, Fang-Tsu; Chang, Cheng-Yi; Su, Ming-Tsan; Kuo, Wen-Chuan

    2014-01-01

    Prior studies have established the necessity of an angiotensin-converting enzyme-related (ACER) gene for heart morphogenesis of Drosophila. Nevertheless, the physiology of ACER has yet to be comprehensively understood. Herein, we employed RNA interference to down-regulate the expression of ACER in Drosophila's heart and swept source optical coherence tomography to assess whether ACER is required for cardiac functions in living adult flies. Several contractile parameters of Drosophila heart, including the heart rate (HR), end-diastolic diameter (EDD), end-systolic diameter (ESD), percent fractional shortening (%FS), and stress-induced cardiac performance, are shown, which are age dependent. These age-dependent cardiac functions declined significantly when ACER was down-regulated. Moreover, the lifespans of ACER knock-down flies were significantly shorter than those of wild-type control flies. Thus, we posit that ACER, the Drosophila ortholog of mammalian angiotensin-converting enzyme 2 (ACE2), is essential for both heart physiology and longevity of animals. Since mammalian ACE2 controls many cardiovascular physiological features and is implicated in cardiomyopathies, our findings that ACER plays conserved roles in genetically tractable animals will pave the way for uncovering the genetic pathway that controls the renin-angiotensin system.

  2. Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay

    PubMed Central

    2013-01-01

    Background and purpose of the study Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension. The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay. Methods The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC). Total phenolic content and antioxidant activity were determined by Folin-Ciocalteu colorimetric method and DPPH radical scavenging assay respectively. Results Six extracts revealed > 50% ACE inhibition activity at 330 μg/ml concentration. They were Berberis integerrima Bunge. (Berberidaceae) (88.2 ± 1.7%), Crataegus microphylla C. Koch (Rosaceae) (80.9 ± 1.3%), Nymphaea alba L. (Nymphaeaceae) (66.3 ± 1.2%), Onopordon acanthium L. (Asteraceae) (80.2 ± 2.0%), Quercus infectoria G. Olivier. (Fagaceae) (93.9 ± 2.5%) and Rubus sp. (Rosaceae) (51.3 ± 1.0%). Q. infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant. Antioxidant activity of Q. infectoria (IC50 value 1.7 ± 0.03 μg/ml) was more than that of BHT (IC50 value of 10.3 ± 0.15 μg/ml) and Trolox (IC50 value of 3.2 ± 0.06 μg/ml) as the positive controls. Conclusions In this study, we introduced six medicinal plants with ACE inhibition activity. Despite the high ACE inhibition and antioxidant activity of Q. infectoria, due to its tannin content (tannins interfere in ACE activity), another plant, O. acanthium, which also had high ACE inhibition and antioxidant activity, but contained no tannin, could be utilized in further studies for isolation of active compounds. PMID:24359711

  3. Peptidase specificity characterization of C- and N-terminal catalytic sites of angiotensin I-converting enzyme.

    PubMed

    Araujo, M C; Melo, R L; Cesari, M H; Juliano, M A; Juliano, L; Carmona, A K

    2000-07-25

    Quenched fluorescence peptides were used to investigate the substrate specificity requirements for recombinant wild-type angiotensin I-converting enzyme (ACE) and two full-length mutants bearing a single functional active site (N- or C-domain). We assayed two series of bradykinin-related peptides flanked by o-aminobenzoic acid (Abz) and N-(2,4-dinitrophenyl)ethylenediamine (EDDnp), namely, Abz-GFSPFXQ-EDDnp and Abz-GFSPFRX-EDDnp (X = natural amino acids), in which the fluorescence appeared when Abz/EDDnp are separated by substrate hydrolysis. Abz-GFSPFFQ-EDDnp was preferentially hydrolyzed by the C-domain while Abz-GFSPFQQ-EDDnp exhibits higher N-domain specificity. Internally quenched fluorescent analogues of N-acetyl-SDKP-OH were also synthesized and assayed. Abz-SDK(Dnp)P-OH, in which Abz and Dnp (2,4-dinitrophenyl) are the fluorescent donor-acceptor pair, was cleaved at the D-K(Dnp) bond with high specificity by the ACE N-domain (k(cat)/K(m) = 1.1 microM(-)(1) s(-)(1)) being practically resistant to hydrolysis by the C-domain. The importance of hydroxyl-containing amino acids at the P(2) position for N-domain specificity was shown by performing the kinetics of hydrolysis of Abz-TDK(Dnp)P-OH and Abz-YDK(Dnp)P-OH. The peptides Abz-YRK(Dnp)P-OH and Abz-FRK(Dnp)P-OH which were hydrolyzed by wild-type ACE with K(m) values of 5.1 and 4.0 microM and k(cat) values of 246 and 210 s(-)(1), respectively, have been shown to be excellent substrates for ACE. The differentiation of the catalytic specificity of the C- and N-domains of ACE seems to depend on very subtle variations on substrate-specific amino acids. The presence of a free C-terminal carboxyl group or an aromatic moiety at the same substrate position determines specific interactions with the ACE active site which is regulated by chloride and seems to distinguish the activities of both domains. PMID:10913258

  4. Weight loss for reduction of proteinuria in diabetic nephropathy: Comparison with angiotensin-converting enzyme inhibitor therapy

    PubMed Central

    Patil, M. R.; Mishra, A.; Jain, N.; Gutch, M.; Tewari, R.

    2013-01-01

    Reduction of weight in obese type 2 diabetes mellitus (T2DM) individuals is emerging as a significant strategy in the reduction of proteinuria in diabetic nephropathy along with control of hyperglycemia, hypertension, and dyslipidemia. The objective was to evaluate the reduction in 24-h proteinuria in T2DM patients with nephropathy by weight loss, with conventional therapy (angiotensin-converting enzyme [ACE] inhibitors) as the control arm. A prospective, randomized controlled trial was conducted between June 2010 and May 2011. T2DM patients with confirmed nephropathy by 24-h urinary protein estimation with a body mass index (BMI) of >25 kg/m2 were studied. Patients who had nondiabetic nephropathy, uncontrolled hypertension (>125/75 mmHg) irrespective of antihypertensive drugs, excess weight due to edema or obesity due to other specific diseases, alcoholics, smokers, and patients who were on hemodialysis were excluded from the study. The patients were divided into three groups, namely, group A, patients on ACE inhibitor therapy; group B, patients on lifestyle modifications for weight loss; and group C, patients on an antiobesity drug (orlistat) and lifestyle modifications. At the end of 6 months, all the three groups were compared. Data were analyzed using software SPSS version 15.0. This study encompassed a total of 88 patients; 12 patients were dropped during the study period and 76 (group A: 22, group B: 23, and group C: 31) patients remained. The mean age of the patients was 58.36 ± 10.87 years (range: 30-70 years). At baseline, age, gender, mean BMI, waist-to-hip ratio (WHR), and 24-h proteinuria did not vary significantly among the three groups. At 6 months, the mean BMI significantly decreased in group C (P < 0.001) compared to that in the other two groups. Among the parameters BMI and WHR, the proportional form of BMI correlated well with the degree of reduction in proteinuria (r = 0.397, P = 0.01). Reduction in weight using lifestyle modifications and

  5. Long-range safety and protective benefits of angiotensin-converting enzyme inhibitors for hypertension. Do we need more clinical trials?

    PubMed Central

    Sambhi, M P; Gavras, H; Robertson, J I; Smith, W M

    1993-01-01

    Inhibition of the renin-angiotensin system is being applied with considerable success to the treatment of hypertension and heart failure. Angiotensin-converting enzyme (ACE) inhibitors are the only currently available agents that can achieve this objective. In general, the major therapeutic effects of these agents in the treatment of mild to moderate hypertension or of heart failure are exerted on the vascular tissue through inhibition of the renin-angiotensin system and, secondarily, of the sympathetic nervous system. When cardiovascular functional reserve is diminished and autoregulation of regional and systemic blood flow is strained, however, ACE inhibitors may affect other organ functions (heart, kidneys, and possibly brain), hormones other than the renin system, and local tissue humoral systems. The interrelations between the renin-angiotensin system and several other vasoactive systems--including circulating and locally generated tissue hormones and centrally acting neurohormonal factors--are complex and unclear. A better understanding of these mechanisms and interrelations would allow for a more rational therapeutic use of these agents. Unknown also are the clinical effects of prolonged ACE inhibition. Whether the use of ACE inhibitors can provide primary cardiorenal protection requires proof through definitive clinical trials. Images PMID:8460511

  6. [STUDIES IN VITRO INHIBITION OF THE ANGIOTENSIN-CONVERTING ENZYME-I, HYPOTENSIVE AND ANTIHYPERTENSIVE EFFECTS OF PEPTIDE FRACTIONS OF V. UNGUICULATA].

    PubMed

    Cú-Cañetas, Trinidad; Betancur Ancona, David; Gallegos Tintoré, Santiago; Sandoval Peraza, Mukthar; Chel Guerrero, Luis

    2015-01-01

    Inhibition of angiotensin-converting enzyme I (ACE-I) in vitro and in vivo from peptide fractions by enzymatic hydrolysis of the Vigna unguiculata protein concentrate was evaluated. Hydrolysis was done with Pepsin-Pancreatin and Flavourzima in two separate systems. The resulting hidrolysates were ultrafiltrated to obtain fractions with different molecular weight. The fractions with better inhibition Flavourzima were size > 1 kDa (> 1 kDa-F) and < 1 kDa (< 1 kDa-F), with an IC50 of 1222.84 and 1098.6 μg/ml respectively. Pepsin-Pancreatin fraction. PMID:26545668

  7. Fixed-Dose Combinations of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension: A Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors.

    PubMed

    Hsiao, Fu-Chih; Tung, Ying-Chang; Chou, Shing-Hsien; Wu, Lung-Sheng; Lin, Chia-Pin; Wang, Chun-Li; Lin, Yu-Sheng; Chang, Chee-Jen; Chu, Pao-Hsien

    2015-12-01

    Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking.Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered.There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98-1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082-1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071-1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050-1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses.ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status. PMID:26705234

  8. Comparative study of Mg/Al- and Zn/Al-layered double hydroxide-perindopril erbumine nanocomposites for inhibition of angiotensin-converting enzyme

    PubMed Central

    Hussein Al Ali, Samer Hasan; Al-Qubaisi, Mothanna; Hussein, Mohd Zobir; Ismail, Maznah; Zainal, Zulkarnain; Hakim, Muhammad Nazrul

    2012-01-01

    The intercalation of a drug active, perindopril, into Mg/Al-layered double hydroxide for the formation of a new nanocomposite, PMAE, was accomplished using a simple ion exchange technique. A relatively high loading percentage of perindopril of about 36.5% (w/w) indicates that intercalation of the active took place in the Mg/Al inorganic interlayer. Intercalation was further supported by Fourier transform infrared spectroscopy, and thermal analysis shows markedly enhanced thermal stability of the active. The release of perindopril from the nanocomposite occurred in a controlled manner governed by pseudo-second order kinetics. MTT assay showed no cytotoxicity effects from either Mg/Al-layered double hydroxide or its nanocomposite, PMAE. Mg/Al-layered double hydroxide showed angiotensin-converting enzyme inhibitory activity, with 5.6% inhibition after 90 minutes of incubation. On incubation of angiotensin-converting enzyme with 0.5 μg/mL of the PMAE nanocomposite, inhibition of the enzyme increased from 56.6% to 70.6% at 30 and 90 minutes, respectively. These results are comparable with data reported in the literature for Zn/Al-perindopril. PMID:22904631

  9. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.

    PubMed

    Zuraw, Bruce L; Bernstein, Jonathan A; Lang, David M; Craig, Timothy; Dreyfus, David; Hsieh, Fred; Khan, David; Sheikh, Javed; Weldon, David; Bernstein, David I; Blessing-Moore, Joann; Cox, Linda; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Randolph, Christopher R; Schuller, Diane E; Spector, Sheldon L; Tilles, Stephen A; Wallace, Dana

    2013-06-01

    These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion

  10. In vitro angiotensin I converting enzyme inhibition by a peptide isolated from Chiropsalmus quadrigatus Haeckel (box jellyfish) venom hydrolysate.

    PubMed

    So, Pamela Berilyn T; Rubio, Peter; Lirio, Stephen; Macabeo, Allan Patrick; Huang, Hsi-Ya; Corpuz, Mary Jho-Anne T; Villaflores, Oliver B

    2016-09-01

    The anti-angiotensin I converting enzyme activity of box jellyfish, Chiropsalmus quadrigatus Haeckel venom hydrolysate was studied. The venom extract was obtained by centrifugation and ultrasonication. Protein concentration of 12.99 μg/mL was determined using Bradford assay. The pepsin and papain hydrolysate was tested for its toxicity by Limit test following the OECD Guideline 425 using 5 female Sprague-Dawley rats. Results showed that the hydrolysate is nontoxic with an LD50 above 2000 mg/kg. In vitro angiotensin I converting enzyme (ACE) inhibitory activity was determined using ACE kit-WST. Isolation of ACE inhibitory peptides using column chromatography with SP-Sephadex G-25 yielded 8 pooled fractions with fraction 3 (86.5%) exhibiting the highest activity. This was followed by reverse phase - high performance liquid chromatography (RP-HPLC) with an octadecyl silica column (Inertsil ODS-3) using methanol:water 15:85 at a flow rate of 1.0 mL/min. Among the 13 fractions separated with the RP-HPLC, fraction 3.5 exhibited the highest ACE inhibitory activity (84.1%). The peptide sequence ACPGPNPGRP (IC50 2.03 μM) from fraction 3.5 was identified using Matrix-assisted laser desorption/ionization with time-of-flight tandem mass spectroscopy analysis (MALDI-TOF/MS). PMID:27163886

  11. HPLC-DAD Analysis and In-Vitro Property of Polyphenols Extracts from (Solanum Aethiopium) Fruits on α -Amylase, α -Glucosidase and Angiotensin - 1- Converting Enzyme Activities

    PubMed Central

    Nwanna, E. E; Ibukun, E. O; Oboh, G.; Ademosun, A. O.; Boligon, A. A.; Athayde, M.

    2014-01-01

    AIM: Garden egg (Solanum aethiopium) is an edible fruits vegetable with  different species.This study investigated characterisation and the effect of the phenolics extracts from S. aethiopium species with enzymes linked with type -2-diabetes (α-amylase and α-glucosidase) and hypertension [Angiotensin-1-converting enzyme (ACE)]. METHODS: Fresh samples of the 5 species of the garden egg namely, [Solanum gilo (PW), Solanum torvum (TWS), Solanum kumba (PGR), Solanum incanum (GSB), and Solanum indicum (WSB)] were oven-dried at 50°C and milled into flour. The aqueous extracts were prepared (1:50 w/v). The phenolic contents (total phenol and total flavonoid), vitamin C and 1,1-diphenyl–2-picrylhydrazyl (DPPH), the antioxidant activities of the extracts were evaluated. The ability of the extracts to inhibit diabetes enzymes in rat pancreas as well as the inhibition of angiotensin-1-converting (ACE) enzyme in lungs homogenates in vitro were investigated. Furthermore, the fruits polyphenols were identified and quantified using HPLC-DAD. RESULTS: The phenolic contents ranged from 2.70-3.76 mgGAE/g, while there were no significant (P>0.05) differences in their flavonoid content and ability to reduce Fe3+ to Fe2+. The vitamin C contents of the species ranged from 4.01-6.52 mg/ml. The extracts scavenged DPPH in a dose dependent manner with the IC50 values ranging from 3.23-4.20 mg/ml. Furthermore, the extracts showed strong inhibition of α-glucosidase, mild inhibition of α-amylase and strong inhibition of ACE activities. CONCLUSION: This study showed that the inhibition of the key enzymes relevant to type-2 diabetes and hypertension could be part of the mechanisms by which garden egg manage/prevent the degenerative conditions. PMID:25598760

  12. Mas-Mediated Antioxidant Effects Restore the Functionality of Angiotensin Converting Enzyme 2-Angiotensin-(1–7)-Mas Axis in Diabetic Rat Carotid

    PubMed Central

    Gomes, Mayara Santos; Restini, Carolina Baraldi Araujo

    2014-01-01

    We hypothesized that endothelial AT1-activated NAD(P)H oxidase-driven generation of reactive oxygen species during type I-diabetes impairs carotid ACE2-angiotensin-(1–7)-Mas axis functionality, which accounts for the impaired carotid flow in diabetic rats. We also hypothesized that angiotensin-(1–7) chronic treatment of diabetic rats restores carotid ACE2-angiotensin-(1–7)-Mas axis functionality and carotid flow. Relaxant curves for angiotensin II or angiotensin-(1–7) were obtained in carotid from streptozotocin-induced diabetic rats. Superoxide or hydrogen peroxide levels were measured by flow cytometry in carotid endothelial cells. Carotid flow was also determined. We found that endothelial AT1-activated NAD(P)H oxidase-driven generation of superoxide and hydrogen peroxide in diabetic rat carotid impairs ACE2-angiotensin-(1–7)-Mas axis functionality, which reduces carotid flow. In this mechanism, hydrogen peroxide derived from superoxide dismutation inhibits ACE2 activity in generating angiotensin-(1–7) seemingly by activating ICl,SWELL, while superoxide inhibits the nitrergic Mas-mediated vasorelaxation evoked by angiotensin-(1–7). Angiotensin-(1–7) treatment of diabetic rats restored carotid ACE2-angiotensin-(1–7)-Mas axis functionality by triggering a positive feedback played by endothelial Mas receptors, that blunts endothelial AT1-activated NAD(P)H oxidase-driven generation of reactive oxygen species. Mas-mediated antioxidant effects also restored diabetic rat carotid flow, pointing to the contribution of ACE2-angiotensin-(1–7)-Mas axis in maintaining carotid flow. PMID:24877125

  13. Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

    SciTech Connect

    Han Suxia; He Guangming; Wang Tao; Chen Lei; Ning Yunye; Luo Feng; An Jin; Yang Ting; Dong Jiajia; Liao Zenglin; Xu Dan; Wen Fuqiang

    2010-05-15

    Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

  14. Effect of temperature and chloride on steady-state inhibition of angiotensin I-converting enzyme by enalaprilat and ramiprilat.

    PubMed Central

    Skoglof, A; Göthe, P O; Deinum, J

    1990-01-01

    The kinetics of the steady-state inhibition of angiotension I-converting enzyme (EC 3.4.15.1) at 25 degrees C and 37 degrees C with enalaprilat and ramiprilat can be simulated, assuming only one inhibitor-binding site, consistent with a 1:1 stoichiometry if the protein concentration was determined by amino acid analysis. In this temperature range the apparent inhibition constants for ramiprilat and enalaprilat were roughly doubled by a decrease in the chloride concentration from 0.300 M to 0.120 M. PMID:2176463

  15. Angioedema of the lips and tongue induced by angiotensin-converting enzyme inhibitor. A report of two cases.

    PubMed

    Stevenson, Helen A; Steele, John C; Field, E Anne; Darroch, Campbell J

    2004-01-01

    The following case reports describe the clinical presentation, diagnosis and management of two patients who attended Liverpool University Dental Hospital with rapidly increasing swelling of the lips and tongue. Both patients were suffering from angioedema and were taking an angiotension-converting enzyme (ACE) inhibitor (ACEI). A provisional diagnosis of ACEI-induced angioedema was made. An intramuscular injection of chlorpheniramine maleate was given to both patients and they were immediately transferred to the local accident and emergency department. These cases illustrate the potential role of the general dental practitioner in the early recognition and management of this potentially life-threatening condition. PMID:14768205

  16. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    PubMed Central

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  17. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema.

    PubMed

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  18. Scleroderma renal crisis during intravenous cyclophosphamide pulse therapy for complicated interstitial lung disease was successfully treated with angiotensin converting enzyme inhibitor and plasma exchange

    PubMed Central

    Nagamura, Norihiro; Kin, Seikon

    2016-01-01

    ABSTRACT Systemic sclerosis (SSc) is a multiorgan disorder involving the skin, heart, lungs, kidneys, and intestines. Progressive interstitial lung disease (ILD) is a serious complication in SSc patients, and cyclophosphamide (CYC) is the only recommended therapy for this condition;1) however, its clinical effectiveness is not sufficient. Scleroderma renal crisis (SRC) is a rare complication, characterized by acute renal failure and progressive hypertension. Angiotensin-converting-enzyme inhibitor (ACE-i) is a widely accepted therapy for SRC. We report an SSc patient with SRC and progressive ILD who underwent treatment with CYC and successful treatment with ACE-i and plasma exchange (PE). SRC and ILD are significant contributors to morbidity and mortality among SSc patients, and the therapy for these disorders is of great interest to rheumatologists. This study presents the possibility of favorable effects of PE for SSc-associated ILD and SRC. PMID:27578917

  19. Systemic administration of platelet-activating factor in rat reduces specific pulmonary uptake of circulating monoclonal antibody to angiotensin-converting enzyme.

    PubMed

    Atochina, E N; Hiemisch, H H; Muzykantov, V R; Danilov, S M

    1992-01-01

    The biodistribution of radiolabeled mouse monoclonal antibody (MoAb) to angiotensin-converting enzyme (ACE) and control, nonimmune mouse IgG in platelet activating factor (PAF)-treated rats was studied. The blood level of both preparations was slightly decreased (90% of the control) in PAF-treated rats. Specific pulmonary accumulation of anti-ACE MoAb was reduced to 50% of control in contrast to a doubling in nonspecific pulmonary uptake of non-immune IgG. The changes in anti-ACE MoAb biodistribution were lung-specific and were accompanied by decrease in the pulmonary ACE activity (to 60% of control) and increase in serum ACE activity (to 170% of control). Thus anti-ACE MoAb reveals PAF-induced changes in the status of the pulmonary ACE and therefore can be used for the studies of pathology of the pulmonary endothelium. PMID:1331624

  20. Scleroderma renal crisis during intravenous cyclophosphamide pulse therapy for complicated interstitial lung disease was successfully treated with angiotensin converting enzyme inhibitor and plasma exchange.

    PubMed

    Nagamura, Norihiro; Kin, Seikon

    2016-08-01

    Systemic sclerosis (SSc) is a multiorgan disorder involving the skin, heart, lungs, kidneys, and intestines. Progressive interstitial lung disease (ILD) is a serious complication in SSc patients, and cyclophosphamide (CYC) is the only recommended therapy for this condition;(1)) however, its clinical effectiveness is not sufficient. Scleroderma renal crisis (SRC) is a rare complication, characterized by acute renal failure and progressive hypertension. Angiotensin-converting-enzyme inhibitor (ACE-i) is a widely accepted therapy for SRC. We report an SSc patient with SRC and progressive ILD who underwent treatment with CYC and successful treatment with ACE-i and plasma exchange (PE). SRC and ILD are significant contributors to morbidity and mortality among SSc patients, and the therapy for these disorders is of great interest to rheumatologists. This study presents the possibility of favorable effects of PE for SSc-associated ILD and SRC. PMID:27578917

  1. Purification and characterisation of a novel angiotensin-I converting enzyme (ACE)-inhibitory peptide derived from the enzymatic hydrolysate of Enteromorpha clathrata protein.

    PubMed

    Pan, Saikun; Wang, Shujun; Jing, Lingling; Yao, Dongrui

    2016-11-15

    Hydrolysates containing angiotensin-I converting enzyme (ACE)-inhibitory peptide were prepared from Enteromorpha clathrata protein using alcalase. The hydrolysates were fractionated into two molecular-weight ranges (below and above 10kDa) by ultrafiltration. The below-10kDa fraction showed higher ACE-inhibitory activity and was subsequently purified by Sephadex G-15 gel filtration chromatography. The structure of active peptide was identified as Pro-Ala-Phe-Gly by HPLC-Q-TOF-MS and its IC50 value was 35.9μM. The yield of this peptide from E. clathrata protein was 0.82%. Lineweaver-Burk plots demonstrated that the inhibitory kinetic mechanism of this peptide was non-competitive. Stability study revealed that the purified peptide showed resistance against gastrointestinal proteases. Thus, E. clathrata protein hydrolysate treated with alcalase is a beneficial ingredient of nutraceuticals and pharmaceuticals against hypertension and related diseases. PMID:27283651

  2. Novel angiotensin I-converting enzyme inhibitory peptides derived from edible mushroom Agaricus bisporus (J.E. Lange) Imbach identified by LC-MS/MS.

    PubMed

    Lau, Ching Ching; Abdullah, Noorlidah; Shuib, Adawiyah Suriza; Aminudin, Norhaniza

    2014-04-01

    Angiotensin I-converting enzyme (ACE) inhibitors derived from foods are valuable auxiliaries to agents such as captopril. Eight highly functional ACE inhibitory peptides from the mushroom, Agaricus bisporus, were identified by LC-MS/MS. Among these peptides, the most potent ACE inhibitory activity was exhibited by AHEPVK, RIGLF and PSSNK with IC₅₀ values of 63, 116 and 129 μM, respectively. These peptides exhibited high ACE inhibitory activity after gastrointestinal digestion. Lineweaver-Burk plots suggested that AHEPVK and RIGLF act as competitive inhibitors against ACE, whereas PSSNK acts as a non-competitive inhibitor. Mushrooms can be a good component of dietary supplement due to their readily available source and, in addition, they rarely cause food allergy. Compared to ACE inhibitory peptides isolated from other edible mushrooms, AHEPVK, RIGLF and PSSNK have lower IC₅₀ values. Therefore, these peptides may serve as an ideal ingredient in the production of antihypertensive supplements. PMID:24262574

  3. [Polymorphism of genes coding for angiotensin I converting enzyme and methylenetetrahydrofolate reductase in patients with ischemic heart disease].

    PubMed

    Goracy, I

    2000-01-01

    Due to its multifarious biological activity the renin-angiotensin system occupies a special position among risk factors of ischemic heart disease. The discovery of I/D polymorphism of the ACE gene led to a better understanding of genetic control of this enzyme. Hyperhomocysteinemia is an independent risk factor of ischemic heart disease. Elevated plasma levels of homocysteine may be due to improper diet (e.g. shortage of folic acid) and/or genetic influence. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine. The present study was performed in 100 patients (14 women and 86 men, mean age 54.2 +/- 9.2 years) with a history of myocardial infarction. The control group included 100 patients (10 women and 90 men, mean age 52.3 +/- 10 years) without such history. PCR was used to detect I/D ACE and C677T MTHFR polymorphisms. Genomic DNA was isolated from peripheral blood nuclear cells and amplified by PCR with two pairs of primers flanking the polymorphic regions. The restriction enzyme Hinf I was used to identify genotypes of the MTHFR polymorphism. No difference between both groups was found concerning the distribution of I/D ACE genotypes (31% II, 51% ID, 18% DD in the study group; 30% II, 57% ID, 13% DD in the control group; Tab. 1) or the distribution of C677T MTHFR genotypes (46% CC, 45% CT, 9% TT in the study group; 39% CC, 50% CT, 11% TT in the control group; Tab. 2). There was a significant effect of I/D genotype on ACE activity (IU/L) in the study (II = 18.2 +/- 17.9; ID = 33.5 +/- 19.9; DD = 68.9 +/- 21.9) and in the control group (II = 24.2 +/- 18.1; ID = 31.5 +/- 20.9; DD = 51.4 +/- 19.5; Tab. 3). No correlation was confirmed between ACE or MTHFR genotypes and age at infarction or left ventricular mass (Tabs. 4, 5, 6). The results indicate that neither the I/D ACE nor the C677T MTHFR polymorphisms are associated with risk of myocardial infarction in the Polish population. PMID:11712321

  4. Neuroprotective Effect of Scutellarin on Ischemic Cerebral Injury by Down-Regulating the Expression of Angiotensin-Converting Enzyme and AT1 Receptor

    PubMed Central

    Han, Jichun; Zhou, Mingjie; Ren, Huanhuan; Pan, Qunwen; Zheng, Chunli; Zheng, Qiusheng

    2016-01-01

    Background and Purpose Previous studies have demonstrated that angiotensin-converting enzyme (ACE) is involved in brain ischemic injury. In the present study, we investigated whether Scutellarin (Scu) exerts neuroprotective effects by down-regulating the Expression of Angiotensin-Converting Enzyme and AT1 receptor in a rat model of permanent focal cerebral ischemia. Methods Adult Sprague–Dawley rats were administrated with different dosages of Scu by oral gavage for 7 days and underwent permanent middle cerebral artery occlusion (pMCAO). Blood pressure was measured 7 days after Scu administration and 24 h after pMCAO surgery by using a noninvasive tail cuff method. Cerebral blood flow (CBF) was determined by Laser Doppler perfusion monitor and the neuronal dysfunction was evaluated by analysis of neurological deficits before being sacrificed at 24 h after pMCAO. Histopathological change, cell apoptosis and infarct area were respectively determined by hematoxylin–eosin staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis and 2,3,5-triphenyltetrazolium chloride staining. Tissue angiotensin II (Ang II) and ACE activity were detected by enzyme-linked immunosorbent assays. The expression levels of ACE, Ang II type 1 receptor (AT1R), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by Western blot and real-time PCR. ACE inhibitory activity of Scu in vitro was detected by the photometric determination. Results Scu treatment dose-dependently decreased neurological deficit score, infarct area, cell apoptosis and morphological changes induced by pMCAO, which were associated with reductions of ACE and AT1R expression and the levels of Ang II, TNF-α, IL-6, and IL-1β in ischemic brains. Scu has a potent ACE inhibiting activity. Conclusion Scu protects brain from acute ischemic injury probably through its inhibitory effect on the ACE/Ang II/AT1 axis, CBF preservation and

  5. Effects of Pleurotus eryngii polysaccharides on bacterial growth, texture properties, proteolytic capacity, and angiotensin-I-converting enzyme-inhibitory activities of fermented milk.

    PubMed

    Li, Siqian; Shah, Nagendra P

    2015-05-01

    Pleurotus eryngii is one of the most favored oyster mushrooms and contains various beneficial bioactive compounds. Polysaccharide extracted from P. eryngii (PEPS) was added as a natural-source ingredient to milk before fermentation, and the effects of additional PEPS on fermented milk were investigated in this study. The PEPS were extracted and added to reconstituted skim milk (12%, wt/vol) at 0.5, 0.25, and 0.125% (wt/vol) and fermented by a non-exopolysaccharide-producing strain, Streptococcus thermophilus Australian Starter Culture Collection (ASCC) 1303 (ST 1303), or an exopolysaccharide-producing Strep. thermophilus ASCC 1275 (ST 1275). Bacterial growth, texture properties, microstructure, proteolytic capacity, and angiotensin-I-converting enzyme-inhibitory activities of fermented milk (FM) were determined during refrigerated storage at 4°C for 21d. Viable counts of starter bacteria in FM with 0.5% PEPS added were the highest. Changes in pH were consistent with changes in titratable acidities for all samples. The FM samples with added PEPS showed denser protein aggregates containing larger serum pores in confocal micrographs compared with those without PEPS at d 0 and 21during refrigerated storage. The values for spontaneous whey separation of FM with added PEPS were significantly higher than those of FM fermented by ST 1303 or ST 1275 without PEPS. The proteolytic activities of ST 1303 of FM with added PEPS were higher than those of FM fermented by ST 1303 without PEPS. The FM with added 0.125% PEPS had similar angiotensin-I-converting enzyme-inhibitory activity to that fermented by ST 1303 without PEPS; both were higher than those of other samples during refrigerated storage. Firmness and gumminess values of FM with added PEPS were higher than those of FM fermented by ST 1303 or ST 1275 without PEPS. PMID:25747830

  6. AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways

    PubMed Central

    Qiu, Yiguo; Tao, Lifei; Zheng, Shijie; Lin, Ru; Fu, Xinyu; Chen, Zihe; Lei, Chunyan; Wang, Jiaming; Li, Hongwei; Li, Qiuhong; Lei, Bo

    2016-01-01

    Renin angiotensin system (RAS) is a key hormonal system which regulates the cardiovascular function and is implicated in several autoimmune diseases. With the discovery of the angiotensin-converting enzyme 2 (ACE2), a protective axis of RAS namely ACE2/Ang-(1–7)/Mas that counteracts the deleterious ACE/AngII/AT1R axis has been established. This axis is emerging as a novel target to attenuate ocular inflammation. However, the underlying molecular mechanisms remain unclear. We investigated the hypothesis that enhancing the activity of the protective axis of RAS by subretinal delivery of an AAV8 (Y733F)-ACE2 vector would protect against the ocular inflammation in experimental autoimmune uveitis (EAU) mice through regulating the local immune responses. Our studies demonstrated that increased ACE2 expression exerts protective effects on inflammation in EAU mouse by modulating ocular immune responses, including the differentiation of Th1/Th17 cells and the polarization of M1/M2 macrophages; whereas the systemic immune responses appeared not affected. These effects were mediated by activating the Ang-(1–7)/Mas and inhibiting the MAPK, NF-κB and STAT3 signaling pathways. This proof-of-concept study suggests that activation of ocular ACE2/Ang-(1–7)/Mas axis with AAV gene transfer modulates local immune responses and may be a promising, long-lasting therapeutic strategy for refractory and recurrent uveitis, as well as other inflammatory eye diseases. PMID:27558087

  7. Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

    PubMed

    Dhamrait, Sukhbir S; Maubaret, Cecilia; Pedersen-Bjergaard, Ulrik; Brull, David J; Gohlke, Peter; Payne, John R; World, Michael; Thorsteinsson, Birger; Humphries, Steve E; Montgomery, Hugh E

    2016-07-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. PMID:27417115

  8. Autoradiographic visualization of angiotensin-converting enzyme in rat brain with (/sup 3/H)captopril: localization to a striatonigral pathway

    SciTech Connect

    Strittmatter, S.M.; Lo, M.M.S.; Javitch, J.A.; Snyder, S.H.

    1984-03-01

    The authors have visualized angiotensin-converting enzyme (ACE; dipeptidyl carboxypeptidase, peptidylpeptide hydrolase, EC 3.4.15.1) in rat brain by in vitro (/sup 3/H)captopril autoradiography. (/sup 3/H)Captopril binding to brain slices displays a high affinity (K/sub d/ = 1.8 x 10/sup -9/ M) and a pharmacological profile similar to that of ACE activity. Very high densities of (/sup 3/H)captopril binding were found in the choroid plexus and the subfornical organ. High densities were present in the caudate putamen and substantia nigra, zona reticulata. Moderate levels were found in the entopeduncular nucleus, globus pallidus, and median eminence of the hypothalamus. Lower levels were detectable in the supraoptic and paraventricular nuclei of the hypothalamus, the media habenula, the median preoptic area, and the locus coeruleus. Injection of ibotenic acid or colchicine into the caudate putamen decreased (/sup 3/H)captopril-associated autoradiographic grains by 85% in the ipsilateral caudate putamen and by > 50% in the ipsilateral substantia nigra. Thus, ACE in the substantia nigra is located on presynaptic terminals of axons originating from the caudate putamen, and ACE in the caudate putamen is situated in neuronal perikarya or at the terminals of striatal interneurons. The lack of effect of similar injections into the substantia nigra confirmed that the caudate putamen injections did not cause trans-synaptic changes. The presence of (/sup 3/H)captopril binding is consistent with an ACE-mediated production of angiotensin II in some brain regions. Although (/sup 3/H)captopril autoradiography reveals ACE in a striatonigral pathway, there is no evidence for angiotensin II involvement in such a neuronal pathway. 26 references, 4 figures, 2 tables.

  9. An Improved Model for Predicting Radiation Pneumonitis Incorporating Clinical and Dosimetric Variables;Lung cancer; Radiation pneumonitis; Dose-volume histogram; Angiotensin converting enzyme inhibitor

    SciTech Connect

    Jenkins, Peter; Watts, Joanne

    2011-07-15

    Purpose: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. Methods and Materials: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. Results: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS{sub 5}). The area under the receiver operator characteristic curve for TFS{sub 5} was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS{sub 5} <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS{sub 5} {>=}2.17. Conclusions: TFS{sub 5} represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.

  10. The Use of Angiotensin-I Converting Enzyme I/D Genetic Polymorphism as a Biomarker of Athletic Performance in Humans

    PubMed Central

    De Mello Costa, Maria Fernanda; Slocombe, Ron

    2012-01-01

    Angiotensin II is a key regulator of blood pressure and cardiovascular function in mammals. The conversion of angiotensin into its active form is carried out by Angiotensin I-Converting Enzyme (ACE). The measurement of ACE concentration in plasma or serum, its enzymatic activity, and the correlation between an insertion/deletion (I/D) genetic polymorphism of the ACE gene have been investigated as possible indicators of superior athletic performance in humans. In this context, other indicators of superior adaptation to exercise resulting in better athletic performance (such as ventricular hypertrophy, VO2 max, and competition results) were mostly used to study the association between ACE I/D polymorphism and improved performance. Despite the fact that the existing literature presents little consensus, there is sufficient scientific evidence to warrant further investigation on the usage of ACE activity and the I/D ACE gene polymorphism as biomarkers of superior athletic performance in humans of specific ethnicities or in athletes involved in certain sports. In this sense, a biomarker would be a substance or genetic component that could be measured to provide a degree of certainty, or an indication, of the presence of a certain trait or characteristic that would be beneficial to the athlete’s performance. Difficulties in interpreting and comparing the results of scientific research on the topic arise from dissimilar protocols and variation in study design. This review aims to investigate the current literature on the use of ACE I/D polymorphism as a biomarker of performance in humans through the comparison of scientific publications. PMID:25586030

  11. In vitro study on digestion of peptides in Emmental cheese: analytical evaluation and influence on angiotensin I converting enzyme inhibitory peptides.

    PubMed

    Parrot, Sandrine; Degraeve, Pascal; Curia, Céline; Martial-Gros, Adèle

    2003-04-01

    A simple in vitro protocol simulating gastrointestinal digestion of proteins and peptides to investigate the effect of digestive enzymes on the biological activity of peptides present in dairy products was developed. This protocol consisted in a 30 min incubation with pepsin followed by a 4 h incubation with trypsin or pancreatin. It was applied to an Emmental cheese water-soluble extract (WSE) and to a casein solution (as a control). Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) allowed to monitor the digestion of proteins. Reversed-phase high-performance liquid chromatography (RP-HPLC) allowed to monitor the conversion of proteins and peptides into peptides and amino acids: it is proposed to use the mean retention time corresponding to the overall retention time distribution of molecules to assess the effect of digestive enzymes. The biological activity focused in this study was the angiotensin I converting enzyme (ACE) inhibitory activity. Digestion of Emmental WSE induced an increase of the ACE inhibition as compared to undigested WSE while a 10 kDa ultrafiltered WSE lost a part of its ACE inhibitory activity after digestion process. These results strongly suggest that digestive enzymes diminished the ACE inhibition by the peptides present in Emmental cheese WSE, while the digestion of peptides of high molecular weight would generate new ACE inhibitory peptides. PMID:12744284

  12. Production of feather hydrolysates with antioxidant, angiotensin-I converting enzyme- and dipeptidyl peptidase-IV-inhibitory activities.

    PubMed

    Fontoura, Roberta; Daroit, Daniel J; Correa, Ana P F; Meira, Stela M M; Mosquera, Mauricio; Brandelli, Adriano

    2014-09-25

    The antioxidant and antihypertensive activities of feather hydrolysates obtained with the bacterium Chryseobacterium sp. kr6 were investigated. Keratin hydrolysates were produced with different concentrations of thermally denatured feathers (10-75 g l(-1)) and initial pH values (6.0-9.0). Soluble proteins accumulated in high amounts in media with 50 and 75 g l(-1) of feathers, reaching values of 18.5 and 22 mg ml(-1), respectively, after 48 hours of cultivation. In media with 50 g l(-1) of feathers, initial pH had minimal effect after 48 hours. Maximal protease production was observed after 24 hours of cultivation, and feather concentration and initial pH values showed no significant effect on enzyme yields at this time. Feather hydrolysates displayed in vitro antioxidant properties, and optimal antioxidant activities were observed in cultures with 50 g l(-1) feathers, at initial pH 8.0, after 48 hours growth at 30°C. Also, feather hydrolysates were demonstrated to inhibit the angiotesin I-converting enzyme by 65% and dipeptidyl peptidase-IV by 44%. The bioconversion of an abundant agroindustrial waste such as chicken feathers can be utilized as a strategy to obtain hydrolysates with antioxidant and antihypertensive activities. Feather hydrolysates might be employed as supplements in animal feed, and also as a potential source of bioactive molecules for feed, food and drug development. PMID:25038398

  13. In silico and in vitro analyses of the angiotensin-I converting enzyme inhibitory activity of hydrolysates generated from crude barley (Hordeum vulgare) protein concentrates.

    PubMed

    Gangopadhyay, Nirupama; Wynne, Kieran; O'Connor, Paula; Gallagher, Eimear; Brunton, Nigel P; Rai, Dilip K; Hayes, Maria

    2016-07-15

    Angiotensin-I-converting enzyme (ACE-I) plays a key role in control of hypertension, and type-2 diabetes mellitus, which frequently co-exist. Our current work utilised in silico methodologies and peptide databases as tools for predicting release of ACE-I inhibitory peptides from barley proteins. Papain was the enzyme of choice, based on in silico analysis, for experimental hydrolysis of barley protein concentrate, which was performed at the enzyme's optimum conditions (60 °C, pH 6.0) for 24 h. The generated hydrolysate was subjected to molecular weight cut-off (MWCO) filtration, following which the non-ultrafiltered hydrolysate (NUFH), and the generated 3 kDa and 10 kDa MWCO filtrates were assessed for their in vitro ACE-I inhibitory activities. The 3 kDa filtrate (1 mg/ml), that demonstrated highest ACE-I inhibitory activity of 70.37%, was characterised in terms of its peptidic composition using mass spectrometry and 1882 peptides derived from 61 barley proteins were identified, amongst which 15 peptides were selected for chemical synthesis based on their predicted ACE-I inhibitory properties. Of the synthesized peptides, FQLPKF and GFPTLKIF were most potent, demonstrating ACE-I IC50 values of 28.2 μM and 41.2 μM respectively. PMID:26948626

  14. Early administration of angiotensin-converting enzyme inhibitor captopril, prevents the development of hypertension programmed by intrauterine exposure to a maternal low-protein diet in the rat.

    PubMed

    Sherman, R C; Langley-Evans, S C

    1998-04-01

    administration of an angiotensin-converting enzyme inhibitor. The actions of angiotensin II in the late suckling period may be a critical determinant of long-term cardiovascular functions in these animals. PMID:9640343

  15. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

    PubMed

    Chia, N; Fulcher, J; Keech, A

    2016-06-01

    Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition. PMID:26109136

  16. LC-MS/MS quantification of bioactive angiotensin I-converting enzyme inhibitory peptides in rye malt sourdoughs.

    PubMed

    Hu, Ying; Stromeck, Achim; Loponen, Jussi; Lopes-Lutz, Daise; Schieber, Andreas; Gänzle, Michael G

    2011-11-23

    This study quantified antiotensin I-converting enzyme (ACE) inhibitory peptides in rye malt sourdoughs supplemented with gluten proteins and fermented with six strains of Lactobacillus spp. Bioinformatic analysis of prolamins from barley, rye, and wheat demonstrated that the ACE inhibitory peptides LQP, LLP, VPP, and IPP are frequently encrypted in their primary sequence. These tripeptides were quantified by liquid chromatography-tandem mass spectrometry. Tripeptide levels in sourdoughs were generally higher as compared to the chemically acidified controls. Sourdoughs fermented with different strains showed different concentrations of LQP and LLP. These differences corresponded to strain-specific differences in PepO and PepN activities. The highest levels of peptides VPP, IPP, LQP, and LLP, 0.23, 0.71, 1.09, and 0.09 mmol (kg DM)(-1), respectively, were observed in rye malt: gluten sourdoughs fermented with Lactobacillus reuteri TMW 1.106 and added protease. These concentrations were 6-7 times higher as compared to sourdough without fungal protease and exceed the IC(50) by 100-1000-fold. PMID:21985248

  17. Human gut endogenous proteins as a potential source of angiotensin-I-converting enzyme (ACE-I)-, renin inhibitory and antioxidant peptides.

    PubMed

    Dave, Lakshmi A; Hayes, Maria; Montoya, Carlos A; Rutherfurd, Shane M; Moughan, Paul J

    2016-02-01

    It is well known that endogenous bioactive proteins and peptides play a substantial role in the body's first line of immunological defence, immune-regulation and normal body functioning. Further, the peptides derived from the luminal digestion of proteins are also important for body function. For example, within the peptide database BIOPEP (http://www.uwm.edu.pl/biochemia/index.php/en/biopep) 12 endogenous antimicrobial and 64 angiotensin-I-converting enzyme (ACE-I) inhibitory peptides derived from human milk and plasma proteins are listed. The antimicrobial peptide database (http://aps.unmc.edu/AP/main.php) lists over 111 human host-defence peptides. Several endogenous proteins are secreted in the gut and are subject to the same gastrointestinal digestion processes as food proteins derived from the diet. The human gut endogenous proteins (GEP) include mucins, serum albumin, digestive enzymes, hormones, and proteins from sloughed off epithelial cells and gut microbiota, and numerous other secreted proteins. To date, much work has been carried out regarding the health altering effects of food-derived bioactive peptides but little attention has been paid to the possibility that GEP may also be a source of bioactive peptides. In this review, we discuss the potential of GEP to constitute a gut cryptome from which bioactive peptides such as ACE-I inhibitory, renin inhibitory and antioxidant peptides may be derived. PMID:26617077

  18. A Bovine Fibrinogen-Enriched Fraction as a Source of Peptides with in Vitro Renin and Angiotensin-I-Converting Enzyme Inhibitory Activities.

    PubMed

    Lafarga, Tomas; Rai, Dilip K; O'Connor, Paula; Hayes, Maria

    2015-10-01

    Bovine fibrinogen is currently used in the food industry as a binding agent in restructured meat products. However, this protein is underused as a source of bioactive peptides. In this study, a number of novel angiotensin-I-converting enzyme (ACE-I) and renin inhibitory peptides were identified and enriched from a bovine fibrinogen fraction. Fibrinogen was isolated and enriched from bovine blood and hydrolyzed with the food-grade enzyme papain, which was selected for use using in silico analysis. The generated hydrolysate was subjected to ultrafiltration and its peptide profile characterized by liquid chromatography-tandem mass spectrometry. A number of peptides were identified and chemically synthesized to confirm their bioactivity in vitro. Identified peptides included the multifunctional tripeptide SLR, corresponding to f(35-37) of the β-chain of bovine fibrinogen with ACE-I and renin IC50 values of 0.17 and 7.2 mM, respectively. Moreover, the resistance of identified peptides to gastrointestinal degradation and their bitterness were predicted using in silico methods. PMID:26373334

  19. Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition.

    PubMed

    Goel, Ruby; Bhat, Shahnawaz Ali; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2015-06-01

    Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition. PMID:25869103

  20. Study of the association between the donors and recipients angiotensin-converting enzyme insertion/deletion gene polymorphism and the acute renal allograft rejection

    PubMed Central

    Azmandian, Jalal; Mohamadifar, Mohamadamir; Rahmanian-Koshkaki, Sara; Mehdipoor, Mohammad; Nematollahi, Mohamad-Hadi; Saburi, Amin; Mandegary, Ali

    2015-01-01

    Background: Angiotensin converting enzyme (ACE) is involved in various pathophysiological conditions including renal function. ACE levels are under genetic control. Objectives: This study was designed to investigate the association between the donors and recipients ACE-I/D gene polymorphism and risk of acute rejection outcome in renal allograft recipients. Patients and Methods: ACE-I/D polymorphism was determined in 200 donor-recipient pairs who had been referred to Afzalipour hospital in Kerman. ACE-I/D polymorphism was detected using polymerase chain reaction (PCR). Acute rejection (AR) during at least six months post-transplantation was defined as a 20% increase in creatinine level from the postoperative baseline in the absence of other causes of graft dysfunction which responded to antirejection therapy. Results: The observed allele frequencies were II 9.8%, ID 35.6% and DD 44.4% in donors and II 9.8%, ID 35.1% and DD 52.7% in recipients. There were no significant association between ACE genotypes and AR episodes (ORID=0.96 [0.18-5.00] and ORDD: 1.24 [0.25-6.07] for the donors) and (ORID: 0.29 [0.06-1.45] and ORDD: 0.75 [0.19-2.90] for the recipients). Conclusions: It seems that donor and recipient ACE-I/D genotype might not be a risk factor for acute renal allograft rejection. However, due to conflicting results from this and other studies, multicenter collaborative studies with more participants and concomitant evaluation of ACE polymorphism with other polymorphisms in renin–angiotensin system (RAS) are suggested to determine whether ACE genotypes are significant predictors of renal allograft rejection. PMID:26311652

  1. Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1.

    PubMed

    Abd Allah, Eman S H; Gomaa, Asmaa M S

    2015-10-01

    Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy. PMID:26398443

  2. Effect of Antiviral Therapy on Serum Activity of Angiotensin Converting Enzyme in Patients with Chronic Hepatitis C

    PubMed Central

    Husic-Selimovic, Azra; Sofic, Amela; Huskic, Jasminko; Bulja, Deniz

    2016-01-01

    Introduction: Renin-angiotenzin system (RAS) is frequently activated in patients with chronic liver disease. Angiotenzin - II (AT-II), produced by angiotenzin converting enzyme (ACE), has many physiological effects, including an important role in liver fibrogenesis. Combined antiviral therapy with PEG-IFN and ribavirin besides its antiviral effect also leads to a reduction in liver parenchyma fibrosis. Aim of the study: Determining the value of ACE in serum of patients with chronic hepatitis C before and after combined antiviral therapy, as well as the value of ACE activities in sera of the control group. Materials and methods: We studied 50 patients treated at Gastroenterohepatology Department, in the time-period of four years. Value of ACE in serum was determined by Olympus AU 400 device, with application of kit “Infinity TN ACE Liquid Stable Reagent”. HCV RNA levels in sera were measured by real time PCR. HCV RNA test was performed with modular analysis of AMPLICOR and COBAS AMPLICOR HCV MONITOR test v2.0, which has proved infection and was used for quantification of the viruses and monitoring of the patients’ response to therapy. Liver histology was evaluated in accordance with the level of necroinflammation activity and stage of fibrosis. Results: Serum activities of ACE in chronic hepatitis C patients is statistically higher than the values in the control group (p=0.02). Antiviral therapy in chronic hepatitis C patients statistically decreases serum activities of ACE (p= 0.02) and indirectly affects fibrogenesis of the liver parenchyma. Correlation between ACE and ALT activity after the therapy was proved (0.3934). Conclusion: Our findings suggest that the activity of ACE in serum is a good indirect parameter of the liver damage, and could be used as an indirect prognostic factor of the level of liver parenchyma damage. Serum activity of ACE can be used as a parameter for non-invasive assessment of intensity of liver damage. PMID:27147779

  3. Angiotensin I-converting enzyme (ACE) inhibitory activities of sardinelle (Sardinella aurita) by-products protein hydrolysates obtained by treatment with microbial and visceral fish serine proteases.

    PubMed

    Bougatef, Ali; Nedjar-Arroume, Naima; Ravallec-Plé, Rozenn; Leroy, Yves; Guillochon, Didier; Barkia, Ahmed; Nasri, Moncef

    2008-11-15

    The angiotensin I-converting enzyme (ACE) inhibitory activities of protein hydrolysates prepared from heads and viscera of sardinelle (Sardinella aurita) by treatment with various proteases were investigated. Protein hydrolysates were obtained by treatment with Alcalase(®), chymotrypsin, crude enzyme preparations from Bacillus licheniformis NH1 and Aspergillus clavatus ES1, and crude enzyme extract from sardine (Sardina pilchardus) viscera. All hydrolysates exhibited inhibitory activity towards ACE. The alkaline protease extract from the viscera of sardine produced hydrolysate with the highest ACE inhibitory activity (63.2±1.5% at 2mg/ml). Further, the degrees of hydrolysis and the inhibitory activities of ACE increased with increasing proteolysis time. The protein hydrolysate generated with alkaline proteases from the viscera of sardine was then fractionated by size exclusion chromatography on a Sephadex G-25 into eight major fractions (P1-P8). Biological functions of all fractions were assayed, and P4 was found to display a high ACE inhibitory activity. The IC50 values for ACE inhibitory activities of sardinelle by-products protein hydrolysates and fraction P4 were 1.2±0.09 and 0.81±0.013mg/ml, respectively. Further, P4 showed resistance to in vitro digestion by gastrointestinal proteases. The amino acid analysis by GC/MS showed that P4 was rich in phenylalanine, arginine, glycine, leucine, methionine, histidine and tyrosine. The added-value of sardinelle by-products may be improved by enzymatic treatment with visceral serine proteases from sardine. PMID:26047434

  4. Involvement of human plasma angiotensin I-converting enzyme in the degradation of the haemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline.

    PubMed Central

    Rieger, K J; Saez-Servent, N; Papet, M P; Wdzieczak-Bakala, J; Morgat, J L; Thierry, J; Voelter, W; Lenfant, M

    1993-01-01

    The degradation of N-Ac-Ser-Asp-Lys-Pro (AcSDKP), a negative regulator controlling the proliferation of the haematopoietic stem cell, by enzymes present in human plasma, has been investigated. Radiolabelled AcSD[4-3H]KP ([3H]AcSDKP, 1 mM) was completely metabolized in human plasma with a half-life of 80 min, leading exclusively to the formation of radiolabelled lysine. The cleavage of AcSDKP was insensitive to classical proteinase inhibitors including leupeptin, but sensitive to metalloprotease inhibitors. The degradation was completely blocked by specific inhibitors of angiotensin I-converting enzyme (ACE; kininase II; peptidyldipeptide hydrolase, EC 3.4.15.1), showing that the first step of the hydrolysis was indeed due to ACE. In dialysed plasma, the hydrolysis proceeded at only 17% of the maximal rate, whereas addition of 20 mM NaCl led to the recovery of the initial rate observed with normal plasma. Hydrolysis of AcSDKP by commercial rabbit lung ACE generated the C-terminal dipeptide Lys-Pro. Thus, ACE cleaves AcSDKP by a dipeptidyl carboxypeptidase activity. In fact the formation of Lys-Pro was observed when AcSDKP was incubated in human plasma in the presence of HgCl2. These results suggest that ACE is involved in the first limiting step of AcSDKP degradation in human plasma. The second step seems to be under the control of a leupeptin- and E-64-insensitive, HgCl2-sensitive plasmatic enzyme. PMID:8257427

  5. Production of angiotensin-I-converting enzyme inhibitory peptides from β-lactoglobulin- and casein-derived peptides: an integrative approach.

    PubMed

    Welderufael, Fisseha T; Gibson, Trevor; Jauregi, Paula

    2012-01-01

    Angiotensin I-converting enzyme (ACE) inhibition is one of the mechanisms by which reduction in blood pressure is exerted. Whey proteins are a rich source of ACE inhibitory peptides and have shown a blood pressure reduction effect i.e. antihypertensive activity. The aim of this work was to develop a simplified process using a combination of adsorption and microfiltration steps for the production of hydrolysates from whey with high ACE inhibitory activity and potency; the latter was measured as the IC50, which is the peptide concentration required to reduce ACE activity by half. This process integrates the selective separation of β-lactoglobulin- and casein-derived peptides (CDP) from rennet whey and their hydrolysis, which results in partially pure, less complex hydrolysates with high bioactive potency. Hydrolysis was carried out with protease N "Amano" in a thermostatically controlled membrane reactor operated in a batch mode. By applying the integrative approach it was possible to produce from the same feedstock two different hydrolysates that exhibited high ACE inhibition. One hydrolysate was mainly composed of casein-derived peptides with IC50=285 μg/mL. In this hydrolysate we identified the well-known potent ACE-inhibitor and antihypertensive tripeptide Ile-Pro-Pro (IPP) and another novel octapeptide Gln-Asp-Lys-Thr-Glu-Ile-Pro-Thr (QDKTEIPT). The second hydrolysate was mainly composed of β-lactoglobulin derived peptides with IC50=28 μg/mL. This hydrolysate contained a tetrapeptide (Ile-Ile-Ala-Glu) IIAE as one of the two major peptides. A further advantage to this process is that enzyme activity was substantially increased as enzyme product inhibition was reduced. PMID:22467199

  6. Angiotensin-converting enzyme/vitamin D receptor gene polymorphisms and bioelectrical impedance analysis in predicting athletic performances of Italian young soccer players.

    PubMed

    Micheli, Matteo Levi; Gulisano, Massimo; Morucci, Gabriele; Punzi, Tiziana; Ruggiero, Marco; Ceroti, Marco; Marella, Mario; Castellini, Elena; Pacini, Stefania

    2011-08-01

    We evaluated the association between 2 genetic polymorphisms known to be involved in fitness and performance, and anthropometric features, body composition, and athletic performances in young male soccer players with the goal of identifying genetic profiles that can be used to achieve maximal results from training. One hundred twenty-five medium-high-level male soccer players were genotyped for angiotensin-converting enzyme (ACE) I/D, and vitamin D receptor (VDR) FokI gene polymorphisms and scored for anthropometric measurements, body composition, and athletic performance. Body mass index, fat mass, fat-free mass, resistance, reactance, impedance, phase angle (PA), and body cell mass were measured. Athletic performance was evaluated by squat jump, countermovement jump (CMJ), 2-kg medicine ball throw, 10- and 20-m sprint time. We observed that the homozygous ff genotype of the VDR gene was significantly more represented in young soccer players than in a matched sedentary population. Values of reactance and PA were differently distributed in ACE and VDR genotypes with high mean values in subjects with DD (ACE) and FF (VDR) genotypes. No correlation was observed between ACE or VDR genotypes and 2-kg medicine ball throw, 10- and 20-m sprint times. The ID genotype of ACE was associated with the best performances in squat jump and CMJ. Our results suggest that determination of ACE and VDR genotypes might help select those young athletes harboring the most favorable genetic potential to succeed in soccer. PMID:21747292

  7. Angiotensin I-converting enzyme (ACE) inhibitory activity and structural properties of oven- and freeze-dried protein hydrolysate from fresh water fish (Cirrhinus mrigala).

    PubMed

    Elavarasan, K; Shamasundar, B A; Badii, Faraha; Howell, Nazlin

    2016-09-01

    The angiotensin I-converting enzyme (ACE) inhibitory activity and structural properties of oven-dried (OD-FPH) and freeze-dried (FD-FPH) protein hydrolysates derived from fresh water fish (Cirrhinus mrigala) muscle, using papain, were investigated. Amino acid profiles indicated a higher proportion of hydrophobic residues in OD-FPH and hydrophilic residues in FD-FPH samples. Fourier transform infrared (FT-IR) spectra revealed random coil structure in OD-FPH and β-sheet in FD-FPH samples. The approximate molecular weight of peptides in OD-FPH and FD-FPH was in the range of 7030-339Da. The IC50 values for ACE inhibition by OD-FPH and FD-FPH samples were found to be 1.15 and 1.53mg of proteinml(-1), respectively. The ACE-inhibitory activity of OD-FPH was more stable (during sequential digestion, using pepsin and pancreatin) than that of FD-FPH sample. The study suggested that the ACE inhibitory activity of protein hydrolysate was not affected by oven-drying. PMID:27041318

  8. Flavonoids from the buds of Rosa damascena inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme a reductase and angiotensin I-converting enzyme.

    PubMed

    Kwon, Eun-Kyung; Lee, Dae-Young; Lee, Hyungjae; Kim, Dae-Ok; Baek, Nam-In; Kim, Young-Eon; Kim, Hae-Yeong

    2010-01-27

    Rosa damascena has been manufactured as various food products, including tea, in Korea. A new flavonoid glycoside, kaempferol-3-O-beta-D-glucopyranosyl(1-->4)-beta-D-xylopyranoside, named roxyloside A was isolated from the buds of this plant, along with four known compounds, isoquercitrin, afzelin, cyanidin-3-O-beta-glucoside, and quercetin gentiobioside. The chemical structures of these compounds were determined by spectroscopic analyses, including FAB-MS, UV, IR, (1)H and (13)C NMR, DEPT, and 2D NMR (COSY, HSQC, and HMBC). All the isolated compounds except cyanidin-3-O-beta-glucoside exhibited high levels of inhibitory activity against 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase with IC(50) values ranging from 47.1 to 80.6 microM. Cyanidin-3-O-beta-glucoside significantly suppressed angiotensin I-converting enzyme (ACE) activity, with an IC(50) value of 138.8 microM, while the other four compounds were ineffective. These results indicate that R. damascena and its flavonoids may be effective to improve the cardiovascular system. PMID:20038104

  9. Angiotensin-converting enzyme levels and activity in Alzheimer's disease: differences in brain and CSF ACE and association with ACE1 genotypes

    PubMed Central

    Miners, Scott; Ashby, Emma; Baig, Shabnam; Harrison, Rachel; Tayler, Hannah; Speedy, Elizabeth; Prince, Jonathan A; Love, Seth; Kehoe, Patrick G

    2009-01-01

    Angiotensin-converting enzyme (ACE) has been implicated in Alzheimer's disease (AD): ACE1 variations influence plasma ACE and risk of AD, and ACE is increased in AD brain. We measured frontal ACE level and activity in 89 AD and 51 control brains, and post-mortem CSF from 101 cases and 19 controls. Neuron-specific enolase (NSE) level and Braak stage were used to indicate neuronal preservation and disease progression. We genotyped the common ACE insertion/deletion polymorphism, rs4343, rs1800764 and rs4921. ACE activity was elevated in AD and correlated with Braak stage. Crude ACE levels were unchanged but adjustment for NSE suggested increased neuronal ACE production with Braak stage. Exposing SH-SY-5Y neurons to oligomeric Aβ1-42 increased ACE level and activity, suggesting Aβ may upregulate ACE in AD. In CSF, ACE level but not activity was reduced in AD. ACE1 genotype did not predict ACE level or activity in brain or CSF. ACE activity and neuronal production increase in AD brain, possibly in response to Aβ. Peripheral measurements do not reflect ACE activity in the brain. PMID:19956428

  10. Distribution of Angiotensin-1 Converting Enzyme Insertion/Deletion and α-Actinin-3 Codon 577 Polymorphisms in Turkish Male Soccer Players.

    PubMed

    Ulucan, Korkut; Sercan, Canan; Biyikli, Türker

    2015-01-01

    Angiotensin-1 converting enzyme (ACE) gene and α-actinin-3 (ACTN3) gene polymorphisms are considered to be the most important candidate genes for genetic predisposition to human athletic performance. In the present study, we aimed to analyze the distribution of ACE and ACTN3 polymorphisms for the first time in male Turkish soccer players. In this prospective study, our cohort consisted of 25 professional players, all with Turkish ancestry. Polymerase chain reaction (PCR)-restriction length polymorphism was used for the characterization of the genotype of ACTN3 and single PCR for ACE. For ACE genotype, 16%, 44%, and 40% of the players had insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD) genotypes, respectively, whereas 20% had XX, 36% had RX, and 44% had RR genotypes for ACTN3. When we examined the allelic percentages, for ACE, D allele was recorded as 62 and I as 38, and for ACTN3, R allele was 62 and X was 38. Our results were in agreement with the previous reports, indicating the presence of ACTN3 D and ACE X allele in soccer players. We suggest that ACE and ACTN3 genotypes are important biomarkers for genetic counseling for the individuals who are prone to be successful soccer players. PMID:26448692

  11. Association between angiotensin converting enzyme gene insertion/deletion polymorphism and renal scar risk in children vesicoureteral reflex: a reappraise meta-analysis

    PubMed Central

    Ai, Jin-Wei; Zeng, Xian-Tao; Liu, Ying; Fu, Yu; Liu, Tong-Zu; Pei, Bin

    2016-01-01

    Vesicoureteral reflex(VUR) is a common disease in children. Some studies indicated that the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism associated with the renal scar in VUR, but not all researchers agreed with it. To clarify the effect of ACE I/D polymorphism on renal scar risk in children with VUR, we performed the present meta-analysis. PubMed, CNKI, CBM, and Embase databases were searched for studies that examined the relationship between ACE I/D polymorphism and renal scar risk in children with VUR. The Stata 12.0 software was used for statistical analyses. 11 case-control studies with 1,032 VUR patients were analyzed. The results showed that the DD genotype and D allele were associated with renal scar risk in overall VUR patients, DD vs. DI + II: OR = 1.61, 95% CI = 1.04–2.49, P = 0.03; DD vs. II: OR = 1.78, 95% CI = 1.20–2.65, P < 0.01; D vs. I: OR = 1.38, 95% CI = 1.02–1.86, P = 0.04. Similar results were revealed in Turks, but not in Caucasians and Asians. Our meta-analysis indicated that the ACE DD genotype may increase the risk of renal scar in children with VUR. PMID:27506878

  12. Comparison of gallium-67 scanning, bronchoalveolar lavage, and serum angiotensin-converting enzyme levels in pulmonary sarcoidosis. Predicting response to therapy

    SciTech Connect

    Baughman, R.P.; Fernandez, M.; Bosken, C.H.; Mantil, J.; Hurtubise, P.

    1984-05-01

    Patients with active pulmonary sarcoidosis underwent bronchoalveolar lavage, gallium scan, and serum angiotensin-converting enzyme (ACE) level determination prior to treatment with corticosteroids. Pulmonary function was tested before and after therapy. Increase in vital capacity after treatment ranged from 40 to 1,030 ml; 12 of the 16 patients studied had an increase of more than 200 ml. There was a close correlation between the percentage uptake of gallium scan and the increase of the vital capacity after therapy (r . 0.95, p less than 0.01). There was no relationship between the percentage of lymphocytes obtained on lavage and the changes in vital capacity with therapy (r . 0.05). There was a positive correlation between the changes in vital capacity and the ratio of T4(+):T8(+)lymphocytes (r . 0.62, p less than 0.05) and number of T4 (+) lymphocytes (r . 0.92, p less than 0.01) in the bronchoalveolar fluid. There was a low correlation between the pretreatment ACE level and the change in vital capacity (r . 0.368, p greater than 0.05).

  13. Prediction of therapeutic response in steroid-treated pulmonary sarcoidosis. Evaluation of clinical parameters, bronchoalveolar lavage, gallium-67 lung scanning, and serum angiotensin-converting enzyme levels

    SciTech Connect

    Hollinger, W.M.; Staton, G.W. Jr.; Fajman, W.A.; Gilman, M.J.; Pine, J.R.; Check, I.J.

    1985-07-01

    To find a pretreatment predictor of steroid responsiveness in pulmonary sarcoidosis the authors studied 21 patients before and after steroid treatment by clinical evaluation, pulmonary function tests, bronchoalveolar lavage (BAL), gallium-67 lung scan, and serum angiotensin-converting enzyme (SACE) level. Although clinical score, forced vital capacity (FVC), BAL percent lymphocytes (% lymphs), quantitated gallium-67 lung uptake, and SACE levels all improved with therapy, only the pretreatment BAL % lymphs correlated with the improvement in FVC (r = 0.47, p less than 0.05). Pretreatment BAL % lymphs of greater than or equal to 35% predicted improvement in FVC of 10/11 patients, whereas among 10 patients with BAL % lymphs less than 35%, 5 patients improved and 5 deteriorated. Clinical score, pulmonary function parameters, quantitated gallium-67 lung uptake, and SACE level used alone, in combination with BAL % lymphs or in combination with each other, did not improve this predictive value. The authors conclude that steroid therapy improves a number of clinical and laboratory parameters in sarcoidosis, but only the pretreatment BAL % lymphs are useful in predicting therapeutic responsiveness.

  14. Short communication: Measuring the angiotensin-converting enzyme inhibitory activity of an 8-amino acid (8mer) fragment of the C12 antihypertensive peptide.

    PubMed

    Paul, Moushumi; Phillips, John G; Renye, John A

    2016-05-01

    An 8-AA (8mer) fragment (PFPEVFGK) of a known antihypertensive peptide derived from bovine αS1-casein (C12 antihypertensive peptide) was synthesized by microwave-assisted solid-phase peptide synthesis and purified by reverse phase HPLC. Its ability to inhibit angiotensin-converting enzyme (ACE) was assessed and compared with that of the parent 12mer peptide (FFVAPFPEVFGK) to determine the effect of truncating the sequence on overall hypotensive activity. The activity of the truncated 8mer peptide was found to be almost 1.5 times less active than that of the 12mer, with ACE-inhibiting IC50 (half-maximal inhibitory concentration) values of 108 and 69μM, for the 8mer and 12mer, respectively. Although the 8mer peptide is less active than the original 12mer peptide, its overall activity is comparable to activities reported for other small proteins that elicit physiological responses within humans. These results suggest that microbial degradation of the 12mer peptide would not result in a complete loss of antihypertensive activity if used to supplement fermented foods and that the stable 8mer peptide could have potential as a blood pressure-lowering agent for use in functional foods. PMID:26971162

  15. Sperm-specific expression of angiotensin-converting enzyme (ACE) is mediated by a 91-base-pair promoter containing a CRE-like element.

    PubMed Central

    Howard, T; Balogh, R; Overbeek, P; Bernstein, K E

    1993-01-01

    The gene encoding the testis isozyme of angiotensin-converting enzyme (testis ACE) is one example of the many genes expressed uniquely during spermatogenesis. This protein is expressed by developing germ cells late in their development and results from the activation of a sperm-specific promoter that is located within intron 12 of the gene encoding the somatic isozyme of ACE. In vitro transcription, DNase footprinting, gel shift assays, and transgenic mouse studies have been used to define the minimal testes ACE promoter and to characterize DNA-protein interactions mediating germ cell-specific expression. These studies show that proper cell- and stage-specific expression of testis ACE requires only a small portion of the immediate upstream sequence extending to -91. A critical motif within this core promoter is a cyclic AMP-responsive element sequence that interacts with a testis-specific transactivating factor. Since this putative cyclic AMP-responsive element has been conserved within the testis ACE promoters of different species and is found at the same site in other genes that are expressed specifically in the testis, it may provide a common mechanism for the recognition of sperm-specific promoters. Images PMID:8380220

  16. Pleiotropic Effect of Common Variants at ABO Glycosyltranferase Locus in 9q32 on Plasma Levels of Pancreatic Lipase and Angiotensin Converting Enzyme

    PubMed Central

    2014-01-01

    For forty-three clinical test values presumably associated to common complex human diseases, we carried out a genome-wide association study using 600K SNPs in a general Japanese population of 1,639 individuals (1,252 after quality control procedures) drawn from a regional cohort, followed by a replication study for statistically significant SNPs (p = 1.95×10−9–8.34×10−39) using an independent population of 1,671 from another cohort. In this single two-stage study, we newly found strong and robust associations of common variants at the ABO histo-blood glycosyltransferase locus in 9q32 with the plasma levels of pancreatic lipase (P-LIP), in addition to successful confirmation of the known ABO association of angiotensin converting enzyme (ACE) independent of the ACE1 gene in 17q23.2 with the ACE level. Our results are compatible with the previously reported association between the ABO gene and pancreatic cancer, and show that the effect of these common variants at the ABO locus on the P-LIP and ACE levels is largely opposing and pleiotropic. PMID:24586218

  17. Molecular analysis of genetic variation in angiotensin I-converting enzyme identifies no association with sporting ability: First report from Indian population

    PubMed Central

    Kothari, Sweta T.; Chheda, Pratiksha; Chatterjee, Leena; Das, Bibhu. R.

    2012-01-01

    INTRODUCTION: A polymorphism in the angiotensin-converting enzyme (ACE) gene was the first performance enhancing polymorphisms (PEPs) to be identified and correlated with athletic abilities. This polymorphism (rs. 5186) is the absence (deletion; D allele), rather than the presence (insertion, I allele) of 287bp Alu repeat element in intron 16. However, the association of ACE I/D polymorphism in sports abilities have been contradicted and debated. No study has evaluated the ACE gene polymorphism in Indian athletes so far. Hence, the genotype distribution and allelic frequency of ACE gene in selected Indian athletic and non-athletic population was studied. MATERIALS AND METHODS: A total of 147 athletes and 131 controls were genotyped for the ACE gene polymorphism using PCR. RESULTS: No significant association was observed between the allelic frequencies of ACE gene in controls and athletes on a whole, as well as after sub-categorizing the athletes based on the type of sport they played (P > 0.1). However, a higher representation of I allele was observed in the athletes. CONCLUSION: ACE genotyping studies need to focus on truly elite athletes of a single sporting discipline, to be able to find an association. The ACE I/D polymorphism may not be considered a marker for human performance, but can be further studied in combination with other potent performance enhancing polymorphisms. PMID:22754223

  18. Bioassay-guided preparative separation of angiotensin-converting enzyme inhibitory C-flavone glycosides from Desmodium styracifolium by recycling complexation high-speed counter-current chromatography.

    PubMed

    Zhang, Ying-Qi; Luo, Jian-Guang; Han, Chao; Xu, Jin-Fang; Kong, Ling-Yi

    2015-01-01

    A new strategy of the convergence of high-speed counter-current chromatography (HSCCC) and bioactive assay technique was developed for rapidly screening and separating the angiotensin-converting enzyme (ACE) inhibitors from the aerial parts of Desmodium styracifolium. Bioactivity-guided fractionation of the crude extract was first established to target the bioactive fractions based on HSCCC coupled with in vitro ACE inhibitory assay. Subsequently, the bioactive fractions were further separated by the recycling complexation HSCCC respectively, using 0.10 mol/L copper sulfate in the lower phase of two-phase solvent system composed of n-butanol/water (1:1, v/v). Five C-glycosylflavones, vicenin 2 (1), carlinoside (2), vicenin 1 (3), schaftoside (4) and vicenin 3 (5), were successfully obtained. Their chemical structures were identified using ESI-MS and NMR. All the isolates showed in vitro ACE inhibitory activity with the IC50 values between 33.62 and 58.37 μM. The results demonstrated that the established method was proposed as an excellent strategy to systematically screen and purify active compounds from traditional Chinese medicines. PMID:25459924

  19. High throughput and rapid screening of marine protein hydrolysates enriched in peptides with angiotensin-I-converting enzyme inhibitory activity by capillary electrophoresis.

    PubMed

    He, Hai-Lun; Chen, Xiu-Lan; Wu, Hao; Sun, Cai-Yun; Zhang, Yu-Zhong; Zhou, Bai-Cheng

    2007-12-01

    Twelve kinds of marine protein materials, including fish, shrimp, seashell, algae and seafood wastes were selected for the hydrolysis using four different proteases. The IC(50) values for angiotensin-converting enzyme (ACE) inhibitory activity of 48 hydrolysates were rapidly determined by capillary electrophoresis (CE). The values ranged from 0.17 to 501.7mg/ml, and were affected by both the marine protein resources and the selected proteases. Hydrolysates of the lowest IC(50) values were from shrimp (Acetes chinensis), shark meat, mackerel bone, Polysiphonia urceolata and Spirulina platensis, indicating these five kinds of marine food proteins contained beneficial materials for the production of ACE inhibitory peptides by proteolysis. The hydrolysates obtained using proteases Protamex and SM98011 had lower IC(50) values, showing these two proteases were superior to others. The CE method achieved the same sensitivity as the high performance liquid chromatography (HPLC) method. However, the CE method was faster and, as a result, more economical. Therefore, CE had potential for rapid screening of marine protein hydrolysates enriched in ACE inhibitory peptides. PMID:17317156

  20. Production of novel angiotensin I-converting enzyme inhibitory peptides by fermentation of marine shrimp Acetes chinensis with Lactobacillus fermentum SM 605.

    PubMed

    Wang, Yu-Kai; He, Hai-Lun; Chen, Xiu-Lan; Sun, Cai-Yun; Zhang, Yu-Zhong; Zhou, Bai-Cheng

    2008-07-01

    Acetes chinensis is an underutilized shrimp species thriving in Bo Hai Gulf of China. Its hydrolysate digested with protease SM98011 has been previously shown to have high angiotensin I-converting enzyme (ACE) inhibitory activity (He et al., J Pept Sci 12:726-733, 2006). In this article, A. chinensis were fermented by Lactobacillus fermentum SM 605 and the fermented sauce presented high ACE inhibitory activity. The minimum IC(50) value (3.37 +/- 0.04 mg/mL) was achieved by response surface methodology with optimized process parameters such as fermentation time of 24.19 h, incubation temperature at 38.10 degrees C, and pH 6.12. Three ACE inhibitory peptides are purified by ultrafiltration, gel filtration, and reverse-phase high performance liquid chromatography. Identified by mass spectrometry, their amino acid sequences are Asp-Pro, Gly-Thr-Gly, and Ser-Thr, with IC(50) values of 2.15 +/- 0.02, 5.54 +/- 0.09, and 4.03 +/- 0.10 microM, respectively. Also, they are all novel ACE inhibitory peptides. Compared with protease digestion, fermentation is a simpler and cheaper method to produce ACE inhibitory peptides from shrimp A. chinensis. PMID:18521593

  1. Association between angiotensin converting enzyme gene insertion/deletion polymorphism and renal scar risk in children vesicoureteral reflex: a reappraise meta-analysis.

    PubMed

    Ai, Jin-Wei; Zeng, Xian-Tao; Liu, Ying; Fu, Yu; Liu, Tong-Zu; Pei, Bin

    2016-01-01

    Vesicoureteral reflex(VUR) is a common disease in children. Some studies indicated that the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism associated with the renal scar in VUR, but not all researchers agreed with it. To clarify the effect of ACE I/D polymorphism on renal scar risk in children with VUR, we performed the present meta-analysis. PubMed, CNKI, CBM, and Embase databases were searched for studies that examined the relationship between ACE I/D polymorphism and renal scar risk in children with VUR. The Stata 12.0 software was used for statistical analyses. 11 case-control studies with 1,032 VUR patients were analyzed. The results showed that the DD genotype and D allele were associated with renal scar risk in overall VUR patients, DD vs. DI + II: OR = 1.61, 95% CI = 1.04-2.49, P = 0.03; DD vs. II: OR = 1.78, 95% CI = 1.20-2.65, P < 0.01; D vs. I: OR = 1.38, 95% CI = 1.02-1.86, P = 0.04. Similar results were revealed in Turks, but not in Caucasians and Asians. Our meta-analysis indicated that the ACE DD genotype may increase the risk of renal scar in children with VUR. PMID:27506878

  2. Angiotensinogen (AGT) M235T, AGT T174M and Angiotensin-1-Converting Enzyme (ACE) I/D Gene Polymorphisms in Essential Hypertension: Effects on Ramipril Efficacy

    PubMed Central

    Kolovou, Vana; Lagou, Evangelia; Mihas, Constantinos; Vasiliki, Giannakopoulou; Katsiki, Niki; Kollia, Aikaterini; Triposkiadis, Filippos; Degiannis, Dimitris; Mavrogeni, Sophie; Kolovou, Genovefa

    2015-01-01

    Background: Hypertension, one of the most important risk factors for premature cardiovascular disease, is a major worldwide public health problem. Angiotensin-1-converting enzyme (ACE) and angiotensinogen (AGT) gene polymorphisms are thought to be associated with primary hypertension. In the present study, we examined the frequency of these gene polymorphisms in an adult population with and without essential hypertension. Furthermore, we evaluated the effect of ACE and AGT gene polymorphisms on ramipril treatment efficacy in the hypertensive patients. Methods: A total of 166 adults (83 hypertensives and 83 normotensives) were involved in the study and genotyped for AGTM235T (rs699), AGTT174M (rs4762) and ACEI/D (rs1799752) gene polymorphisms. Results: The genotype and allele distribution of the AGTM235T variant significantly differed between hypertensives and normotensives [odds ratio (OR) = 1.57% (T vs M allele), 95% confidence intervals (CIs): 1.01 - 2.44; p=0.045 for hypertensives]. However, none of the 3 studied Simple Nucleotide Polymorphisms were associated with the blood pressure-lowering response to ramipril. Conclusion: These results suggest that AGTM235T gene polymorphism is associated with essential hypertension. However, none of the AGTM235T, AGTT174M and ACEI/D gene polymorphisms influenced ramipril effectiveness. PMID:27006715

  3. Recovery of casein-derived peptides with in vitro inhibitory activity of angiotensin converting enzyme (ACE) using aqueous two-phase systems.

    PubMed

    de Souza, Evaldo Cardozo; Coimbra, Jane Sélia Dos Reis; de Oliveira, Eduardo Basílio; Bonomo, Renata Cristina Ferreira

    2014-10-22

    Peptides inhibiting the activity of angiotensin converting enzyme (ACE) were obtained by trypsin-catalyzed hydrolysis of bovine milk casein, performed at 37°C, during 1, 2, 5, 8 and 24h. Results of in vitro inhibitory activity ranged between 13.4% and 78.5%. The highest ACE inhibitory activity was evidenced for hydrolysates obtained after 2h of reaction. Aqueous two-phase systems (ATPS) formed by polyethylene glycol of 1500gmol(-1) (PEG 1500)+sodium phosphate or potassium phosphates were produced and evaluated, in terms of partition coefficients (K) and extraction yields (y), to recovery the casein hydrolysates at room temperature. In ATPS containing sodium phosphate, the peptides showed a slightly greater affinity toward the bottom salt-rich phase (0.1≤K≤0.9; 5.7%≤y≤47%). In the case of ATPS containing potassium phosphates, these molecules showed substantially greater affinity toward the top polymer-rich phase (137≤K≤266; y≥99%). These results point out extraction using PEG 1500/potassium phosphate ATPS is an efficient technique to recover casein hydrolysates containing ACE inhibitors peptides. Outlined data will be helpful in integrating such unit operation to larger scale processes. PMID:25464099

  4. Distribution of Angiotensin-1 Converting Enzyme Insertion/Deletion and α-Actinin-3 Codon 577 Polymorphisms in Turkish Male Soccer Players

    PubMed Central

    Ulucan, Korkut; Sercan, Canan; Biyikli, Türker

    2015-01-01

    Angiotensin-1 converting enzyme (ACE) gene and α-actinin-3 (ACTN3) gene polymorphisms are considered to be the most important candidate genes for genetic predisposition to human athletic performance. In the present study, we aimed to analyze the distribution of ACE and ACTN3 polymorphisms for the first time in male Turkish soccer players. In this prospective study, our cohort consisted of 25 professional players, all with Turkish ancestry. Polymerase chain reaction (PCR)-restriction length polymorphism was used for the characterization of the genotype of ACTN3 and single PCR for ACE. For ACE genotype, 16%, 44%, and 40% of the players had insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD) genotypes, respectively, whereas 20% had XX, 36% had RX, and 44% had RR genotypes for ACTN3. When we examined the allelic percentages, for ACE, D allele was recorded as 62 and I as 38, and for ACTN3, R allele was 62 and X was 38. Our results were in agreement with the previous reports, indicating the presence of ACTN3 D and ACE X allele in soccer players. We suggest that ACE and ACTN3 genotypes are important biomarkers for genetic counseling for the individuals who are prone to be successful soccer players. PMID:26448692

  5. N- vs. C-Domain Selectivity of Catalytic Inactivation of Human Angiotensin Converting Enzyme by Lisinopril-Coupled Transition Metal Chelates

    PubMed Central

    Hocharoen, Lalintip; Joyner, Jeff C.; Cowan, J. A.

    2014-01-01

    The N- and C-terminal domains of human somatic Angiotensin I Converting Enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates were tested for both reversible binding and irreversible catalytic inactivation of sACE-1. C/N domain binding selectivity ratios ranged from 1 to 350, while rates of irreversible catalytic inactivation of the N- and C-domains were found to be significantly greater for the N-domain, suggesting a more optimal orientation of the M-chelate-lisinopril complexes within the active site of the N-domain of sACE-1. Finally, the combined effect of binding selectivity and inactivation selectivity was assessed for each catalyst (double-filter selectivity factors), and several catalysts were found to cause domain-selective catalytic inactivation. The results of this study demonstrate the ability to optimize the target selectivity of catalytic metallopeptides through both binding and orientation factors (double-filter effect). PMID:24228790

  6. Green asparagus (Asparagus officinalis) prevented hypertension by an inhibitory effect on angiotensin-converting enzyme activity in the kidney of spontaneously hypertensive rats.

    PubMed

    Sanae, Matsuda; Yasuo, Aoyagi

    2013-06-12

    Green asparagus (Asparagus officinalis) is known to be rich in functional components. In the present study, spontaneously hypertensive rats (SHR) were used to clarify whether green asparagus prevents hypertension by inhibition of angiotensin-converting enzyme (ACE) activity. Six-week-old male SHR were fed a diet with (AD group) or without (ND group) 5% asparagus for 10 weeks. Systolic blood pressure (SBP) (AD: 159 ± 4.8 mmHg, ND: 192 ± 14.7 mmHg), urinary protein excretion/creatinine excretion, and ACE activity in the kidney were significantly lower in the AD group compared with the ND group. Creatinine clearance was significantly higher in the AD group compared with the ND group. In addition, ACE inhibitory activity was observed in a boiling water extract of asparagus. The ACE inhibitor purified and isolated from asparagus was identified as 2″-hydroxynicotianamine. In conclusion, 2″-hydroxynicotianamine in asparagus may be one of the factors inhibiting ACE activity in the kidney, thus preventing hypertension and preserving renal function. PMID:23647085

  7. Fermentation characteristics and angiotensin I-converting enzyme-inhibitory activity of Lactobacillus helveticus isolate H9 in cow milk, soy milk, and mare milk.

    PubMed

    Wang, Jicheng; Li, Changkun; Xue, Jiangang; Yang, Jie; Zhang, Qing; Zhang, Heping; Chen, Yongfu

    2015-06-01

    Lactobacillus helveticus isolate H9 demonstrated high angiotensin I-converting enzyme (ACE)-inhibitory activity in previous research. Here, we evaluated the fermentation characteristics (pH, titratable acidity, free amino nitrogen, and viable bacterial counts), ACE-inhibitory activity, and contents of Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) peptides of stored yogurt (4°C for 28 d) fermented by L. helveticus isolate H9 (initially inoculated at 4 concentrations), from cow, mare, and soy milks. During storage, the pH and titratable acidity remained stable in yogurts produced from all milk types and all inoculation concentrations. The viable bacterial counts in all stored yogurts ranged between 10(6.72) and 10(8.59) cfu/g. The highest ACE-inhibitory activity (70.9-74.5%) was achieved at inoculation concentrations of 5×10(6) cfu/mL. The ACE-inhibitory tripeptides VPP and IPP as determined by ultra-performance liquid chromatography-tandem mass spectrometry were not produced in yogurt made from soy milk or mare milk. These evaluations indicate that L. helveticus H9 has good probiotic properties and would be a promising candidate for production of fermented food with probiotic properties. PMID:25892687

  8. Effects of Metabolites Produced from (-)-Epigallocatechin Gallate by Rat Intestinal Bacteria on Angiotensin I-Converting Enzyme Activity and Blood Pressure in Spontaneously Hypertensive Rats.

    PubMed

    Takagaki, Akiko; Nanjo, Fumio

    2015-09-23

    Inhibitory activity of angiotensin I-converting enzyme (ACE) was examined with (-)-epigallocatechin gallate (EGCG) metabolites produced by intestinal bacteria, together with tea catechins. All of the metabolites showed ACE inhibitory activities and the order of IC50 was hydroxyphenyl valeric acids > 5-(3,4,5-trihydroxyphenyl)-γ-valerolactone (1) > trihydroxyphenyl 4-hydroxyvaleric acid ≫ dihydroxyphenyl 4-hydroxyvaleric acid ≫ 5-(3,5-dihydroxyphenyl)-γ-valerolactone (2). Among the catechins, galloylated catechins exhibited stronger ACE inhibitory activity than nongalloylated catechins. Furthermore, the effects of a single oral intake of metabolites 1 and 2 on systolic blood pressure (SBP) were examined with spontaneously hypertensive rats (SHR). Significant decreases in SBP were observed between 2 h after oral administration of 1 (150 mg/kg in SHR) and the control group (p = 0.002) and between 4 h after administration of 2 (200 mg/kg in SHR) and the control group (p = 0.044). These results suggest that the two metabolites have hypotensive effects in vivo. PMID:26323573

  9. An SNP within the Angiotensin-Converting Enzyme Distinguishes between Sprint and Distance Performing Alaskan Sled Dogs in a Candidate Gene Analysis

    PubMed Central

    Huson, Heather J.; Byers, Alexandra M.; Runstadler, Jonathan

    2011-01-01

    The Alaskan sled dog offers a unique mechanism for studying the genetics of elite athletic performance. They are a group of mixed breed dogs, comprised of multiple common breeds, and a unique breed entity seen only as a part of the sled dog mix. Alaskan sled dogs are divided into 2 primary groups as determined by their racing skills. Distance dogs are capable of running over 1000 miles in 10 days, whereas sprint dogs run much shorter distances, approximately 30 miles, but in faster times, that is, 18–25 mph. Finding the genes that distinguish these 2 types of performers is likely to illuminate genetic contributors to human athletic performance. In this study, we tested for association between polymorphisms in 2 candidate genes; angiotensin-converting enzyme (ACE) and myostatin (MSTN) and enhanced speed and endurance performance in 174 Alaskan sled dogs. We observed 81 novel genetic variants within the ACE gene and 4 within the MSTN gene, including a polymorphism within the ACE gene that significantly (P value 2.38 × 10−5) distinguished the sprint versus distance populations. PMID:21846742

  10. In Vitro and In Vivo Assessment of Angiotensin-Converting Enzyme (ACE) Inhibitory Activity of Fermented Soybean Milk by Lactobacillus casei Strains.

    PubMed

    Bao, Zhijie; Chi, Yujie

    2016-08-01

    Angiotensin-converting enzyme (ACE) inhibitory activity of fermented soybean milk (FSM) by Lactobacillus casei strains in vitro was investigated in this study. Effects of fermented soybean milk administration by gavage on systolic blood pressure and diastolic blood pressure was also evaluated in spontaneously hypertensive rats (SHR) rats and Wistar-Kyoto (WKY) rats. Results showed that, CICC 20280 and CICC 23184 FSM showed high ACE inhibitory activity in vitro test and ACE inhibitory activity of CICC 23184 FSM was higher than CICC 20280 FSM. The bioactive substances of FSM were peptide and γ-aminobutyric acid (GABA). Their contents in CICC 20280 FSM and CICC 23184 FSM were 3.97 ± 0.67 mg/ml (peptide), 1.71 ± 0.36 mg/ml (GABA) and 5.17 ± 0.22 mg/ml (peptide), 1.57 ± 0.21 mg/ml (GABA), respectively. Moreover, CICC 20280 and CICC 23184 FSM administration by gavage could effectively lower the blood pressure of SHR to a normal level, while there was no effect on blood pressure of WKY rats. This result indicated that the bioactive substances could play an antihypertensive role when the blood pressure was not within the normal levels (high levels). PMID:27139252

  11. Angiotensin I-Converting Enzyme inhibitory and antioxidant activities and surfactant properties of protein hydrolysates as obtained of Amaranthus hypochondriacus L. grain.

    PubMed

    Soriano-Santos, J; Escalona-Buendía, H

    2015-04-01

    Even though some research has been carried out on surfactant properties of amaranth protein hydrolysates, their bio-functionality has not been studied yet. In this work amaranth grain Alb 1 and Glob were hydrolyzed (Alb 1H, Glob H) and foams and emulsions at optimal conditions (t, E/S, pH5) were prepared in order to assess techno-functional properties such as foaming (F) and emulsifying (E) (capacity (C) and stability (S)). FC and EC were much better for Glob H than for Alb H. Angiotensin I-converting enzyme-inhibitory activity was higher for Alb 1H (roughly 50 %) than that of Glob H (roughly 30 %). Scavenging of radicals activity (DPPH· or ABTS· (+) ) of Alb 1H and Glob H, at 2 mg/mL, was similar (approx. 40 %), but lower than Alb 1 (approx. 70 %), which was the best antioxidant. The low reducing power showed that hydrolysates barely donate an electron or hydrogen. Chelating activity on Cu(2+) was lower than that exhibited by Fe(2+,) which was remarkable, approx. 80 % as long as DH% > 10 %, where hydrolysates displayed high solubility (Alb 1H = 85 %, Glob H = 70 %) because of occurrence of 1-10 kDa peptides. Amaranth foams and emulsions prepared with protein hydrolysates have a potential as a nutraceutical food. PMID:25829587

  12. Improved synthesis of lysine- and arginine-derived Amadori and Heyns products and in vitro measurement of their angiotensin I-converting enzyme inhibitory activity.

    PubMed

    Srinivas, Sudhanva M; Harohally, Nanishankar V

    2012-02-15

    The L-lysine- and L-arginine-derived Amadori and Heyns products consisting of N-(1-deoxy-d-fructos-1-yl)amino acid and N-(2-deoxy-d-glucos-2-yl)amino acid were prepared by reaction of d-fructose and d-glucose with l-lysine hydrochloride and l-arginine hydrochloride using commercial zinc powder as deprotonating reagent and also as catalyst precursor in a simple synthetic route in high yield. These compounds were screened for angiotensin I-converting enzyme (ACE) inhibitory activity using a high-throughput colorimetric assay (utilizing porcine kidney ACE). The IC(50) values fall in the range of 1030-1175 μM, with N(α)-(1-deoxy-d-fructos-1-yl)arginine showing the best IC(50) value (1030 ± 38 μM). This study demonstrates an improved synthetic method for simple Amadori and Heyns products and their moderate ACE inhibitor activity. PMID:22242891

  13. Interdependent effect of angiotensin-converting enzyme and platelet-activating factor acetylhydrolase gene polymorphisms on the progression of immunoglobulin A nephropathy.

    PubMed

    Yoon, H-J; Kim, H; Kim, H L; Lee, S G; Zheng, S-H; Shin, J H; Lim, C S; Kim, S; Lee, J S; Lee, D S; Kim, Y S

    2002-08-01

    In order to investigate the interdependent action of the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and polymorphism in exon 11 (C1136-->T; Ala379Val) of the platelet-activating factor acetylhydrolase (PAF-AH) gene, which encodes a functional antagonist of PAF, on the progression of immunoglobulin A (IgA) nephropathy, we analysed both polymorphisms in patients with primary IgA nephropathy, who were followed-up for longer than 3 years. During the follow-up (87.3 +/- 50.0 months), the disease progressed in 38 of the 191 patients (19.9%). The D allele of the ACE gene in the absence of the T allele of the PAF-AH gene did not affect the prognosis [odds ratio (OR), 3.6; 95% confidence interval (CI), 0.8-16.4] and neither did the T allele in the absence of the D allele (OR, 3.0; 95% CI, 0.4-24.2). However, the presence of both was a significant prognostic factor (OR, 6.6; 95% CI, 1.4-31.3). After adjusting for other risk factors, the presence of both proved to be an independent risk factor (OR, 4.5; 95% CI, 1.6-12.7). These results suggest that the interdependent effects of ACE and PAF-AH polymorphisms on the progression of IgA nephropathy might be more important than the effect of the individual polymorphisms. PMID:12220450

  14. Short communication: Potential of Fresco-style cheese whey as a source of protein fractions with antioxidant and angiotensin-I-converting enzyme inhibitory activities.

    PubMed

    Tarango-Hernández, S; Alarcón-Rojo, A D; Robles-Sánchez, M; Gutiérrez-Méndez, N; Rodríguez-Figueroa, J C

    2015-11-01

    Recently, traditional Mexican Fresco-style cheese production has been increasing, and the volume of cheese whey generated represents a problem. In this study, we investigated the chemical composition of Fresco-style cheese wheys and their potential as a source of protein fractions with antioxidant and angiotensin-I-converting enzyme (ACE)-inhibitory activities. Three samples from Fresco, Panela, and Ranchero cheeses whey were physicochemically characterized. Water-soluble extracts were fractionated to obtain whey fractions with different molecular weights: 10-5, 5-3, 3-1 and <1 kDa. The results indicated differences in the lactose, protein, ash, and dry matter contents (% wt/wt) in the different Fresco-style cheese wheys. All whey fractions had antioxidant and ACE-inhibitory activities. The 10-5 kDa whey fraction of Ranchero cheese had the highest Trolox equivalent antioxidant capacity (0.62 ± 0.00 mM), and the 3-1 kDa Panela and Fresco cheese whey fractions showed the highest ACE-inhibitory activity (0.57 ± 0.02 and 0.59 ± 0.04 μg/mL 50%-inhibitory concentration values, respectively). These results suggest that Fresco-style cheese wheys may be a source of protein fractions with bioactivity, and thus could be useful ingredients in the manufacture of functional foods with increased nutritional value. PMID:26364114

  15. Characterization of angiotensin converting enzyme (ACE) in the testis and assessment of the in vivo effects of the ACE inhibitor perindopril

    SciTech Connect

    Jackson, B.; Cubela, R.B.; Sakaguchi, K.; Johnston, C.I.

    1988-07-01

    Angiotensin converting enzyme (ACE) was characterized by radioligand studies utilizing the potent ACE inhibitor 351A, a derivative of lisinopril. Ligand binding characteristics were similar for ACE derived from testis, lung, and kidney, despite known differences in structure between ACe from these sources. This observation suggests that the ACE active enzymatic site is similar in different tissues. The effect of the orally active ACE inhibitor perindopril was studied ex vivo in tissues of the rat after oral gavage. Radioligand bound to tissue ACE was reduced after perindopril treatment, in tissue homogenates of lung and kidney, but not testis. Autoradiographs of radioligand binding to tissue sections obtained ex vivo after oral perindopril showed inhibition of ACE in the aorta, lung, and kidney, but did not reveal any inhibition of ACE in the testis. ACE in small vessels of the testis was inhibited as in the aorta, while at the same time testicular ACE was unaffected. ACE in rat testis appears to have a similar enzymatic binding site to ACE from the lung and kidney. Perindopril inhibited ACE in the lung and kidney but did not affect ACE in the testis, suggesting the drug is limited in testicular penetration by the blood-testis barrier. This may explain the lack of any reports of adverse effects of ACE inhibitors on testicular function.

  16. In Vitro Studies on the Antioxidant Property and Inhibition of α-Amylase, α-Glucosidase, and Angiotensin I-Converting Enzyme by Polyphenol-Rich Extracts from Cocoa (Theobroma cacao) Bean

    PubMed Central

    Ademosun, Ayokunle O.; Ademiluyi, Adedayo O.; Omojokun, Olasunkanmi S.; Nwanna, Esther E.; Longe, Kuburat O.

    2014-01-01

    Background. This study sought to investigate the antidiabetic and antihypertensive mechanisms of cocoa (Theobroma cacao) bean through inhibition of α-amylase, α-glucosidase, angiotensin-1 converting enzyme, and oxidative stress. Methodology. The total phenol and flavonoid contents of the water extractable phytochemicals from the powdered cocoa bean were determined and the effects of the extract on α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities were investigated in vitro. Furthermore, the radicals [1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2..-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), hydroxyl (OH), and nitric oxide (NO)] scavenging ability and ferric reducing antioxidant property of the extract were assessed. Results. The results revealed that the extract inhibited α-amylase (1.81 ± 0.22 mg/mL), α-glucosidase (1.84 ± 0.17 mg/mL), and angiotensin-1 converting enzyme (0.674 ± 0.06 mg/mL [lungs], 1.006 ± 0.08 mg/mL [heart]) activities in a dose-dependent manner and also showed dose-dependent radicals [DPPH (16.94 ± 1.34 mg/mL), NO (6.98 ± 0.886 mg/mL), OH (3.72 ± 0.26 mg/mL), and ABTS (15.7 ± 1.06 mmol/TEAC·g] scavenging ability. Conclusion. The inhibition of α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities by the cocoa bean extract could be part of the possible mechanism by which the extract could manage and/or prevent type-2 diabetes and hypertension. PMID:25295218

  17. Angiotensin-converting enzyme 2 (ACE2) from raccoon dog can serve as an efficient receptor for the spike protein of severe acute respiratory syndrome coronavirus.

    PubMed

    Xu, Lili; Zhang, Yanfang; Liu, Yun; Chen, Zhiwei; Deng, Hongkui; Ma, Zhongbin; Wang, Hualin; Hu, Zhihong; Deng, Fei

    2009-11-01

    Raccoon dog is one of the suspected intermediate hosts of severe acute respiratory syndrome coronavirus (SARS-CoV). In this study, the angiotensin-converting enzyme 2 (ACE2) gene of raccoon dog (rdACE2) was cloned and sequenced. The amino acid sequence of rdACE2 has identities of 99.3, 89.2, 83.9 and 80.4 % to ACE2 proteins from dog, masked palm civet (pcACE2), human (huACE2) and bat, respectively. There are six amino acid changes in rdACE2 compared with huACE2, and four changes compared with pcACE2, within the 18 residues of ACE2 known to make direct contact with the SARS-CoV S protein. A HeLa cell line stably expressing rdACE2 was established; Western blot analyses and an enzyme-activity assay indicated that the cell line expressed ACE2 at a similar level to two previously established cell lines that express ACE2 from human and masked palm civet, respectively. Human immunodeficiency virus-backboned pseudoviruses expressing spike proteins derived from human SARS-CoV or SARS-CoV-like viruses of masked palm civets and raccoon dogs were tested for their entry efficiency into these cell lines. The results showed that rdACE2 is a more efficient receptor for human SARS-CoV, but not for SARS-CoV-like viruses of masked palm civets and raccoon dogs, than huACE2 or pcACE2. This study provides useful data to elucidate the role of raccoon dog in SARS outbreaks. PMID:19625462

  18. Aib-containing analogues of the insect kinin neuropeptide family demonstrate resistance to an insect angiotensin-converting enzyme and potent diuretic activity.

    PubMed

    Nachman, R J; Isaac, R E; Coast, G M; Holman, G M

    1997-01-01

    Analogues of the insect kinin family in which the Xaa2 residue of the C-terminal pentapeptide core sequence Phe-Xaa1-Xaa2-Trp-Gly-NH2 (Xaa1 = Asn, His, Phe, Ser, or Tyr; Xaa2 = Ala, Ser, or Pro) is replaced with sterically hindered aminoisobutyric acid (Aib) prove to be resistant to hydrolysis by housefly (Musca domestica) angiotensin-converting enzyme (ACE), an endopeptidase capable of hydrolysis and inactivation of the naturally occurring insect kinin peptides. The Aib residue is compatible with formation of turn in the active core region that is important for the biological activity of the insect kinins. One of the Aib-containing analogues, pGlu-Lys-Phe-Phe-Aib-Trp-Gly-NH2, is five- and eightfold more active than the most active endogenous insect kinins in cockroach (Leucophaea maderae) hindgut myotropic and cricket (Acheta domesticus) Malpighian tubule fluid secretion assays, respectively. As the analogue is blocked at both the amino- and the carboxyl-terminus and resistant to an endopeptidase present in insects, it is better adapted than the endogenous peptides to survive for long periods in the hemolymph. Enzyme-resistant insect kinin analogues can provide useful tools to insect researchers studying the neuroendocrine control of water and ion balance and the physiological consequences of challenging insect with diuretic factors that demonstrate enhanced resistance to peptidase attack. If these analogues, whether in isolation or in combination with other factors, can disrupt the water and/or ion balance they hold potential utility for the control of pest insect populations in the future. PMID:9114452

  19. Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study).

    PubMed

    AlJaroudi, Wael A; Refaat, Marwan M; Habib, Robert H; Al-Shaar, Laila; Singh, Madhurmeet; Gutmann, Rebecca; Bloom, Heather L; Dudley, Samuel C; Ellinor, Patrick T; Saba, Samir F; Shalaby, Alaa A; Weiss, Raul; McNamara, Dennis M; Halder, Indrani; London, Barry

    2015-04-01

    Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events study that included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no-ACEi/ARB was physician dependent. There were 1,509 patients (mean age [SD] 63 [12] years, 80% men, mean [SD] EF 21% [6%]) with 1,213 (80%) on ACEi/ARB and 296 (20%) not on ACEi/ARB. We identified 574 propensity-matched patients (287 in each group). After a mean (SD) of 2.5 (1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3, and 5 years in the matched cohort (7.7%, 16.7%, and 18.5% vs 13.2%, 27.5%, and 32.0%; RR = 0.61 [0.43 to 0.86]; p = 0.005). Among patients with glomerular filtration rate (GFR) >60 and 30 to 60 ml/min/1.73 m(2), those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock compared with those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73 m(2) and with neutral effect in those with GFR <30 ml/min/1.73 m(2). PMID:25682436

  20. Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status

    PubMed Central

    Alsafar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Almaini, Mustafa; Odama, Unini; Rais, Naushad

    2015-01-01

    The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, p = 0.086] or hypertension [odd ratio (OR) = 1.02, p = 0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, p = 0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, p = 0.01). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population. PMID:26491214

  1. Angiotensin-converting enzyme inhibition prevents myocardial infarction-induced increase in renal cortical cGMP and cAMP phosphodiesterase activities.

    PubMed

    Clauss, François; Charloux, Anne; Piquard, François; Doutreleau, Stéphane; Talha, Samy; Zoll, Joffrey; Lugnier, Claire; Geny, Bernard

    2015-08-01

    We investigated whether myocardial infarction (MI) enhances renal phosphodiesterases (PDE) activities, investigating particularly the relative contribution of PDE1-5 isozymes in total PDE activity involved in both cGMP and cAMP pathways, and whether angiotensin-converting enzyme inhibition (ACEi) decreases such renal PDE hyperactivities. We also investigated whether ACEi might thereby improve atrial natriuretic peptide (ANP) efficiency. We studied renal cortical PDE1-5 isozyme activities in sham (SH)-operated, MI rats and in MI rats treated with perindopril (ACEi) 1 month after coronary artery ligation. Circulating atrial natriuretic peptide (ANP), its second intracellular messenger cyclic guanosine monophosphate (cGMP) and cGMP/ANP ratio were also determined. Cortical cGMP-PDE2 (80.3 vs. 65.1 pmol/min/mg) and cGMP-PDE1 (50.7 vs. 30.1 pmol/min/mg), and cAMP-PDE2 (161 vs. 104.1 pmol/min/mg) and cAMP-PDE4 (307.5 vs. 197.2 pmol/min/mg) activities were higher in MI than in SH rats. Despite increased ANP plasma level, ANP efficiency tended to be decreased in MI compared to SH rats. Perindopril restored PDE activities and tended to improve ANP efficiency in MI rats. One month after coronary ligation, perindopril treatment of MI rats prevents the increase in renal cortical PDE activities. This may contribute to increase renal ANP efficiency in MI rats. PMID:25939307

  2. Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

    PubMed

    White, William B; Wilson, Craig A; Bakris, George L; Bergenstal, Richard M; Cannon, Christopher P; Cushman, William C; Heller, Simon K; Mehta, Cyrus R; Nissen, Steven E; Zannad, Faiez; Kupfer, Stuart

    2016-09-01

    Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. PMID:27480840

  3. Angiotensin-converting Enzyme Inhibitor and Statin Medication Use and Incident Mobility Limitation in Community Older Adults. The Health, Aging and Body Composition Study

    PubMed Central

    Gray, Shelly L.; Boudreau, Robert M.; Newman, Anne B.; Studenski, Stephanie A.; Shorr, Ronald I; Bauer, Douglas C.; Simonsick, Eleanor M.; Hanlon, Joseph T

    2012-01-01

    Objective Angiotensin-converting enzyme (ACE) inhibitors and statin medications have been proposed as potential agents to prevent or delay physical disability; yet limited research has evaluated whether such use in older community dwelling adults is associated with a lower risk of incident mobility limitation. Design Longitudinal cohort study Setting Health, Aging and Body Composition (Health ABC) Participants 3055 participants who were well functioning at baseline (e.g., no mobility limitations). Measurements Summated standardized daily doses (low, medium and high) and duration of ACE inhibitor and statin use was computed. Mobility limitation (two consecutive self-reports of having any difficulty walking 1/4 mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazard analyses were conducted adjusting for demographics, health status, and health behaviors. Results At baseline, ACE inhibitors and statins were used by 15.2% and 12.9%, respectively and both increased to over 25% by year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.82–1.09) nor statin use (multivariate HR 1.02; 95% CI 0.87–1.17) was associated with a lower risk for mobility limitation. Similar findings were seen in analyses examining dose- and duration-response relationships and sensitivity analyses restricted to those with hypertension. Conclusions These findings indicate that ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively do not lower risk of mobility limitation, an important life quality indicator. PMID:22092102

  4. Impact of non-starter lactobacilli on release of peptides with angiotensin-converting enzyme inhibitory and antioxidant activities during bovine milk fermentation.

    PubMed

    Solieri, Lisa; Rutella, Giuseppina Sefora; Tagliazucchi, Davide

    2015-10-01

    This study aimed at evaluating non-starter lactobacilli (NSLAB) isolated from cheeses for their proteolytic activity and capability to produce fermented milk enriched in angiotensin-converting enzyme (ACE)-inhibitory and antioxidant peptides. Preliminarily, 34 NSLAB from Parmigiano Reggiano (PR) and 5 from Pecorino Siciliano cheeses were screened based on their capacity to hydrolyze milk proteins. Two NSLAB strains from PR, Lactobacillus casei PRA205 and Lactobacillus rhamnosus PRA331, showed the most proteolytic phenotype and were positively selected to inoculate sterile cow milk. The fermentation process was monitored by measuring viable cell population, kinetic of acidification, consumption of lactose, and synthesis of lactic acid. Milk fermented with Lb. casei PRA205 exhibited higher radical scavenging (1184.83 ± 40.28 mmol/L trolox equivalents) and stronger ACE-inhibitory (IC50 = 54.57 μg/mL) activities than milk fermented with Lb. rhamnosus PRA331 (939.22 ± 82.68 mmol/L trolox equivalents; IC50 = 212.38 μg/mL). Similarly, Lb. casei PRA205 showed the highest production of ACE-inhibitory peptides Val-Pro-Pro and Ile-Pro-Pro, which reached concentrations of 32.88 and 7.52 mg/L after 87 and 96 h of milk fermentation, respectively. This evidence supports Lb. casei PRA205, previously demonstrated to possess characteristics compatible with probiotic properties, as a promising functional culture able to promote health benefits in dairy foods. PMID:26187835

  5. In vivo kinetics of indoxyl sulfate in humans and its renal interaction with angiotensin-converting enzyme inhibitor quinapril in rats.

    PubMed

    Fujita, Tomoe; Ishihara, Kazuhiko; Yasuda, Shuichi; Nakamura, Tomomi; Maeda, Mika; Kobayashi, Mami; Sahashi, Kunihiko; Ikeda, Yasuhiko; Kumagai, Yuji; Majima, Masataka

    2012-06-01

    Indoxyl sulfate (IS) is an organic anion uremic toxin that accumulates in patients with chronic kidney disease (CKD). The aims of this study were to examine the kinetic profiles of IS in humans at a steady state after multiple doses of L-Trp, a precursor of IS, and the in vivo interaction of IS with the angiotensin-converting enzyme inhibitor quinapril, whose active metabolite is a substrate of organic anion transporter 3 (OAT3) in rats. First, 12-h kinetics after single doses of Trp (2, 4, and 8 g) were examined in two healthy volunteers. Second, 24-h kinetics after a single dose of 2 g of Trp was studied in six volunteers. Third, 35-h kinetics after single and multiple doses of 2 g of Trp were examined in five volunteers. In anesthetized rats, quinapril or probenecid, an inhibitor of OATs, was given intravenously before IS, and blood and urine samples were taken until 90 min. Trp and IS concentrations were determined by high-performance liquid chromatography. Ultrafiltration was used to measure serum unbound IS concentrations. Renal tubular secretion of IS accounted for more than 90% of its renal clearance in the steady state of serum IS levels after multiple doses in humans. In animals, the serum area under the curve of IS increased in conjunction with a decrease in renal clearances after coadministration of IS with quinapril or probenecid. It is concluded that quinapril may inhibit the urine excretion of IS via OAT3-mediated renal tubular transport in patients with CKD. PMID:22389425

  6. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock in Patients with Severe Systolic Heart Failure (From the GRADE Multicenter Study)

    PubMed Central

    AlJaroudi, Wael A.; Refaat, Marwan M.; Habib, Robert H.; Al-Shaar, Laila; Singh, Madhurmeet; Gutmann, Rebecca; Bloom, Heather L.; Dudley, Samuel C.; Ellinor, Patrick T.; Saba, Samir F.; Shalaby, Alaa A.; Weiss, Raul; McNamara, Dennis M.; Halder, Indrani; London, Barry

    2015-01-01

    Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. While angiotensin converting enzyme inhibitors (ACEi) and receptor blockers (ARB) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events (GRADE) study which included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no ACEi/ARB was physician dependent. There were 1509 patients (mean age [SD] 63[12] years, 80% male, mean [SD] EF 21% [6%]) with 1213 (80%) on ACEi/ARB, and 296 (20%) not on ACEi/ARB. We identified 574 propensity matched patients (287 in each group). After a mean (SD) of 2.5(1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3 and 5 years in the matched cohort (7.7%, 16.7%, 18.5% vs. 13.2%, 27.5%, and 32.0% (RR= 0.61[0.43–0.86], p =0.005). Among patients with GFR >60 and 30–60 ml/min/1.73m2, those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock as compared to those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73m2, and with neutral effect among those GFR <30 ml/min/1.73m2. PMID:25682436

  7. Fast high-throughput screening of angiotensin-converting enzyme insertion/deletion polymorphism by variable programmed electric field strength-based microchip electrophoresis.

    PubMed

    Sun, Yucheng; Kim, Su-Kang; Zhang, Peng; Woo, Nain; Kang, Seong Ho

    2016-08-15

    An insertion (I)/deletion (D) polymorphism in angiotensin-converting enzyme (ACE) has been associated with susceptibility to various diseases in numerous studies. Traditionally, slab gel electrophoresis (SGE) after polymerase chain reaction (PCR) has been used to genotype this ACE I/D polymorphism. In this study, single- and multi-channel microchip electrophoresis (ME) methods based on variable programmed electric field strength (PEFS) (i.e., low constant, high constant, (+)/(-) staircase, and random electric field strengths) were developed for fast high-throughput screening of this specific polymorphism. The optimum PEFS conditions were set as 470V/cm for 0-9s, 129V/cm for 9-13s, 470V/cm for 13-13.9s, 294V/cm for 13.9-16s, and 470V/cm for 16-20s for single-channel ME, and 615V/cm for 0-22.5s, 231V/cm for 22.5-28.5s, and 615V/cm for 28.5-40s for multi-channel ME, respectively. In the multi-channel PEFS-ME, target ACE I/D polymorphism DNA fragments (D=190bp and I=490bp) were identified within 25s without loss of resolving power, which was ∼300 times faster than conventional SGE. In addition, PCR products of the ACE gene from human blood samples were detected after only 10 cycles by multi-channel PEFS-ME, but not by SGE. This parallel detection multichannel-based PEFS-ME method offers a powerful tool for fast high-throughput ACE I/D polymorphism screening with high sensitivity. PMID:27322633

  8. Serum angiotensin-converting enzyme 2 is an independent risk factor for in-hospital mortality following open surgical repair of ruptured abdominal aortic aneurysm

    PubMed Central

    Nie, Wanpin; Wang, Yan; Yao, Kai; Wang, Zheng; Wu, Hao

    2016-01-01

    Open surgical repair (OSR) is a conventional surgical method used in the repair a ruptured abdominal aortic aneurysm (AAA); however, OSR results in high perioperative mortality rates. The level of serum angiotensin-converting enzyme 2 (ACE2) has been reported to be an independent risk factor for postoperative in-hospital mortality following major cardiopulmonary surgery. In the present study, the association of serum ACE2 levels with postoperative in-hospital mortality was investigated in patients undergoing OSR for ruptured AAA. The study enrolled 84 consecutive patients underwent OSR for ruptured AAA and were subsequently treated in the intensive care unit. Patients who succumbed postoperatively during hospitalization were defined as non-survivors. Serum ACE2 levels were measured in all patients prior to and following the surgery using ELISA kits. The results indicated that non-survivors showed significantly lower mean preoperative and postoperative serum ACE2 levels when compared with those in survivors. Multivariate logistic regression analysis also showed that, subsequent to adjusting for potential confounders, the serum ACE2 level on preoperative day 1 showed a significant negative association with the postoperative in-hospital mortality. This was confirmed by multivariate hazard ratio analysis, which showed that, subsequent to adjusting for the various potential confounders, the risk of postoperative in-hospital mortality remained significantly higher in the two lowest serum ACE2 level quartiles compared with that in the highest quartile on preoperative day 1. In conclusion, the present study provided the first evidence supporting that the serum ACE2 level is an independent risk factor for the in-hospital mortality following OSR for ruptured AAA. Furthermore, low serum ACE2 levels on preoperative day 1 were found to be associated with increased postoperative in-hospital mortality. Therefore, the serum ACE2 level on preoperative day 1 may be a potential

  9. Screening assay of angiotensin-converting enzyme inhibitory activity from complex natural colourants and foods using high-throughput LC-MS/MS.

    PubMed

    Inoue, Koichi; Kitade, Marie; Hino, Tomoaki; Oka, Hisao

    2011-06-15

    Inhibition of angiotensin-converting enzyme (ACE) by various foods decreases the blood pressure. ACE inhibitors derived from natural components may be of therapeutic value in preventive medicine. In this study, we report a novel screening assay of ACE inhibitors from complex natural colourants and foods that employ solid phase extraction (SPE), high-throughput liquid chromatography (LC) separation, and stable isotope dilution electrospray tandem mass spectrometry (SID-ESI-MS/MS). When a target sample was subjected to N-Hippuryl-His-Leu (HHL) and ACE in phosphate buffer (pH 7.4), generated hippuric acid (HA) was extracted by SPE. LC/SID-ESI-MS/MS detection of HA allowed us to accurately identify the effects of complex substances such natural colourants and foods that inhibit the ACE of HHL. The major HA and HA-d5 fragment ions at m/z 180→105 and 185→110 in the multiple reaction monitoring (MRM) mode can quantify levels that are lower than other methods. The LC/SID-ESI-MS/MS method described here is a rapid, selective, sensitive, and highly reproducible method for the determination of HA in various samples. Based on the assay developed, all samples such as natural colourants, infant formula, soy paste, ketchup, mayonnaise, wheat flour, orange juice, supplement drink, tea, and coffee could be accurately measured for ACE inhibition in various matrices. High-throughput LC/SID-ESI-MS/MS assay has no limitations in the evaluation of inhibition activity in various natural samples such as colour, high-matrix, and processed foods. PMID:25213976

  10. A Virus-Binding Hot Spot on Human Angiotensin-Converting Enzyme 2 Is Critical for Binding of Two Different Coronaviruses▿

    PubMed Central

    Wu, Kailang; Chen, Lang; Peng, Guiqing; Zhou, Wenbo; Pennell, Christopher A.; Mansky, Louis M.; Geraghty, Robert J.; Li, Fang

    2011-01-01

    How viruses evolve to select their receptor proteins for host cell entry is puzzling. We recently determined the crystal structures of NL63 coronavirus (NL63-CoV) and SARS coronavirus (SARS-CoV) receptor-binding domains (RBDs), each complexed with their common receptor, human angiotensin-converting enzyme 2 (hACE2), and proposed the existence of a virus-binding hot spot on hACE2. Here we investigated the function of this hypothetical hot spot using structure-guided biochemical and functional assays. The hot spot consists of a salt bridge surrounded by hydrophobic tunnel walls. Mutations that disturb the hot spot structure have significant effects on virus/receptor interactions, revealing critical energy contributions from the hot spot structure. The tunnel structure at the NL63-CoV/hACE2 interface is more compact than that at the SARS-CoV/hACE2 interface, and hence RBD/hACE2 binding affinities are decreased either by NL63-CoV mutations decreasing the tunnel space or by SARS-CoV mutations increasing the tunnel space. Furthermore, NL63-CoV RBD inhibits hACE2-dependent transduction by SARS-CoV spike protein, a successful application of the hot spot theory that has the potential to become a new antiviral strategy against SARS-CoV infections. These results suggest that the structural features of the hot spot on hACE2 were among the driving forces for the convergent evolution of NL63-CoV and SARS-CoV. PMID:21411533

  11. Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

    PubMed

    Wang, Wang; McKinnie, Shaun M K; Farhan, Maikel; Paul, Manish; McDonald, Tyler; McLean, Brent; Llorens-Cortes, Catherine; Hazra, Saugata; Murray, Allan G; Vederas, John C; Oudit, Gavin Y

    2016-08-01

    Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. PMID:27217402

  12. Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea and creatinine variations in patients with dementia due to Alzheimer disease

    PubMed Central

    Berretta, Juliana Marília; Suchi Chen, Elizabeth; Cardoso Smith, Marilia; Ferreira Bertolucci, Paulo Henrique

    2016-01-01

    Background: Renal function declines according to age and vascular risk factors, whereas few data are available regarding genetically-mediated effects of anti-hypertensives over renal function. Objective: To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Methods: Consecutive outpatients older than 60 years-old with AD and no history of kidney transplant or dialytic therapy were recruited for prospective correlations regarding variations in fasting blood levels of urea and creatinine in one year, considering ACE genotypes of rs1800764 and rs4291 and their respective haplotypes, and treatment with ACEis along with blood pressure variations. Results: For 190 patients, 152 had arterial hypertension, and 122 used ACEis. Minor allele frequencies were 0.492 for rs1800764-C and 0.337 for rs4291-T, both in Hardy-Weinberg equilibrium. There were no overall significant yearly variations in levels of urea and creatinine, but their concurrent variations were positively correlated (ρ <0.0001). Each A allele of rs4291 led to an yearly urea increase of 3,074 mg/dL, and an yearly creatinine increase of 0.044 mg/dL, while the use of ACEis was protective regarding creatinine variations. The use of ACEis was also protective for carriers of rs1800764-CT/rs4291-AA, while carriers of rs1800764-CT/rs4291-AT had steeper reductions in creatinine levels, particularly when they were treated with ACEis. Conclusions: Effects of ACEis over creatinine variations are genetically mediated and independent of blood pressure variations in older people with AD. PMID:27546928

  13. Angiotensin-converting enzyme gene polymorphism (insertion/deletion) and liver fibrosis in Turkish patients from the western Black Sea region, Turkey.

    PubMed

    Turhan, N K; Ilikhan, S Uygun; Hamamcioglu, A C; Ustundag, Y; Dursun, A; Kokturk, F

    2015-01-01

    Chronic viral hepatitis B, chronic viral hepatitis C, non-alcoholic steatohepatitis, alcoholic liver disease, autoimmune hepatitis, primary biliary cirrhosis, and secondary biliary cirrhosis are important health issues worldwide. While an association between angiotensin-converting enzyme gene insertion/deletion (ACE gene I/D) polymorphism and liver fibrosis has been demonstrated in rat studies, the results of clinical studies area have been contradictory. The aim of this study was to assess the possible association between ACE gene I/D polymorphism and liver fibrosis in a large group of Turkish patients from the western Black Sea region. In 418 patients with different etiologies, ACE gene I/D polymorphism and serum ACE levels were investigated. The distribution of the "DD", "ID", "II" genotypes of the ACE gene were 32.5, 48.8, and 18.7% in the mild to moderate fibrosis group (N = 246, F:1-3 according to Ishak's score) and 39.0, 44.2, and 16.9% in the advanced fibrosis group (N = 172, F:4-6 according to Ishak's score). A significant correlation between serum ACE levels and ACE gene alleles was identified (P < 0.001): serum ACE levels of patients with D alleles were higher than those of patients with I alleles [44 (min 7-max 101) versus 29 (min 7-max 96)]. Patients with advanced fibrosis were also found to be older than those with mild to moderate fibrosis (P < 0.001). No significant association was noted between the patient gender and fibrosis severity. We conclude that ACE I/D polymorphism is not associated with the degree of liver fibrosis. PMID:26681055

  14. Preparation of bioactive peptides with high angiotensin converting enzyme inhibitory activity from winged bean [Psophocarpus tetragonolobus (L.) DC.] seed.

    PubMed

    Wan Mohtar, Wan Abd Al-Qadr Imad; Hamid, Azizah Abdul; Abd-Aziz, Suraini; Muhamad, Sharifah Kharidah Syed; Saari, Nazamid

    2014-12-01

    Winged bean [Psophocarpus tetragonolobus (L.) DC.] seed is a potential underexploited source of vegetable protein due to its high protein content. In the present work, undefatted and defatted winged bean seed hydrolysates, designated as UWBSH and DWBSH, respectively were produced separately by four proteolytic enzymes namely Flavourzyme, Alcalase, Bromelain, and Papain using pH-stat method in a batch reactor. Enzymatic hydrolysis was carried out over a period of 0.5 to 5 h. UWBSH and DWBSH produced were tested for their ACE inhibitory activity in relation to the hydrolysis time and degree of hydrolysis (DH). Maximum ACE inhibitory activity, both for UWBSH and DWBSH, were observed during 3 to 5 h of hydrolysis. Both, UWBSH (DH 91.84 %), and DWSBH (DH 18.72 %), produced by Papain at 5 h hydrolysis, exhibited exceptionally high ACE inhibitory activity with IC50 value 0.064 and 0.249 mg mL(-1), respectively. Besides, papain-produced UWBSH and DWBSH were further fractionated into three fractions based on molecular weight (UWBSH-I, <10 kDa; UWBSH-II, <5 kDa; UWBSH-III, <2 kDa) and (DWBSH-I, <10 kDa; DWBSH-II, <5 kDa; DWBSH-III, <2 kDa). UWBSH-III revealed the highest ACE inhibitory activity (IC50 0.003 mg mL(-1)) compared with DWBSH-III (IC50 0.130 mg mL(-1)). The results of the present investigation revealed that winged bean seed hydrolysates can be explored as a potential source of ACE inhibitory peptides suggesting their uses for physiological benefits as well as for other functional food applications. PMID:25477632

  15. Endopeptidase 3.4.24.11 converts N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide into a potent inhibitor of angiotensin-converting enzyme.

    PubMed Central

    Williams, C H; Yamamoto, T; Walsh, D M; Allsop, D

    1993-01-01

    It was reported recently that N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide (CPP-A-A-F-pAB), an inhibitor of endopeptidase 3.4.24.15 (E-24.15), also inhibits angiotensin-converting enzyme (ACE) from rabbit lung. We have found that this compound is without effect on ACE purified from pig kidney, at a concentration some 1000-fold greater than the Ki reported for inhibition of the enzyme from lung. However, preincubation of CPP-A-A-F-pAB with neutral endopeptidase 3.4.24.11 (E-24.11) does result in potent inhibitory effects on ACE. We have shown this to be due to formation of a fragment, CPP-A-A, the structure of which is closely related to ACE inhibitors such as enalaprilat. CPP-A-A was found to be a potent inhibitor of pig ACE. Under the conditions used it had an IC50 value of 1.6 x 10(-8) M, compared with the value obtained for captopril of 7.5 x 10(-10) M. These results have important implications for studies of E-24.15 when using CPP-A-A-F-pAB in vivo or in crude tissue extracts where E-24.11 might also be present. PMID:8379924

  16. Kinetics of the inhibition of renin and angiotensin I-converting enzyme by cod (Gadus morhua) protein hydrolysates and their antihypertensive effects in spontaneously hypertensive rats

    PubMed Central

    Girgih, Abraham T.; Nwachukwu, Ifeanyi D.; Hasan, Fida; Fagbemi, Tayo N.; Gill, Tom; Aluko, Rotimi E.

    2015-01-01

    Background Cod muscle has a balanced protein profile that contains potentially bioactive amino acid sequences. However, there is limited information on release of these peptides from the parent proteins and their ability to modulate mammalian blood pressure. Objective The aim of this study was to generate cod antihypertensive peptides with potent in vitro inhibitory effects against angiotensin-converting enzyme (ACE) and renin. The most active peptides were then tested for systolic blood pressure (SBP)-reducing ability in spontaneously hypertensive rats (SHRs). Design Cod protein hydrolysate (CPH) was produced by subjecting the muscle proteins to proteolysis first by pepsin and followed by trypsin+chymotrypsin combination. In order to enhance peptide activity, the CPH was subjected to reverse-phase (RP)-HPLC separation to yield four fractions (CF1, CF2, CF3, and CF4). The CPH and RP-HPLC fractions were each tested at 1 mg/mL for ability to inhibit in vitro ACE and renin activities. CPH and the most active RP-HPLC fraction (CF3) were then used for enzyme inhibition kinetics assays followed by oral administration (200 and 30 mg/kg body weight for CPH and CF3, respectively) to SHRs and SBP measurements within 24 h. Results The CPH, CF3, and CF4 had similar ACE-inhibitory activities of 84, 85, and 87%, which were significantly (p<0.05) higher than the values for CF1 (69%) and CF2 (79%). Conversely, the CF3 had the highest (63%) renin-inhibitory activity (p<0.05) when compared to CPH (43%), CF1 (15%), and CF4 (44%). CPH and CF3 exhibited uncompetitive mode of ACE inhibition, whereas renin inhibition was non-competitive. Even at a 6.7-fold lower dosage, the CF3 significantly (p<0.05) reduced SBP (maximum −40.0 mmHg) better than CPH (maximum −19.1 mmHg). Conclusions RP-HPLC fractionation led to enhanced antihypertensive effects of cod peptides, which may be due to a stronger renin-inhibitory activity. PMID:26715103

  17. Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function

    PubMed Central

    Becerra-Tomás, Nerea; Guasch-Ferré, Marta; Quilez, Joan; Merino, Jordi; Ferré, Raimon; Díaz-López, Andrés; Bulló, Mònica; Hernández-Alonso, Pablo; Palau-Galindo, Antoni; Salas-Salvadó, Jordi

    2015-01-01

    Abstract Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function. A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained. After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and −0.63 mm Hg in diastolic BP for CB; −0.71 mm Hg in systolic BP and −1.08 mm Hg in diastolic BP for LSB; and −0.75 mm Hg in systolic BP and −2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters. Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the

  18. Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura.

    PubMed

    Paterna, S; Di Pasquale, P; D'Angelo, A; Seidita, G; Tuttolomondo, A; Cardinale, A; Maniscalchi, T; Follone, G; Giubilato, A; Tarantello, M; Licata, G

    2000-01-01

    Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 +/- 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1. 44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies

  19. Plasma Kallikrein and Angiotensin I-converting enzyme N- and C-terminal domain activities are modulated by the insertion/deletion polymorphism.

    PubMed

    Almeida, S S; Barros, C C; Moraes, M R; Russo, F J; Haro, A S; Rosa, T S; Alves, M F; Pesquero, J B; Carmona, A K; Bacurau, R F P; Araújo, R C

    2010-04-01

    Angiotensin I-converting enzyme (ACE) is recognized as one of the main effector molecules involved in blood pressure regulation. In the last few years some polymorphisms of ACE such as the insertion/deletion (I/D) polymorphism have been described, but their physiologic relevance is poorly understood. In addition, few studies investigated if the specific activity of ACE domain is related to the I/D polymorphism and if it can affect other systems. The aim of this study was to establish a biochemical and functional characterization of the I/D polymorphism and correlate this with the corresponding ACE activity. For this purpose, 119 male brazilian army recruits were genotyped and their ACE plasma activities evaluated from the C- and N-terminal catalytic domains using fluorescence resonance energy transfer (FRET) peptides, specific for the C-domain (Abz-LFK(Dnp)OH), N-domain (Abz-SDK(Dnp)P-OH) and both C- and N-domains (Abz-FRK(Dnp)P-OH). Plasma kallikrein activity was measured using Z-Phe-Arg-AMC as substrate and inhibited by selective plasma kallikrein inhibitor (PKSI). Some physiological parameters previously described related to the I/D polymorphism such as handgrip strength, blood pressure, heart rate and BMI were also evaluated. The genotype distribution was II n=27, ID n=64 and DD n=28. Total plasma ACE activity of both domains in II individuals was significantly lower in comparison to ID and DD. This pattern was also observed for C- and N-domain activities. Difference between ID and DD subjects was observed only with the N-domain specific substrate. Blood pressure, heart rate, handgrip strength and BMI were similar among the genotypes. This polymorphism also affected the plasma kallikrein activity and DD group presents high activity level. Thus, our data demonstrate that the I/D ACE polymorphism affects differently both ACE domains without effects on handgrip strength. Moreover, this polymorphism influences the kallikrein-kinin system of normotensive individuals

  20. Angiotensin converting enzyme-regulated, noncholinergic sympathoadrenal catecholamine release mediates the cardiovascular actions of human ‘new pressor protein’ related to coagulation beta-factor XIIa

    PubMed Central

    Papageorgiou, Peter C; Simos, Demetrios; Boomsma, Frans; Rojkjaer, Rasmus; Osmond, Daniel H

    2009-01-01

    BACKGROUND: Human ‘new pressor protein’ (NPP), related to coagulation beta-factor XIIa (β-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/β-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/β-FXIIa contributed to their hypertension. OBJECTIVE: To investigate the mechanism of action of NPP/β-FXIIa. METHODS: Hemodynamic and sympathoadrenal responses to NPP (20 µL plasma equivalent/rat) or coagulation β-FXIIa (300 ng/kg intravenously) were measured in rats treated with pentolinium (ganglion blockade [+GB]) and/or captopril (+CAP; angiotensin converting enzyme [ACE] inhibition). RESULTS: In controls not receiving GB or CAP (–GB–CAP), NPP/β-FXIIa raised plasma epinephrine (E) sixfold, SBP/DBP by 14/8 mmHg and HR by 15 beats/min. With blockade of the cholinergic pathway to the sympathoadrenal system (+GB), basal E, norepinephrine (NE), SBP, DBP and HR all dropped. However NPP/β-FXIIa remained capable of raising E 20-fold, NE fourfold, SBP/DBP by 27/11 mmHg and HR by 20 beats/min, suggesting that it acted through a ‘noncholinergic’ mechanism. With +CAP alone, NPP/β-FXIIa raised plasma E 18-fold, NE threefold, SBP/DBP by 29/8 mmHg and HR by 73 beats/min, implicating an ACE-regulated ‘peptidergic’ mechanism. Combining +GB with +CAP potentiated NPP/β-FXIIa actions further by raising E 50-fold, NE sevenfold, SBP/DBP by 55/20 mmHg and HR by 87 beats/min, strengthening the efficacy of this alternate pathway. CONCLUSIONS: The cardiovascular effects of NPP/β-FXIIa are considerably mediated by a noncholinergic (peptidergic) ACE-regulated mechanism for sympathoadrenal catecholamine release that is enhanced by +GB and/or +CAP. Under inflammatory procoagulant conditions, endogenously produced

  1. Novel angiotensin I-converting enzyme inhibitory peptides derived from an edible mushroom, Pleurotus cystidiosus O.K. Miller identified by LC-MS/MS

    PubMed Central

    2013-01-01

    Background Angiotensin I-converting enzyme (ACE) inhibitors have been reported to reduce mortality in patients with hypertension. Compared to chemosynthetic drugs, ACE inhibitors derived from natural sources such as food proteins are believed to be safer for consumption and to have fewer adverse effects. Some edible mushrooms have been reported to significantly reduce blood pressure after oral administration. In addition, mushrooms are known to be rich in protein content. This makes them a potential source of ACE inhibitory peptides. Hence, the objective of the current study was to isolate and characterise ACE inhibitory peptides from an edible mushroom, Pleurotus cystidiosus. Methods ACE inhibitory proteins were isolated from P. cystidiosus based on the bioassay guided purification steps, i.e. ammonium sulphate precipitation, reverse phase high performance liquid chromatography and size exclusion chromatography. Active fraction was then analysed by LC-MS/MS and potential ACE inhibitory peptides identified were chemically synthesized. Effect of in vitro gastrointestinal digestions on the ACE inhibitory activity of the peptides and their inhibition patterns were evaluated. Results Two potential ACE inhibitory peptides, AHEPVK and GPSMR were identified from P. cystidiosus with molecular masses of 679.53 and 546.36 Da, respectively. Both peptides exhibited potentially high ACE inhibitory activity with IC50 values of 62.8 and 277.5 μM, respectively. SEC chromatograms and BIOPEP analysis of these peptides revealed that the peptide sequence of the hexapeptide, AHEPVK, was stable throughout gastrointestinal digestion. The pentapeptide, GPSMR, was hydrolysed after digestion and it was predicted to release a dipeptide ACE inhibitor, GP, from its precursor. The Lineweaver-Burk plot of AHEPVK showed that this potent and stable ACE inhibitor has a competitive inhibitory effect against ACE. Conclusion The present study indicated that the peptides from P. cystidiosus could be

  2. Angiotensin I-Converting-Enzyme-Inhibitory and Antibacterial Peptides from Lactobacillus helveticus PR4 Proteinase-Hydrolyzed Caseins of Milk from Six Species

    PubMed Central

    Minervini, F.; Algaron, F.; Rizzello, C. G.; Fox, P. F.; Monnet, V.; Gobbetti, M.

    2003-01-01

    Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine αS1-casein (αS1-CN) 24-47 fragment (f24-47), f169-193, and β-CN f58-76; ovine αS1-CN f1-6 and αS2-CN f182-185 and f186-188; caprine β-CN f58-65 and αS2-CN f182-187; buffalo β-CN f58-66; and a mixture of three tripeptides originating from human β-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 μg/ml (100 μmol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC50) of some of the crude peptide fractions was very low (16 to 100 μg/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC50s were confirmed. An antibacterial peptide corresponding to β-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 μg/ml. Once generated, the bioactive peptides were resistant to further

  3. Omapatrilat, an Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibitor, Attenuates Early Atherosclerosis in Diabetic and in Nondiabetic Low-Density Lipoprotein Receptor–Deficient Mice

    PubMed Central

    Levy, Zohar; Dvir, Ayana; Shaish, Aviv; Trestman, Svetlana; Cohen, Hofit; Levkovietz, Hana; Rhachmani, Rita; Harats, Dror

    2003-01-01

    Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor– deficient mice despite effective inhibition of the reninangiotensin- aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor–deficient mice. LDL receptor–deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilattreated nondiabetic mice was 9357 ± 7293 μm2, versus 71977 ± 34610 μm2 in the nontreated mice (P = .002). In the diabetic animals, the plaque area was 8887 ± 5386 μm2 and 23220 ± 10400 μm2, respectively for treated and nontreated mice (P = .001). Plasma lipids were increased by omapatrilat: Meanplasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 ± 6.00 mmol/L, versus 33.12 ± 7.64 mmol/L in the nontreated animals (P = .008). The corresponding combined mean values of triglycerides were 4.83 ± 1.93 versus 3.00 ± 1.26 mmol/L (P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor–deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial

  4. Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.

    PubMed

    Galinsky, D; Tysoe, C; Brayne, C E; Easton, D F; Huppert, F A; Dening, T R; Paykel, E S; Rubinsztein, D C

    1997-03-21

    Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study

  5. Short communication: Effect of casein haplotype on angiotensin-converting enzyme inhibitory and antioxidant capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes.

    PubMed

    Perna, Annamaria; Simonetti, Amalia; Gambacorta, Emilio

    2016-09-01

    The aim of this work was to investigate the effect of casein haplotype (αS1, β, and κ) on antioxidative and angiotensin-converting enzyme (ACE) inhibitory capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes. The antioxidant capacity was measured using 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid and ferric-reducing antioxidant power assays, whereas ACE inhibition was determined by ACE-inhibitory assay. The ACE-inhibitory and antioxidant capacities of milk casein increased during in vitro gastrointestinal digestion. Casein haplotype significantly influenced the antioxidative and ACE-inhibitory capacities of digested casein. In particular, BB-A(2)A(1)-AA casein and BB-A(1)A(1)-AA casein showed the highest ACE-inhibitory capacity, BB-A(2)A(2)-AA casein showed the highest antioxidant capacity, whereas BB-A(2)A(2)-BB casein showed the lowest biological capacity. To date, few studies have been done on the effect of casein haplotype on biological capacity of milk casein, thus the present study sets the basis for a new knowledge that could lead to the production of milk with better nutraceutical properties. PMID:27289148

  6. Diagnostic use of angiotensin converting enzyme (ACE)-inhibited renal scintigraphy in the identification of selective renal artery stenosis in the presence of multiple renal arteries: A case report

    SciTech Connect

    Morton, K.A.; Rose, S.C.; Haakenstad, A.O.; Handy, J.E.; Scuderi, A.J.; Datz, F.L. )

    1990-11-01

    In patients with renovascular hypertension, it is unknown whether the angiotensin converting enzyme-(ACE) inhibited renal scan will identify stenosis of a segmental branch of a single renal artery or of an accessory artery where multiple renal arteries are present. Since multiple renal arteries may be present in approximately 25% of all individuals, it will be important to establish whether the ACE-inhibited renal scan is useful in this population. We report a case of stenosis involving a renal artery in a patient with multiple renal arteries, successfully identified by ACE-inhibited renal scintigraphy.

  7. An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK).

    PubMed Central

    Kiru, Gaia; Bicknell, Colin; Falaschetti, Emanuela; Powell, Janet; Poulter, Neil

    2016-01-01

    BACKGROUND Although data are inconsistent, angiotensin-converting enzyme inhibitors (ACE-Is) have been associated with a reduced incidence of abdominal aortic aneurysm (AAA) rupture in analysis of administrative databases. OBJECTIVES (1) To investigate whether or not the ACE-I perindopril (Coversyl arginine, Servier) reduces small AAA growth rate and (2) to evaluate blood pressure (BP)-independent effects of perindopril on small AAA growth and to compare the repeatability of measurement of internal and external aneurysm diameters. DESIGN A three-arm, multicentre, single-blind, randomised placebo-controlled trial. SETTING Fourteen hospitals in England. PARTICIPANTS Men or women aged ≥ 55 years with an AAA of 3.0-5.4 cm in diameter by internal or external measurement according to ultrasonography and who met the trial eligibility criteria. INTERVENTIONS Patients were randomised to receive 10 mg of perindopril arginine daily, 5 mg of the calcium channel blocker amlodipine daily or placebo daily. MAIN OUTCOME MEASURES The primary outcome was AAA diameter growth using external measurements in the longitudinal plane, which in-trial studies suggested was the preferred measure. Secondary outcome measures included AAA rupture, AAA repair, modelling of the time taken for the AAA to reach the threshold for intervention (5.5 cm) or referral for surgery, tolerance of study medication (measured by compliance, adverse events and quality of life) and a comparison of the repeatability of measures of internal and external AAA diameter. Patients were followed up every 3-6 months over 2 years. RESULTS In total, 227 patients were recruited and randomised into the three groups, which were generally well matched at baseline. Multilevel modelling was used to determine the maximum likelihood estimates for AAA diameter growth. No significant differences in the estimates of annual growth were apparent [1.68 (standard error 0.02) mm, 1.77 (0.02) mm and 1.81 (0.02) mm in the

  8. Pulmonary Embolism in a Sarcoidosis Patient Double Heterozygous for Methylenetetrahydrofolate Reductase Gene Polymorphisms and Factor V Leiden and Homozygous for the D-Allele of Angiotensin Converting Enzyme Gene

    PubMed Central

    El-Majzoub, Nadim; Mahfouz, Rami; Kanj, Nadim

    2015-01-01

    Sarcoidosis is a multisystem granulomatous disease of unknown etiology and pathogenesis. It presents in patients younger than 40 years of age. The lungs are the most commonly affected organ. Till the present day, there is no single specific test that will accurately diagnose sarcoidosis; as a result, the diagnosis of sarcoidosis relies on a combination of clinical, radiologic, and histologic findings. Patients with sarcoidosis have been found to have an increased risk of pulmonary embolism compared to the normal population. MTHFR and factor V Leiden mutations have been reported to increase the risk of thrombosis in patients. We hereby present a case of a middle aged man with sarcoidosis who developed a right main pulmonary embolism and was found to be double heterozygous for methylenetetrahydrofolate reductase gene polymorphisms and factor V Leiden and homozygous for the D-allele of the angiotensin converting enzyme gene. PMID:26347783

  9. Data of the natural and pharmaceutical angiotensin-converting enzyme inhibitor isoleucine-tryptophan as a potent blocker of matrix metalloproteinase-2 expression in rat aorta.

    PubMed

    Kopaliani, Irakli; Martin, Melanie; Zatschler, Birgit; Müller, Bianca; Deussen, Andreas

    2016-09-01

    The present data are related to the research article entitled "Whey peptide isoleucine-tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta" [1]. Here we present data on removal of endothelium from aorta, endothelium dependent aortic relaxation and inhibition of expression of pro-MMP2 by di-peptide isoleucine-tryptophan (IW). Experiments were performed in rat aortic endothelial cells (EC) and smooth muscle cells (SMC) in vitro, along with isolated rat aorta ex vivo. The cells and isolated aorta were stimulated with angiotensin II (ANGII) or angiotensin I (ANGI). ACE activity was inhibited by treatment with either IW or captopril (CA). Losartan was used as a blocker of angiotensin type-1 receptor. IW inhibited MMP2 protein expression induced with ANGI in a dose-dependent manner. IW was effective both in ECs and SMCs, as well as in isolated aorta. Similarly, captopril (CA) inhibited ANGI-induced MMP2 protein expression in both in vitro and ex vivo. Neither IW nor CA inhibited ANGII-induced MMP2 protein expression in contrast to losartan. The data also displays that removal of endothelium in isolated rat aorta abolished the endothelium-dependent relaxation induced with acetylcholine. However, SMC-dependent relaxation induced with sodium nitroprusside remained intact. Finally, the data provides histological evidence of selective removal of endothelial cells from aorta. PMID:27508250

  10. The Evaluation of Dipeptidyl Peptidase (DPP)-IV, α-Glucosidase and Angiotensin Converting Enzyme (ACE) Inhibitory Activities of Whey Proteins Hydrolyzed with Serine Protease Isolated from Asian Pumpkin (Cucurbita ficifolia).

    PubMed

    Konrad, Babij; Anna, Dąbrowska; Marek, Szołtysik; Marta, Pokora; Aleksandra, Zambrowicz; Józefa, Chrzanowska

    2014-01-01

    In the present study, whey protein concentrate (WPC-80) and β-lactoglobulin were hydrolyzed with a noncommercial serine protease isolated from Asian pumpkin (Cucurbita ficifolia). Hydrolysates were further fractionated by ultrafiltration using membranes with cut-offs equal 3 and 10 kDa. Peptide fractions of molecular weight lower than 3 and 3-10 kDa were further subjected to the RP-HPLC. Separated preparations were investigated for their potential as the natural inhibitors of dipeptidyl peptidase (DPP-IV), α-glucosidase and angiotensin converting enzyme (ACE). WPC-80 hydrolysate showed higher inhibitory activities against the three tested enzymes than β-lactoglobulin hydrolysate. Especially high biological activities were exhibited by peptide fractions of molecular weight lower than 3 kDa, with ACE IC50 <0.64 mg/mL and DPP-IV IC50 <0.55 mg/mL. This study suggests that peptides generated from whey proteins may support postprandial glycemia regulation and blood pressure maintenance, and could be used as functional food ingredients in the diet of patients with type 2 diabetes. PMID:25364320

  11. The influence of angiotensin converting enzyme and bradykinin receptor B2 gene variants on voluntary fluid intake and fluid balance in healthy men during moderate-intensity exercise in the heat.

    PubMed

    Yau, Adora M W; Moss, Andrew D; James, Lewis John; Gilmore, William; Ashworth, Jason J; Evans, Gethin H

    2015-02-01

    Angiotensin converting enzyme (ACE) and bradykinin receptor B2 (B2R) genetic variation may affect thirst because of effects on angiotensin II production and bradykinin activity, respectively. To examine this, 45 healthy Caucasian men completed 60 min of cycle exercise at 62% ± 5% peak oxygen uptake in a room heated to 30.5 ± 0.3 °C with ad libitum fluid intake. Blood samples were collected pre-, mid-, and immediately post-cycle. Fluid intake, body mass loss (BML), sweat loss (determined via changes in body mass and fluid intake), and thirst sensation were recorded. All participants were genotyped for the ACE insert fragment (I) and the B2R insert sequence (P). Participants were homozygous for the wild-type allele (WW or MM), heterozygous (WI or MP) or homozygous for the insert (II or PP). No differences between genotype groups were found in mean (±SD) voluntary fluid intake (WW: 613 ± 388, WI: 753 ± 385, II: 862 ± 421 mL, p = 0.31; MM: 599 ± 322, MP: 745 ± 374, PP: 870 ± 459 mL, p = 0.20), percentage BML or any other fluid balance variables for both the ACE and B2R genes, respectively. Mean thirst perception in the B2R PP group, however, was higher (p < 0.05) than both MM and MP at 30, 45, and 60 min. In conclusion, the results of this study suggest that voluntary fluid intake and fluid balance in healthy men performing 60 min of moderate-intensity exercise in the heat are not predominantly influenced by ACE or B2R genetic variation. PMID:25641172

  12. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury.

    PubMed

    Min, Fang; Gao, Fengying; Li, Qian; Liu, Zhenwei

    2015-04-01

    The aim of the present study was to evaluate the therapeutic effects of human umbilical cord mesenchymal stem cells (uMSCs) in the presence of angiotensin‑converting enzyme 2 gene (ACE2; ACE2‑uMSCs) on bleomycin (BLM)‑induced lung injury and pulmonary fibrosis in mice. A total of 100 male C57BL/6 mice were divided at random into five groups (n=20) as follows: Control group, BLM group, ACE2 group, uMSC group and ACE2‑uMSC group. At 7, 14 and 28 days post‑treatment, the following parameters were evaluated in lung tissue: Oxidation indexes [malondialedehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and oxidized glutathione (GSSG)]; fibrosis factors [tumor necrosis factor (TNF)‑α, interferon (IFN)‑γ and transforming growth factor (TGF)‑β]; inflammatory cytokines [Interleukin (IL)‑1, IL‑2, IL‑6 and IL‑10]; ACE2 gene expression; hydroxyproline and collagen type 1 messenger RNA (mRNA) concentration; as well as matrix metalloproteinase (MMPs; 2 and 9) and tissue inhibitor of metalloproteinase (TIMP)1‑4 expression. ACE2‑uMSC injection following bleomycin pretreatment significantly alleviated lung injury in mice. In addition, treatment with ACE2‑uMSCs demonstrated a stronger therapeutic effect than ACE2‑ or uMSC treatment alone, indicated by decreased expression of MDA, GSSG, TNF‑α, IFN‑γ, TGF‑β, IL‑1, IL‑2, IL‑6, collagen type 1 mRNA, MMPs and TIMPs as well as hydroxyproline concentration, and upregulation of SOD, GSH and ACE2 and IL‑10. In conclusion, the results of the present study demonstrated that ACE2 and uMSCs had a synergistic therapeutic effect on bleomycin‑induced acute lung injury. PMID:25435005

  13. Angiotensin converting enzyme inhibition reveals an important role for the renin system in the control of normal and high blood pressure in man.

    PubMed

    MacGregor, G A; Markandu, N D; Smith, S J; Sagnella, G A; Morton, J J

    1983-01-01

    Captopril, given for 5 days to normotensive healthy subjects caused a significant fall in blood pressure. The fall in mean supine blood pressure was greater on a low sodium diet (10 mmols/day) - 19.6% and was less on a high sodium diet (350 mmols/day) - 11% compared to the normal sodium intake (120 mmols/day) when the fall in blood pressure was 16.5%. Patients with essential hypertension who were studied on their normal diet had a similar fall in blood pressure for a given plasma renin activity. It seems likely that the predominant mechanism whereby captopril lowers blood pressure is through the inhibition of the formation of angiotensin II. If this is so, our results suggest that the renin system is an important control of both normal and high blood pressure when on a normal sodium intake. PMID:6315274

  14. In vitro investigations of the potential health benefits of Australian-grown faba beans (Vicia faba L.): chemopreventative capacity and inhibitory effects on the angiotensin-converting enzyme, α-glucosidase and lipase.

    PubMed

    Siah, Siem D; Konczak, Izabela; Agboola, Samson; Wood, Jennifer A; Blanchard, Christopher L

    2012-08-01

    The functional properties, including antioxidant and chemopreventative capacities as well as the inhibitory effects on angiotensin-converting enzyme (ACE), α-glucosidase and pancreatic lipase, of three Australian-grown faba bean genotypes (Nura, Rossa and TF(Ic*As)*483/13) were investigated using an array of in vitro assays. Chromatograms of on-line post column derivatisation assay coupled with HPLC revealed the existence of active phenolics (hump) in the coloured genotypes, which was lacking in the white-coloured breeding line, TF(Ic*As)*483/13. Roasting reduced the phenolic content, and diminished antioxidant activity by 10-40 % as measured by the reagent-based assays (diphenylpicrylhydrazyl, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) and oxygen radical absorbance capacity) in all genotypes. Cell culture-based antioxidant activity assay (cellular antioxidant activity) showed an increase of activity in the coloured genotypes after roasting. Faba bean extracts demonstrated cellular protection ability against H₂O₂-induced DNA damage (assessed using RAW264.7 cells), and inhibited the proliferation of all human cancer cell lines (BL13, AGS, Hep G2 and HT-29) evaluated. However, the effect of faba bean extracts on the non-transformed human cells (CCD-18Co) was negligible. Flow cytometric analyses showed that faba bean extracts successfully induced apoptosis of HL-60 (acute promyelocytic leukaemia) cells. The faba bean extracts also exhibited ACE, α-glucosidase and pancreatic lipase inhibitory activities. Overall, extracts from Nura (buff-coloured) and Rossa (red-coloured) were comparable, while TF(Ic*As)*483/13 (white-coloured) contained the lowest phenolic content and exhibited the least antioxidant and enzyme inhibition activities. These results are important to promote the utilisation of faba beans in human diets for various health benefits. PMID:22916808

  15. Effects of palladacycle complex on hematopoietic progenitor cells proliferation in vivo and in vitro and its relation with the inhibitory properties of this compound on the angiotensin-I converting enzyme activity.

    PubMed

    Caires, Antonio C F; Oliveira, Carlos R; Smith, Mickaela C M; Hemerly, Jefferson P; Juliano, Maria A; Bincoletto, Claudia

    2004-01-01

    In the present study, we introduce a new class of organometallic compound, the Biphosphinic Palladacycle Complex [Pd (C2, N-S(-)(dmpa)(dppf)] Cl (BPC), as an angiotensin-I converting-enzyme inhibitor (ACEI) with hematological regulation properties. When BPC was assayed as a competitive inhibitor over the hydrolysis of Abz-YRK (Dnp)-P-OH (Km = 7.0 microM), it showed a Kiapp = 0.2259 ng and a Ki value of 94.12 pg. Using murine long-term bone marrow cultures (LTBMCs) and clonal culture techniques, we also evaluated the capacity of this drug (1.18 microM) to module haematopoietic progenitor cells proliferation in vitro and in vivo. Our results demonstrated that BPC produces no toxicity to bone marrow cells, as determined by the unchanged cell number in the non-adherent layer at weeks 1, 2, and 8 and the increased number of adherent cells present in the BPC-treated LTBMCs. However, the proportion of CFU-Cs in the non-adherent cell layer was reduced at weeks 5, 6, 8, and 9. In vivo studies using the dose of 1 mg/kg of BPC, administered by subcutaneous route, presented similar result as those found in vitro, in the number of CFU-Cs. This latter finding may be explained by the inhibitory effects of this drug on the ACE activity, which probably result in increased levels of its substrate AcSDKP, a negative regulator of hematopoiesis. PMID:15658600

  16. Fast gradient high performance liquid chromatography method with UV detection for simultaneous determination of seven angiotensin converting enzyme inhibitors together with hydrochlorothiazide in pharmaceutical dosage forms and spiked human plasma and urine.

    PubMed

    Elsebaei, Fawzi; Zhu, Yan

    2011-07-15

    The development of a reversed phase liquid chromatographic method for the simultaneous determination of seven angiotensin converting enzyme (ACE) inhibitors; five drugs namely benazepril HCl (BZL), enalapril maleate (ENL), fosinopril sodium (FSP), lisinopril (LSP) and ramipril (RMP) and two metabolites captopril disulfide (CPD) and enalaprilat (ENT) together with hydrochlorothiazide (HCT) is described. The method can serve as a substitute for many published papers for the analysis of the targeted compounds with or without hydrochloothiazide in pharmaceutical formulations as well as in spiked human plasma and urine samples. The method utilizes a simple gradient procedure for the separation in a 11 min run time using acetonitrile aqueous ammonia buffer (pH 9) solution and an Extend RP-C18 (25 μm particle size, 4.6 mm×250 mm, Agilent) HPLC column. The effluent was monitored on a UV detector at 215 nm. The effect of pH, solvent strength and analysis time on the peak shape and quantification were carefully studied in order to optimize the method. Adopting the proposed procedure, the analytes produce well-shaped peaks with good linear relationship over the investigated concentration ranges. The limits of detection (LOD) and limits of quantification (LOQ) from standard drug solutions lie in the range of 17-64 and 56-212 ng mL(-1), respectively. Correlation coefficient values (r) higher than 0.997 were obtained for all the studied drugs in spiked human plasma and urine samples. The intra-day and inter-day precision of the method was evaluated with relative standard deviation values being satisfactory for their purposed analysis. The method was validated with respect to specificity, recovery, accuracy, precision and linearity. PMID:21645680

  17. Peptides present in the non-digestible fraction of common beans (Phaseolus vulgaris L.) inhibit the angiotensin-I converting enzyme by interacting with its catalytic cavity independent of their antioxidant capacity.

    PubMed

    Luna-Vital, Diego A; González de Mejía, Elvira; Mendoza, Sandra; Loarca-Piña, Guadalupe

    2015-05-01

    The aim was to evaluate the angiotensin-I converting enzyme (ACE) inhibitory potential and the antioxidant capacity of pure synthesized peptides (GLTSK, LSGNK, GEGSGA, MPACGSS and MTEEY) originally identified in the non-digestible fraction (NDF) of common beans (P. vulgaris L.) that had previously demonstrated antiproliferative activity against human colorectal cancer cells. The five peptides were able to inhibit ACE with half maximal inhibitory concentration (IC50) values ranging from 65.4 (GLTSK) to 191.5 μM (MPACGSS). The combination of GLTSK and MTEEY increased the ACE inhibition by 30% compared to equieffective doses of the single peptides. According to molecular docking analysis, the five peptides had lower estimated free energy values (-6.47 to -9.34 kcal mol(-1)) when they interacted with the catalytic site of ACE than that of the substrate hippuryl-histidyl-leucine (-5.41 kcal mol(-1)), thus inhibiting the enzymatic activity. According to molecular docking analysis, the five peptides interacted with four (His353, Ala354, Glu411 and Tyr523) out of 6 catalytic residues. Moreover, MPACGSS had the highest antioxidant activity according to Ferric reducing antioxidant power (FRAP) (421.58 μmol FeSO4 mg(-1)), Fe(2+) chelation (2.01 μmol Na2EDTA mg(-1)) assays, and also in DPPH (748.39 μmol Trolox per mg of dry peptide) and ABTS (561.42 μmol Trolox mg(-1)) radical scavenging assays. The results support the hypothesis that peptides present in the non-digestible fraction of common beans (Phaseolus vulgaris L.) may exert their physiological benefits independent of their antioxidant capacity, by ACE inhibition through interaction with its catalytic cavity. PMID:25881860

  18. Angiotensin-converting enzyme gene insertion-deletion polymorphism is a risk marker for Alzheimer's disease in a Chinese population: a meta-analysis of case-control studies.

    PubMed

    Yuan, Ye; Piao, Jin-hua; Ma, Ke; Lu, Na

    2015-08-01

    It has long been known that the polymorphisms of angiotensin-converting enzyme gene (ACE) are associated to increase risk of Alzheimer's disease (AD) in Chinese population. However, consistent results were not obtained among studies. This study is aimed to clarify the association between ACE insertion (I)/deletion (D) polymorphism (rs1799752) and AD. Literatures were searched from PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases without language restrictions. Eleven separate studies were suitable for the inclusion criterion. The selected studies contained 2,763 Chinese participants, including 1,383 in AD group and 1,380 controls. Pooled odds ratios (ORs) were calculated to assess the association between ACE I/D polymorphism and AD. Our case-control data indicated that ACE insertion is a risk allele in all genetic models: additive model (I vs. D: OR = 1.32, 95 % CI 1.07-1.62, P = 0.008), dominant model (II + ID vs. DD: OR = 1.61, 95 % CI 1.08-2.41, P = 0.02) and recessive model (II vs. ID + DD: OR = 1.39, 95 % CI 1.07-1.81, P = 0.01). Heterogeneity between studies was significant (P < 0.10) but not in stratification defined by the selection of controls (P > 0.10). After stratification according to the selection of controls, the carrier of ACE I allele remained a high risk for AD in population-based samples subgroup (I vs. D: P = 0.008, OR = 1.32, 95 % CI 1.07-1.61, P(heterogeneity) = 0.47, I (2) = 0 %). Our study provided solid evidence suggesting that ACE gene I/D polymorphism is a genetic risk factor for AD in Chinese population. PMID:25596842

  19. Do Angiotensin-Converting Enzyme Inhibitors Reduce the Risk of Symptomatic Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer After Definitive Radiation Therapy? Analysis of a Single-Institution Database

    SciTech Connect

    Wang, Hongmei; Liao, Zhongxing; Zhuang, Yan; Xu, Ting; Nguyen, Quynh-Nhu; Levy, Lawrence B.; O'Reilly, Michael; Gold, Kathryn A.; Gomez, Daniel R.

    2013-12-01

    Purpose: Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non–small cell lung cancer (NSCLC). Methods and Materials: We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP. Results: Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04). Conclusions: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP.

  20. The associations of apolipoprotein E and angiotensin-converting enzyme polymorphisms and cognitive function in Type 1 diabetes based on an 18-year follow-up of the DCCT cohort

    PubMed Central

    Jacobson, A. M.; Paterson, A. D.; Ryan, C. M.; Cleary, P. A.; Waberski, B. H.; Weinger, K.; Musen, G.; Dahms, W.; Bayless, M.; Silvers, N.; Harth, J.; Boright, A. P.

    2010-01-01

    Aims Specific polymorphisms of the apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes appear to increase risk for Alzheimer’s disease and cognitive dysfunction in the general population, yet little research has examined whether genetic factors influence risk of cognitive dysfunction in patients with Type 1 diabetes. The long-term follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) population provides an opportunity to examine if specific genetic variations in APOE and ACE alter risk for cognitive decline. Methods Neurocognitive function in Type 1 diabetic subjects from the DCCT/EDIC study was assessed at DCCT entry and re-assessed approximately 18 years later, using a comprehensive cognitive test battery. Glycated haemoglobin (HbA1c) and the frequency of severe hypoglycaemic events leading to coma or seizures were measured over the 18-year follow-up. We determined whether the APO εs4 and ACE intron 16 indel genotypes were associated with baseline cognitive function and with change over time, and whether they conferred added risk in those subjects experiencing severe hypoglycaemic events or greater glycaemic exposure. Results None of the APOE or ACE polymorphisms were associated with either baseline cognitive performance or change in cognition over the 18-year follow-up. Moreover, none of the genotype variations altered the risk of cognitive dysfunction in those subjects with severe hypoglycaemic episodes or high HbA1c. Conclusions In this sample of young and middle-aged adults with Type 1 diabetes, APOε4 and ACED alleles do not appear to increase risk of cognitive dysfunction. PMID:20121884

  1. Effects of angiotensin-converting enzyme inhibitors and beta blockers on clinical outcomes in patients with and without coronary artery obstructions at angiography (from a Register-Based Cohort Study on Acute Coronary Syndromes).

    PubMed

    Manfrini, Olivia; Morrell, Christine; Das, Rajiv; Barth, Julian H; Hall, Alistair S; Gale, Christopher P; Cenko, Edina; Bugiardini, Raffaele

    2014-05-15

    We sought to determine the effectiveness of angiotensin-converting enzyme (ACE) inhibition and β-blocker treatment as a function of the degree of coronary artery disease (CAD) obstruction at angiography. The Evaluation of Methods and Management of Acute Coronary Events registry enrolled patients who had been hospitalized for an acute coronary syndrome. There were 1,602 patients who had cardiac catheterization that were used for this analysis. The main outcome measures were evidence-based therapies prescribed at discharge and 6-month incidence of all-cause mortality. The cohort consisted of 1,252 patients with obstructive CAD (>50% luminal diameter obstructed) and 350 patients with nonobstructive CAD. Multivariate logistic regression analysis adjusted for further medications and other clinical factors was performed. Patients with nonobstructive CAD had significantly (p <0.001) higher rates of β-blocker (77.8% vs 63.3%) and lower rates of ACE-inhibitor (57.7% vs 66.4%) prescriptions. In patients with nonobstructive CAD, ACE-inhibitor therapy was clearly associated with a lower 6-month mortality (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.03 to 0.78, p = 0.004). No significant association between β-blocker use and death was found. In patients with obstructive CAD, both β blockers (OR 0.47, 95% CI 0.32 to 0.67, p <0.001) and ACE inhibitors (OR 0.47, 95% CI 0.26 to 0.87, p = 0.01) were significantly associated with a reduced risk of 6-month mortality. In conclusion, ACE-inhibitor therapy seems to be an effective first-line treatment for preventing the occurrence of mortality in patients with nonobstructive CAD. PMID:24698468

  2. Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model

    PubMed Central

    2014-01-01

    Background We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins. Methods Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA). Results A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group. Conclusions The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of

  3. Release of angiotensin converting enzyme-inhibitor peptides during in vitro gastrointestinal digestion of Parmigiano Reggiano PDO cheese and their absorption through an in vitro model of intestinal epithelium.

    PubMed

    Basiricò, L; Catalani, E; Morera, P; Cattaneo, S; Stuknytė, M; Bernabucci, U; De Noni, I; Nardone, A

    2015-11-01

    The occurrence of 8 bovine casein-derived peptides (VPP, IPP, RYLGY, RYLG, AYFYPEL, AYFYPE, LHLPLP, and HLPLP) reported as angiotensin converting enzyme-inhibitors (ACE-I) was investigated in the 3-kDa ultrafiltered water-soluble extract (WSE) of Parmigiano Reggiano (PR) cheese samples by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry via an electrospray ionization source. Only VPP, IPP, LHLPLP, and HLPLP were revealed in the WSE, and their total amount was in the range of 8.46 to 21.55 mg/kg of cheese. Following in vitro static gastrointestinal digestion, the same ACE-I peptides along with the newly formed AYFYPEL and AYFYPE were found in the 3 kDa WSE of PR digestates. Digestates presented high amounts (1,880-3,053 mg/kg) of LHLPLP, whereas the remaining peptides accounted for 69.24 to 82.82 mg/kg. The half-maximal inhibitory concentration (IC50) values decreased from 7.92 ± 2.08 in undigested cheese to 3.20 ± 1.69 after in vitro gastrointestinal digestion. The 3-kDa WSE of digested cheeses were used to study the transport of the 8 ACE-I peptides across the monolayers of the Caco-2 cell culture grown on a semipermeable membrane of the transwells. After 1h of incubation, 649.20 ± 148.85 mg/kg of LHLPLP remained in the apical compartment, whereas VPP, IPP, AYFYPEL, AYFYPE, and HLPLP accounted in total for less than 36.78 mg/kg. On average, 0.6% of LHLPLP initially present in the digestates added to the apical compartment were transported intact to the basolateral chamber after the same incubation time. Higher transport rate (2.9%) was ascertained for the peptide HLPLP. No other intact ACE-I peptides were revealed in the basolateral compartment. For the first time, these results demonstrated that the ACE-I peptides HLPLP and LHLPLP present in the in vitro digestates of PR cheese are partially absorbed through an in vitro model of human intestinal epithelium. PMID:26364103

  4. Effects of Atorvastatin Dose and Concomitant Use of Angiotensin-Converting Enzyme Inhibitors on Renal Function Changes over Time in Patients with Stable Coronary Artery Disease: A Prospective Observational Study.

    PubMed

    Wieczorek-Surdacka, Ewa; Świerszcz, Jolanta; Surdacki, Andrzej

    2016-01-01

    Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. We studied 78 men with stable CAD referred for an elective coronary angiography who attained the then-current guideline-recommended target level of low-density lipoproteins (LDL) cholesterol below 2.5 mmol/L in a routine fasting lipid panel on admission and were receiving atorvastatin at a daily dose of 10-40 mg for ≥3 months preceding the index hospitalization. Due to an observational study design, atorvastatin dosage was not intentionally modified for other reasons. GFR was estimated during index hospitalization and at about one year after discharge from our center. Irrespective of ACEI use, a prevention of kidney function loss was observed only in those treated with the highest atorvastatin dose. In 38 subjects on ACEI, both of the higher atorvastatin doses were associated with increasing beneficial effects on GFR changes (mean ± SEM: -4.2 ± 2.4, 1.1 ± 1.6, 5.2 ± 2.4 mL/min per 1.73 m² for the 10-mg, 20-mg and 40-mg atorvastatin group, respectively, p = 0.02 by ANOVA; Spearman's rho = 0.50, p = 0.001 for trend). In sharp contrast, in 40 patients without ACEI, no significant trend effect was observed across increasing atorvastatin dosage (respective GFR changes: -1.3 ± 1.0, -4.7 ± 2.1, 4.8 ± 3.6 mL/min per 1.73 m², p = 0.02 by ANOVA; rho = 0.08, p = 0.6 for trend). The results were substantially unchanged after adjustment for baseline GFR or time-dependent variations of LDL cholesterol. Thus, concomitant ACEI use appears to facilitate the ability of increasing atorvastatin doses to beneficially modulate time-dependent changes in GFR in men with stable CAD. PMID:26848655

  5. Effects of Atorvastatin Dose and Concomitant Use of Angiotensin-Converting Enzyme Inhibitors on Renal Function Changes over Time in Patients with Stable Coronary Artery Disease: A Prospective Observational Study

    PubMed Central

    Wieczorek-Surdacka, Ewa; Świerszcz, Jolanta; Surdacki, Andrzej

    2016-01-01

    Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. We studied 78 men with stable CAD referred for an elective coronary angiography who attained the then-current guideline-recommended target level of low-density lipoproteins (LDL) cholesterol below 2.5 mmol/L in a routine fasting lipid panel on admission and were receiving atorvastatin at a daily dose of 10–40 mg for ≥3 months preceding the index hospitalization. Due to an observational study design, atorvastatin dosage was not intentionally modified for other reasons. GFR was estimated during index hospitalization and at about one year after discharge from our center. Irrespective of ACEI use, a prevention of kidney function loss was observed only in those treated with the highest atorvastatin dose. In 38 subjects on ACEI, both of the higher atorvastatin doses were associated with increasing beneficial effects on GFR changes (mean ± SEM: −4.2 ± 2.4, 1.1 ± 1.6, 5.2 ± 2.4 mL/min per 1.73 m2 for the 10-mg, 20-mg and 40-mg atorvastatin group, respectively, p = 0.02 by ANOVA; Spearman’s rho = 0.50, p = 0.001 for trend). In sharp contrast, in 40 patients without ACEI, no significant trend effect was observed across increasing atorvastatin dosage (respective GFR changes: −1.3 ± 1.0, −4.7 ± 2.1, 4.8 ± 3.6 mL/min per 1.73 m2, p = 0.02 by ANOVA; rho = 0.08, p = 0.6 for trend). The results were substantially unchanged after adjustment for baseline GFR or time-dependent variations of LDL cholesterol. Thus, concomitant ACEI use appears to facilitate the ability of increasing atorvastatin doses to beneficially modulate time-dependent changes in GFR in men with stable CAD. PMID:26848655

  6. Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function: A Double-blind Randomized Crossover Clinical Trial.

    PubMed

    Becerra-Tomás, Nerea; Guasch-Ferré, Marta; Quilez, Joan; Merino, Jordi; Ferré, Raimon; Díaz-López, Andrés; Bulló, Mònica; Hernández-Alonso, Pablo; Palau-Galindo, Antoni; Salas-Salvadó, Jordi

    2015-11-01

    Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function.A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained.After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and -0.63 mm Hg in diastolic BP for CB; -0.71 mm Hg in systolic BP and -1.08 mm Hg in diastolic BP for LSB; and -0.75 mm Hg in systolic BP and -2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters.Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the effect of GABA on BP

  7. Effect of a cheese rich in angiotensin-converting enzyme-inhibiting peptides (Gamalost®) and a Gouda-type cheese on blood pressure: results of a randomised trial

    PubMed Central

    Nilsen, Rita; Pripp, Are H.; Høstmark, Arne T.; Haug, Anna; Skeie, Siv

    2016-01-01

    Background High blood pressure (BP) is the leading risk factor for global disease burden, contributing to 7% of global disability adjusted life years. Angiotensin converting enzyme (ACE)-inhibiting bioactive peptides have the potential to reduce BP in humans. These peptides have been identified in many dairy products and have been associated with significant reductions in BP. Objective The objective of this trial was to examine whether a cheese rich in ACE-inhibiting peptides (Gamalost®), or a standard Gouda-type cheese could lower BP. Design A total of 153 healthy participants were randomised to one of three parallel arms: Gamalost® (n=53, 50 g/day for 8 weeks), Gouda-type cheese (n=50, 80 g/day for 8 weeks), and control (n=50). BP and anthropometric measurements were taken at the baseline and at the end, with an additional BP measurement midway. Based on BP at baseline, participants were categorised as having optimal BP (<120/<80 mmHg), normal-high BP (120–139/80–89 mmHg), or being hypertensive (>140/>90 mmHg). Questionnaires about lifestyle, health, and dietary habits were completed at baseline, midway and end. Results In total, 148 participants (mean age 43, 52% female) completed the intervention. There were no differences among the three groups in relevant baseline characteristics. BP was reduced in the entire study population, but the cheese groups did not differ from control. However, in a subgroup of participants with slightly elevated BP, BP at 4 weeks of intervention seemed to be borderline significantly more reduced in the Gamalost® group compared with the control group (Dunnett test: diastolic BP −3.5 mmHg, 95% confidence interval (CI) −7.3, 0.4, systolic BP: −4.3 mmHg, 95% CI −9.8, 1.1). Conclusion An intention-to-treat analysis of the data showed no cheese effect upon BP compared to control, but Gamalost® seemed to have a small, non-significant lowering effect on diastolic BP after 4 weeks in people with a normal-high BP. PMID:27495734

  8. Responses to converting-enzyme inhibition and hemorrhage in newborn lambs and adult sheep

    SciTech Connect

    Rose, J.C.; Block, S.M.; Flowe, K.; Morris, M.; South, S.; Sundberg, D.K.; Zimmerman, C.

    1987-02-01

    The authors compared the cardiovascular and hormonal responses to angiotensin converting enzyme inhibition and hemorrhage of 20% of blood volume in chronically instrumented unanesthetized newborn lambs and adult sheep. Administration of the nonsulfhydryl-containing converting-enzyme inhibitor enalapril reduced mean arterial pressure in the newborn but not in the adult animals. Blood pressure fell in both age groups after hemorrhage, and the hemorrhage-induced fall in blood pressure, integrated over the period of hypovolemia, was more pronounced when converting-enzyme inhibition was present in the lambs. This was not observed in the adults. Cardiac output fell following hemorrhage in both age groups, and the fall was greater when enalapril was present in the lambs, but this was not the case in the adults. Hemorrhage increased plasma renin activity in both groups, and enalapril augmented this increase. Plasma concentrations of vasopressin, measured by radioimmunoassay, and catecholamines measured by radio enzymatic assay, increased following hemorrhage within and between groups. Taken together these data suggest that the renin-angiotensin systems plays a more important role in the maintenance of cardiovascular homeostasis in newborn lambs than it does in adult sheep, and catecholamine and vasopressin responses to volume loss can occur in the presence of blockade of the renin-angiotensin system.

  9. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)

    PubMed Central

    McMurray, John J. V.; Packer, Milton; Desai, Akshay S.; Gong, Jim; Lefkowitz, Martin P.; Rizkala, Adel R.; Rouleau, Jean; Shi, Victor C.; Solomon, Scott D.; Swedberg, Karl; Zile, Michael R.

    2013-01-01

    Aims Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides. Methods Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death. Perspectives PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF. Trial registration NCT01035255 PMID:23563576

  10. Cholecystokinin-converting enzymes in brain.

    PubMed Central

    Malesci, A; Straus, E; Yalow, R S

    1980-01-01

    Crude extracts of porcine cerebral cortical tissue convert cholecystokinin (CCK) to its COOH-terminal fragments, the dodecapeptide (CCK-12) and the octapeptide (CCK-8). The Sephadex G-75 void volume eluate of the crude extract cleaves the arginine-isoleucine bond and effects conversion only to CCK-12; the Sephadex G-50 void volume eluate of the same extract cleaves the arginine-aspartate bond as well, so that both CCK-12 and CCK-8 are end products. Thus, there are at least two enzymes; the one involved in the conversion to CCK-12 is of larger molecular radius than the other. The Km for the cleavage of CCK at the arginine-isoleucine bond by the Sephadex G-75 void volume eluate enzyme is 1.1 X 10(-6) M; the Km for trypsin cleavage of the same bond is 4.7 x 10(-6) M. The lower Vmax for the brain enzyme (1.5 x 10(-11) mol/min per g of extract) compared with trypsin (66 x 10(-11) mol/min per g of trypsin) simply reflects the lesser degree of purify of the brain extract than of the highly purified trypsin. Images PMID:6987659

  11. Expression of apical Na(+)-L-glutamine co-transport activity, B(0)-system neutral amino acid co-transporter (B(0)AT1) and angiotensin-converting enzyme 2 along the jejunal crypt-villus axis in young pigs fed a liquid formula.

    PubMed

    Yang, Chengbo; Yang, Xiaojian; Lackeyram, Dale; Rideout, Todd C; Wang, Zirong; Stoll, Barbara; Yin, Yulong; Burrin, Douglas G; Fan, Ming Z

    2016-06-01

    Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B(0) Na(+)-neutral AA co-transporter (B(0)AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including L-Gln, we hypothesized that high apical Na(+)-Gln co-transport activity, and B(0)AT1 (SLC6A19) in co-expression with angiotensin-converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt-villus axis in young animals via unique control mechanisms. Kinetics of Na(+)-Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt-villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na(+)-Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na(+)-Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B(0)AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40-47 %) than in the villus cells. There were no significant differences in B(0)AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na(+)-neutral AA uptake activities via abundantly co-expressing B(0)AT1 and ACE2 proteins in the apical membrane and by transcribing the B(0)AT1 (SLC6A19) gene in the epithelia along the entire crypt-villus axis. PMID:26984322

  12. Congestive heart failure and converting enzyme inhibition: failure of current prognostic criteria for predicting subsequent renal insufficiency.

    PubMed Central

    Odum, J.; Carson, P.; Russell, G.

    1991-01-01

    Angiotensin-1-converting enzyme inhibitors have an effective and established role in the treatment of patients with congestive heart failure. However, a small number of such patients will subsequently develop renal insufficiency. These patients may be identified prior to, or shortly after, commencement of therapy by recognized criteria. This report describes 4 patients with congestive heart failure who developed severe renal insufficiency secondary to either enalapril or captopril therapy in the absence of any currently recognized predisposing factors. One patient died. PMID:2068028

  13. Characterization of a nontrypsin cholecystokinin converting enzyme in mammalian brain

    PubMed Central

    Straus, Eugene; Malesci, Alberto; Yalow, Rosalyn S.

    1978-01-01

    An enzyme has been partially purified from canine and porcine cerebral cortical extracts that differs from trypsin in that it manifests some degree of hormone specificity since it converts porcine cholecystokinin to smaller immunoreactive forms, i.e., the COOH-terminal dodecapeptide and octapeptide fragments, but fails to convert big gastrin (34 amino acids) to heptadecapeptide gastrin. This enzyme is distinguishable from trypsin not only in substrate specificity, but also in several physiochemical properties. It is not inhibited in the presence of concentrations of lima bean trypsin inhibitor sufficient to inhibit 1 mg of trypsin per ml of incubation mixture. It is inactivated when incubated with substrate at 45°C for 1 hr, whereas trypsin remains fully active when incubated under the same conditions at 55°C. The enzyme elutes in the void volume on Sephadex G-50 and G-75 gel filtration. On sucrose gradient centrifugation, the proteolytic activity associated with trypsin is recovered above albumin but that of the solubilized brain enzyme is recovered below gamma globulin. The enzyme is not detectable in splenic extracts, which do contain nonspecific proteases capable of completely degrading cholecystokinin. Further investigation is required to determine whether the enzyme in the gut that converts cholecystokinin to the bioactive and immunoactive COOH-terminal fragments resembles or is different from the brain converting enzyme. Images PMID:281718

  14. Aronia melanocarpa Elliot Reduces the Activity of Angiotensin I-Converting Enzyme—In Vitro and Ex Vivo Studies

    PubMed Central

    Sikora, Joanna; Broncel, Marlena; Mikiciuk-Olasik, Elżbieta

    2014-01-01

    Purpose. The aim of the study was to analyze the effects of two-month supplementation with chokeberry preparation on the activity of angiotensin I-converting enzyme (ACE) in patients with metabolic syndrome (MS). During the in vitro stage of the study, we determined the concentration of chokeberry extract, which inhibited the activity of ACE by 50% (IC50). Methods. The participants (n = 70) were divided into three groups: I—patients with MS who received chokeberry extract supplements, II—healthy controls, and III—patients with MS treated with ACE inhibitors. Results. After one and two months of the experiment, a decrease in ACE activity corresponded to 25% and 30%, respectively. We documented significant positive correlations between the ACE activity and the systolic (r = 0.459, P = 0.048) and diastolic blood pressure, (r = 0.603, P = 0.005) and CRP. The IC50 of chokeberry extract and captopril amounted to 155.4 ± 12.1 μg/mL and 0.52 ± 0.18 μg/mL, respectively. Conclusions. Our in vitro study revealed that chokeberry extract is a relatively weak ACE inhibitor. However, the results of clinical observations suggest that the favorable hypotensive action of chokeberry polyphenols may be an outcome of both ACE inhibition and other pleotropic effects, for example, antioxidative effect. PMID:25050143

  15. Angiotensin-II blockage, muscle strength, and exercise capacity in physically independent older adults

    PubMed Central

    Coelho, Vinícius A.; Probst, Vanessa S.; Nogari, Bruna M.; Teixeira, Denilson C.; Felcar, Josiane M.; Santos, Denis C.; Gomes, Marcus Vinícius M.; Andraus, Rodrigo A. C.; Fernandes, Karen B. P.

    2016-01-01

    [Purpose] This study aimed to assess the exercise capacity and muscle strength in elderly people using drugs for angiotensin-II blockage. [Subjects and Methods] Four hundred and seven older adults were recruited for this study. Data about comorbidities and medication use were recorded and the individuals were divided into three groups: control group- elderly people with normal exercise capacity (n=235); angiotensin-converting enzyme inhibitor group − individuals using angiotensin-converting enzyme inhibitors (n=140); and angiotensin-II receptor blocker group- patients using angiotensin-II receptor blockers (n= 32). Exercise capacity was evaluated by a 6-minute walking test and muscle strength was measured using a handgrip dynamometer. [Results] Patients from the angiotensin-converting enzyme inhibitor group (mean: 99 ± 12%) and the angiotensin-II receptor blocker group (mean: 101 ± 14%) showed higher predicted values in the 6-minute walking test than the control group patients (mean: 96 ± 10%). Patients from the angiotensin-converting enzyme inhibitor group (mean: 105 ± 19%) and the angiotensin-II receptor blocker group (mean: 105.1 ± 18.73%) showed higher predicted values of muscle strength than control group patients (mean: 98.15 ± 18.77%). [Conclusion] Older adults using angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers have better functional exercise capacity and muscle strength. PMID:27065543

  16. Synthesis of angiotensins by cultured granuloma macrophages in murine schistosomiasis mansoni

    SciTech Connect

    Weinstock, J.V.; Blum, A.M.

    1986-03-01

    Components of the angiotensin system are present in granulomas of murine schistosomiasis mansoni. Angiotensins may have immunoregulatory function. Granuloma macrophages cultured for up to 3 days generated substantial angiotensin I (AI) and angiotensin II (AII) which appeared in the culture supernatants. Macrophage monolayers were incubated with (/sup 3/H) amino acids, and culture supernatants were extracted with acetone and analyzed by HPLC. Radiolabeled products eluded at times corresponding to those of authentic angiotensins. Immunoadsorption of angiotensins with angiotensin antisera removed reputed radiolabeled angiotensins from the supernatants. Treatment of the elution fraction corresponding to that of authentic AI with angiotensin converting enzyme resulted in the generation of radiolabeled polypeptides which co-eluted with authentic AII and His-Leu. Similar experiments conducted with nonadherent granuloma cells devoid of macrophages failed to demonstrate angiotensin production. These results suggest that granuloma macrophages can synthesize angiotensin.

  17. Prodrug converting enzyme gene delivery by L. monocytogenes

    PubMed Central

    Stritzker, Jochen; Pilgrim, Sabine; Szalay, Aladar A; Goebel, Werner

    2008-01-01

    Background Listeria monocytogenes is a highly versatile bacterial carrier system for introducing protein, DNA and RNA into mammalian cells. The delivery of tumor antigens with the help of this carrier into tumor-bearing animals has been successfully carried out previously and it was recently reported that L. monocytogenes is able to colonize and replicate within solid tumors after local or even systemic injection. Methods Here we report on the delivery of two prodrug converting enzymes, purine-deoxynucleoside phosphorylase (PNP) and a fusion protein consisting of yeast cytosine deaminase and uracil phosphoribosyl transferase (FCU1) into cancer cells in culture by L. monocytogenes. Transfer of the prodrug converting enzymes was achieved by bacterium mediated transfer of eukaryotic expression plasmids or by secretion of the proteins directly into the host cell cytosol by the infecting bacteria. Results The results indicate that conversion of appropriate prodrugs to toxic drugs in the cancer cells occured after both procedures although L. monocytogenes-mediated bactofection proved to be more efficient than enzyme secretion 4T1, B16 and COS-1 tumor cells. Exchanging the constitutively PCMV-promoter with the melanoma specific P4xTETP-promoter resulted in melanoma cell-specific expression of the prodrug converting enzymes but reduced the efficiencies. Conclusion These experiments open the way for bacterium mediated tumor specific activation of prodrugs in live animals with tumors. PMID:18402662

  18. Development of enzymes and enzyme systems by genetic engineering to convert biomass to sugars

    Technology Transfer Automated Retrieval System (TEKTRAN)

    TITLE Development of Enzymes and Enzyme Systems by Genetic Engineering to Convert Biomass to Sugars ABSTRACT Plant cellulosic material is one of the most viable renewable resources for the world’s fuel and chemical feedstock needs. Currently ethanol derived from corn starch is the most common li...

  19. Further characterization of brain cholecystokinin-converting enzymes.

    PubMed Central

    Ryder, S W; Straus, E; Yalow, R S

    1980-01-01

    The brain cholecystokinin-converting enzymes that cleave intact cholecystokinin to its COOH-terminal dodecapeptide and octapeptide also cleave the synthetic dipeptides Arg-Ile (or Arg-Val or Arg-Leu) and Arg-Asp, respectively. Thus, they are not hormone-specific enzymes but are bond-specific. Ultracentrifuge studies demonstrate that there is Arg-Ile hydrolase activity associated with a protein greater in molecular weight than gamma globulin and that both Arg-Ile and Arg-Asp hydrolase activities are associated with one or more proteins between albumin and gamma globulin in molecular weight. Images PMID:6997879

  20. Converting enzyme inhibition and the glomerular hemodynamic response to glycine in diabetic rats.

    PubMed

    Slomowitz, L A; Peterson, O W; Thomson, S C

    1999-07-01

    GFR normally increases during glycine infusion. This response is absent in humans and rats with established diabetes mellitus. In diabetic patients, angiotensin-converting enzyme inhibition (ACEI) restores the effect of glycine on GFR. To ascertain the glomerular hemodynamic basis for this effect of ACEI, micropuncture studies were performed in male Wistar-Froemter rats after 5 to 6 wk of insulin-treated streptozotocin diabetes. The determinants of single-nephron GFR (SNGFR) were assessed in each rat before and during glycine infusion. Studies were performed in diabetics, diabetics after 5 d of ACEI (enalapril in the drinking water), and weight-matched controls. Diabetic rats manifest renal hypertrophy and glomerular hyperfiltration but not glomerular capillary hypertension. ACEI reduced glomerular capillary pressure, increased glomerular ultrafiltration coefficient, and did not mitigate hyperfiltration. In controls, glycine increased SNGFR by 30% due to increased nephron plasma flow. In diabetics, glycine had no effect on any determinant of SNGFR. In ACEI-treated diabetics, the SNGFR response to glycine was indistinguishable from nondiabetics, but the effect of glycine was mediated by greater ultrafiltration pressure rather than by greater plasma flow. These findings demonstrate that: (1) The absent response to glycine in established diabetes does not indicate that renal functional reserve is exhausted by hyperfiltration; and (2) ACEI restores the GFR response to glycine in established diabetes, but this response is mediated by increased ultrafiltration pressure rather than by increased nephron plasma flow. PMID:10405200

  1. ACE2: Angiotensin II/Angiotensin-(1-7) balance in cardiorenal injury

    PubMed Central

    Varagic, Jasmina; Ahmad, Sarfaraz; Nagata, Sayaka; Ferrario, Carlos M.

    2014-01-01

    Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent to this interactive biochemical cascade. Over the last decade angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses a considerable advancement in research on the role of tissue ACE2 in development and progression of hypertension and cardiorenal injury. We also summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. Recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis are also reviewed. PMID:24510672

  2. Identification of prolyl carboxypeptidase as an alternative enzyme for processing of renal angiotensin II using mass spectrometry

    PubMed Central

    Grobe, Nadja; Weir, Nathan M.; Leiva, Orly; Ong, Frank S.; Bernstein, Kenneth E.; Schmaier, Alvin H.; Morris, Mariana

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) catalyzes conversion of ANG II to ANG-(1–7). The present study uses newly established proteomic approaches and genetic mouse models to examine the contribution of alternative renal peptidases to ACE2-independent formation of ANG-(1–7). In situ and in vitro mass spectrometric characterization showed that substrate concentration and pH control renal ANG II processing. At pH ≥6, ANG-(1–7) formation was significantly reduced in ACE2 knockout (KO) mice. However, at pH <6, formation of ANG-(1–7) in ACE2 KO mice was similar to that in wild-type (WT) mice, suggesting alternative peptidases for renal ANG II processing. Furthermore, the dual prolyl carboxypeptidase (PCP)-prolyl endopeptidase (PEP) inhibitor Z-prolyl-prolinal reduced ANG-(1–7) formation in ACE2 KO mice, while the ACE2 inhibitor MLN-4760 had no effect. Unlike the ACE2 KO mice, ANG-(1–7) formation from ANG II in PEP KO mice was not different from that in WT mice at any tested pH. However, at pH 5, this reaction was significantly reduced in kidneys and urine of PCP-depleted mice. In conclusion, results suggest that ACE2 metabolizes ANG II in the kidney at neutral and basic pH, while PCP catalyzes the same reaction at acidic pH. This is the first report demonstrating that renal ANG-(1–7) formation from ANG II is independent of ACE2. Elucidation of ACE2-independent ANG-(1–7) production pathways may have clinically important implications in patients with metabolic and renal disease. PMID:23392115

  3. Classical Renin-Angiotensin System in Kidney Physiology

    PubMed Central

    Sparks, Matthew A.; Crowley, Steven D.; Gurley, Susan B.; Mirotsou, Maria; Coffman, Thomas M.

    2014-01-01

    The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts. PMID:24944035

  4. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase.

    PubMed

    Albiston, A L; McDowall, S G; Matsacos, D; Sim, P; Clune, E; Mustafa, T; Lee, J; Mendelsohn, F A; Simpson, R J; Connolly, L M; Chai, S Y

    2001-12-28

    Central infusion of angiotensin IV or its more stable analogues facilitates memory retention and retrieval in normal animals and reverses amnesia induced by scopolamine or by bilateral perforant pathway lesions. These peptides bind with high affinity and specificity to a novel binding site designated the angiotensin AT(4) receptor. Until now, the AT(4) receptor has eluded molecular characterization. Here we identify the AT(4) receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP). HEK 293T cells transfected with IRAP exhibit typical AT(4) receptor binding characteristics; the AT(4) receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [(125)I]Nle(1)-angiotensin IV with IC(50) values of 32 and 140 nm, respectively. The distribution of IRAP and its mRNA in the brain, determined by immunohistochemistry and hybridization histochemistry, parallels that of the AT(4) receptor determined by radioligand binding. We also show that AT(4) receptor ligands dose-dependently inhibit the catalytic activity of IRAP. We have therefore demonstrated that the AT(4) receptor is IRAP and propose that AT(4) receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates. PMID:11707427

  5. The role of the renin–angiotensin system blocking in the management of atrial fibrillation

    PubMed Central

    Cliff, Brett; Younis, Naveed; Hama, Salam; Soran, Handrean

    2012-01-01

    Objective To review current available evidence for the role of renin–angiotensin system blockade in the management of atrial fibrillation. Method We conducted a PubMed and Medline literature search (January 1980 through July 2011) to identify all clinical trials published in English concerning the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers for primary and secondary prevention of atrial fibrillation. We also discussed renin–angiotensin system and its effects on cellular electrophysiology. Conclusion The evidence from the current studies discussed does not provide a firm definitive indication for the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in the primary or secondary prevention of atrial fibrillation. Nevertheless, modest benefits were observed in patients with left ventricular dysfunction. In view of the possible benefits and the low incidence of side-effects with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, they can be given to patients with recurrent AF, specifically those with hypertension, heart failure and diabetes mellitus.

  6. Molecular characterization of human and bovine endothelin converting enzyme (ECE-1).

    PubMed

    Schmidt, M; Kröger, B; Jacob, E; Seulberger, H; Subkowski, T; Otter, R; Meyer, T; Schmalzing, G; Hillen, H

    1994-12-19

    A membrane-bound protease activity that specifically converts Big endothelin-1 has been purified from bovine endothelial cells (FBHE). The enzyme was cleaved with trypsin and the peptide sequencing analysis confirmed it to be a zinc chelating metalloprotease containing the typical HEXXH (HELTH) motif. RT-PCR and cDNA screens were employed to isolate the complete cDNAs of the bovine and human enzymes. This human metalloprotease was expressed heterologously in cell culture and oocytes. The catalytic activity of the recombinant enzyme is the same as that determined for the natural enzyme. The data suggest that the characterized enzyme represents the functional human endothelin converting enzyme ECE-1. PMID:7805846

  7. The binding of metal ions and angiotensin converting enzyme (ACE) inhibitor by 13C NMR

    NASA Astrophysics Data System (ADS)

    Sakamoto, Yohko; Sakamoto, Yuko; Ishii, Tomoko; Ohmoto, Taichi

    1991-06-01

    Enalaprilat (MK-422, 1- [ N- [1 (S)-carboxy-3-phenylpropyl]- L-alanyl]- L-proline (1)) and Lisinopril (MK521, N- N- [ (s)-l-carboxy-3- phenylpropyl]- L-lysyl- L-proline, (2)) exhibit the capacity to act as a chelate, unidentate or bridge towards metal ions in aqueous solution, as determined by 13C NMR. By adding metal ions, in the series of Zn 2+, Ni 2+, Pb 2+, Pd 2+ and Cd 2+, the active site of the ACE inhibitor was well defined. MK-521 was more influenced by nuclei that were distant from the active site than MK-422.

  8. Angiotensin-I-converting enzyme inhibitory peptides: Chemical feature based pharmacophore generation.

    PubMed

    Wang, Zhanli; Zhang, Saisai; Jin, Hongwei; Wang, Wei; Huo, Jianxin; Zhou, Lishe; Wang, Yongfu; Feng, Fengqin; Zhang, Liangren

    2011-08-01

    A validated 3D pharmacophore model was generated for a series of ACE inhibitory peptides, which consisted of five features (two hydrophobic functions, two hydrogen bond acceptors, and a negative ionizable function). The built model was able to correctly predict the activity of known ACE inhibitors. The model was then used as query to search 3D databases of peptides. Three novel peptides (I, II and III) were synthesized and biologically evaluated in vitro. It appears that the in vitro activity of peptides I, II and III was consistent with their molecular modeling results. Our results provided confidence for the utility of the pharmacophore model to retrieve novel ACE inhibitory peptides with desired biological activity by virtual screening. PMID:21621881

  9. Encapsulation of Phaseolus lunatus Protein Hydrolysate with Angiotensin-Converting Enzyme Inhibitory Activity

    PubMed Central

    Ruiz Ruiz, Jorge Carlos; Segura Campos, Maira Rubí; Betancur Ancona, David Abram; Chel Guerrero, Luis Antonio

    2013-01-01

    The objective of recent research has been to seek alternative therapeutic treatments; for this reason, the use of protein hydrolysates from diverse sources has been studied. A way to guarantee that these treatments reach the site of action is through protection with covers, such as microcapsules. Therefore, proteins from the legume Phaseolus lunatus were hydrolyzed and encapsulated with a blend of Delonix regia carboxymethylated gum/sodium alginate (50 : 50 w/w). Hydrolysis release conditions in a simulated gastrointestinal system were obtained using CaCl2 concentrations as the main factor, indicating that lower CaCl2 concentrations lead to an increased hydrolysis release. Beads obtained with 1.0 mM of CaCl2 exhibited a better hydrolysate release rate under intestinal simulated conditions and the proteins maintained an IC50 of 2.9 mg/mL. Capsules obtained with the blend of Delonix regia carboxymethylated gum/sodium alginate would be used for the controlled delivery of hydrolysates with potential use as nutraceutical or therapeutic agents. PMID:25937975

  10. Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae).

    PubMed

    Loizzo, Monica Rosa; Said, Ataa; Tundis, Rosa; Rashed, Khaled; Statti, Giancarlo Antonio; Hufner, Antje; Menichini, Francesco

    2007-01-01

    In our screening program for antihypertensive properties of plants, the leaves of Ailanthus excelsa (Roxb), a plant used in Egyptian traditional medicine, were analysed. Chromatographic separation of A. excelsa MeOH extract yielded six flavonoids for the first time from this species, namely apigenin, luteolin, kaempferol-3-O-alpha-arabinopyranoside, kaempferol-3-O-beta-galactopyranoside, quercetin-3-O-alpha-arabinopyranoside and luteolin-7-O-beta-glucopyranoside. The in vitro hypotensive activities of the MeOH extract and the isolated compounds were elucidated. All the flavonoids tested exhibited ACE inhibitory activity, in particular the most active compound was kaempferol-3-O-beta-galactopyranoside with an IC(50) value of 260 microm. PMID:17072829

  11. Isolation of angiotensin converting enzyme (ACE) inhibiting triterpenes from Schinus molle.

    PubMed

    Olafsson, K; Jaroszewski, J W; Smitt, U W; Nyman, U

    1997-08-01

    Bioactivity-guided fractionation of extracts of Schinus molle leaves, using an in vitro assay, led to the isolation of ACE-inhibitory steroidal triterpenes of the euphane type, identified by means of NMR spectroscopic methods. One of the triterpenes was isolated as an equilibrium mixture of epimeric aldehydes. The triterpenes showed moderate ACE-inhibitory activity (IC(50) about 250 microM). PMID:17252394

  12. Identification of two novel shear stress responsive elements in rat angiotensin I converting enzyme promoter.

    PubMed

    Miyakawa, Ayumi Aurea; de Lourdes Junqueira, Maria; Krieger, José Eduardo

    2004-04-13

    Mechanical forces contribute to maintenance of cardiovascular homeostasis via the control of release and production of vasoactive substances. We demonstrated previously that shear stress decreases rat ACE activity and expression. Using a reporter gene approach and mutagenesis, we show now that the classic shear stress responsive element or SSRE (GAGACC) contained within 1,274 bp of this promoter is not functional in response to shear stress (15 dyn/cm2, 18 h) [for the wild-type ACE promoter (WLuc), static control (C) = 107 +/- 6.5%, shear stress (SS) = 65.9 +/- 9.4%, n = 8; for the promoter with the classic SSRE mutated (WSS-mut), C = 100 +/- 8.2%, SS = 60.2 +/- 5.2%, n = 10, respectively]. Analysis of progressive deletion mutants unraveled a 57-bp fragment, position -251 to -195, from the transcription start site, containing functional SSRE (for WLuc, C = 107 +/- 6.5%, SS = 65.9 +/- 9.4%, n = 8; for 378, C = 100 +/- 6.4%, SS = 60.4 +/- 4.3%, n = 11; for 251, C = 99.7 +/- 2.6%, SS = 63.2 +/- 5.5%, n = 7; for 194, C = 104.6 +/- 8.1%, SS = 92.4 +/- 6.9%, n = 9). This fragment responded to shear stress even in the context of a heterologous promoter. Finally, functional analysis of mutated candidate regulatory elements identified by gel shift, DNase I footprint, and conservation of aligned sequences revealed that only the double mutant (Barbie/GAGA-mut) but not isolated disruption of the Barbie (WBarbie-mut) or the GAGA (WGAGA-mut) prevented the shear-stress-induced response (for Barbie/GAGA-mut, C = 97.9 +/- 5%, SS = 99.4 +/- 7.2%, n = 6; for WBarbie-mut, C = 106.1 +/- 8.6%, SS = 65.9 +/- 9.4%, n = 6; for WGAGA-mut, C = 100.1 +/- 2.9%, SS = 66.7 +/- 1.6, n = 6;). Taken together, these data provide direct evidence for the new role of Barbie and GAGA boxes in mediating the shear-stress-induced downregulation of rat ACE expression and demonstrate that the classic SSRE (GAGACC) is not functional under the experimental conditions tested. PMID:14872008

  13. N-Domain Isoform of Angiotensin I Converting Enzyme as a Marker of Hypertension: Populational Study

    PubMed Central

    Maluf-Meiken, Leila C. V.; Fernandes, Fernanda B.; Aragão, Danielle S.; Ronchi, Fernanda A.; Andrade, Maria C. C.; Franco, Maria C.; Febba, Andreia C. S.; Plavnik, Frida L.; Krieger, José E.; Mill, Jose G.; Sesso, Ricardo C. C.; Casarini, Dulce E.

    2012-01-01

    The aim of this paper was to investigate the presence of the urinary 90 kDa N-domain ACE in a cohort of the population from Vitoria, Brazil, to verify its association with essential hypertension since this isoform could be a possible genetic marker of hypertension. Anthropometric, clinical, and laboratory parameters of the individuals were evaluated (n = 1150) and the blood pressure (BP) was measured. The study population was divided according to ACE isoforms in urine as follows: ACE 65/90/190, presence of three ACE isoforms (n = 795), ACE 90+ (65/90) (n = 186), and ACE 90− (65/190) (n = 169) based on the presence (+) or absence (−) of the 90 kDa ACE isoform. The anthropometric parameters, lipid profile, serum levels of uric acid, glucose, and the systolic and diastolic BP were significantly greater in the ACE 90+ compared with the ACE 90− and ACE 65/90/190 individuals. We found that 98% of individuals from the ACE 90+ group and 38% from the ACE 65/90/190 group had hypertension, compared to only 1% hypertensive individuals in the ACE 90− group. There is a high presence of the 90 kDa N-domain ACE isoform (85%) in the studied population. The percentile of normotensive subjects with three isoforms was 62%. Our findings could contribute to the development of new efficient strategy to prevent and treat hypertension to avoid the development of cardiovascular disease. PMID:22666552

  14. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure.

    PubMed

    Braunwald, Eugene

    2015-03-17

    The PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated that a new angiotensin receptor antagonist-neprilysin inhibitor was superior to an angiotensin-converting enzyme inhibitor in reducing mortality in patients with heart failure and reduced ejection fraction. This paper traces the research path that culminated in the development of this drug. The first phase, elucidation of the renin-angiotensin-aldosterone system, began with Tigerstedt's discovery of renin, followed by isolation of angiotensin, isolation of angiotensin-converting enzyme, and synthesis of its inhibitors and of angiotensin receptor blockers. Phase 2 began with de Bold's discovery of atrial natriuretic peptide, followed by isolation of the enzyme that degrades it (neprilysin) and its inhibitors. Phase 3 consists of blocking both the renin-angiotensin-aldosterone and atrial natriuretic peptide-degrading systems simultaneously. A molecular complex, LCZ696, developed by scientists at Novartis, combines an angiotensin receptor blocker with a neprilysin inhibitor, is well tolerated, and represents an important step in the management of heart failure and reduced ejection fraction. PMID:25766951

  15. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

    SciTech Connect

    Muchir, Antoine; Wu, Wei; Sera, Fusako; Homma, Shunichi; Worman, Howard J.

    2014-10-03

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left

  16. Inhibition of the renin-angiotensin system for lowering coronary artery disease risk.

    PubMed

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects. PMID:23523606

  17. Sensitivity and robustness in covalent modification cycles with a bifunctional converter enzyme.

    PubMed

    Straube, Ronny

    2013-10-15

    Regulation by covalent modification is a common mechanism to transmit signals in biological systems. The modifying reactions are catalyzed either by two distinct converter enzymes or by a single bifunctional enzyme (which may employ either one or two catalytic sites for its opposing activities). The reason for this diversification is unclear, but contemporary theoretical models predict that systems with distinct converter enzymes can exhibit enhanced sensitivity to input signals whereas bifunctional enzymes with two catalytic sites are believed to generate robustness against variations in system's components. However, experiments indicate that bifunctional enzymes can also exhibit enhanced sensitivity due to the zero-order effect, raising the question whether both phenomena could be understood within a common mechanistic model. Here, I argue that this is, indeed, the case. Specifically, I show that bifunctional enzymes with two catalytic sites can exhibit both ultrasensitivity and concentration robustness, depending on the kinetic operating regime of the enzyme's opposing activities. The model predictions are discussed in the context of experimental observations of ultrasensitivity and concentration robustness in the uridylylation cycle of the PII protein, and in the phosphorylation cycle of the isocitrate dehydrogenase, respectively. PMID:24138868

  18. LinA2, a HCH-converting bacterial enzyme that dehydrohalogenates HBCDs.

    PubMed

    Heeb, Norbert V; Wyss, Simon A; Geueke, Birgit; Fleischmann, Thomas; Kohler, Hans-Peter E; Lienemann, Peter

    2014-07-01

    Hexabromocyclododecanes (HBCDs) and hexachlorocyclohexanes (HCHs) are lipophilic, polyhalogenated hydrocarbons with comparable stereochemistry. Bacterial evolution in HCH-contaminated soils resulted in the development of several Spingomonadaceae which express a series of HCH-converting enzymes. We showed that LinB, a haloalkane dehalogenase from Sphingobium indicum B90A, also transforms various HBCDs besides HCHs. Here we present evidence that LinA2, another dehalogenase from S. indicum also converts certain HBCDs to pentabromocyclododecenes (PBCDEs). Racemic mixtures of α-, β-, γ-HBCDs, a mixture of them, and δ-HBCD, a meso form, were exposed to LinA2. Substantial conversion of (-)β-HBCD was observed, but all other stereoisomers were not transformed significantly. The enantiomeric excess (EE) of β-HBCDs increased up to 60% in 32 h, whereas EE values of α- and γ-HBCDs were not affected. Substrate conversion and product formation were described with second-order kinetic models. One major (P1β) and possibly two minor (P2β, P3β) metabolites were detected. Respective mass spectra showed the characteristic isotope pattern of PBCDEs, the HBr elimination products of HBCDs. Michaelis-Menten parameters KM=0.47 ± 0.07 μM and vmax=0.17 ± 0.01 μmoll(-1)h(-1) were deduced from exposure data with varying enzyme/substrate ratios. LinA2 is more substrate specific than LinB, the latter converted all tested HBCDs, LinA2 only one. The widespread HCH pollution favored the selection and evolution of bacteria converting these compounds. We found that LinA2 and LinB, two of these HCH-converting enzymes expressed in S. indicum B90A, also dehalogenate HBCDs to lower brominated compounds, indicating that structural similarities of both classes of compounds are recognized at the level of substrate-protein interactions. PMID:24444415

  19. 6β-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice.

    PubMed

    Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet; Brand, David D; Katsurada, Akemi; Majid, Dewan S A; Navar, L Gabriel; Gonzalez, Frank J; Malik, Kafait U

    2016-05-01

    6β-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in maleCyp1b1(+/+)andCyp1b1(-/-)mice. Castration ofCyp1b1(+/+)mice orCyp1b1(-/-)gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality inCyp1b1(+/+)mice, but restored these effects of angiotensin II inCyp1b1(-/-)or castratedCyp1b1(+/+)mice.Cyp1b1gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin-converting enzyme inCyp1b1(+/+)mice. However, inCyp1b1(-/-)or castratedCyp1b1(+/+)mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice. PMID:26928804

  20. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

    PubMed

    Hubers, Scott A; Brown, Nancy J

    2016-03-15

    Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  1. Crystal Structures of Protein Glutaminase and Its Pro Forms Converted into Enzyme-Substrate Complex*

    PubMed Central

    Hashizume, Ryota; Maki, Yukiko; Mizutani, Kimihiko; Takahashi, Nobuyuki; Matsubara, Hiroyuki; Sugita, Akiko; Sato, Kimihiko; Yamaguchi, Shotaro; Mikami, Bunzo

    2011-01-01

    Protein glutaminase, which converts a protein glutamine residue to a glutamate residue, is expected to be useful as a new food-processing enzyme. The crystal structures of the mature and pro forms of the enzyme were refined at 1.15 and 1.73 Å resolution, respectively. The overall structure of the mature enzyme has a weak homology to the core domain of human transglutaminase-2. The catalytic triad (Cys-His-Asp) common to transglutaminases and cysteine proteases is located in the bottom of the active site pocket. The structure of the recombinant pro form shows that a short loop between S2 and S3 in the proregion covers and interacts with the active site of the mature region, mimicking the protein substrate of the enzyme. Ala-47 is located just above the pocket of the active site. Two mutant structures (A47Q-1 and A47Q-2) refined at 1.5 Å resolution were found to correspond to the enzyme-substrate complex and an S-acyl intermediate. Based on these structures, the catalytic mechanism of protein glutaminase is proposed. PMID:21926168

  2. Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System

    PubMed Central

    Wadelius, M; Marshall, S E; Islander, G; Nordang, L; Karawajczyk, M; Yue, Q-Y; Terreehorst, I; Baranova, E V; Hugosson, S; Sköldefors, K; Pirmohamed, M; Maitland-van der Zee, A-H; Alfirevic, A; Hallberg, P; Palmer, C N A

    2014-01-01

    Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema. PMID:24960520

  3. Producing enzymes from molds to convert cellulose into glucose and alcohol. Final report

    SciTech Connect

    Bassi, S.; Curran, P.

    1982-11-29

    The following significant results were obtained: (1) extracts of various tree barks were made and used to determine if any of the chemicals had growth stimulating effects on the molds. The extracts from the oak and elm tree bark were very active in inducing and stimulating the mycelial growth of the molds Trichoderma reesei, Pleurotus ostreatus and Aspergillus awamori. Efforts to determine what specific chemical caused the increase in growth were unsuccessful but are being continued. This information will be very useful because it was discovered that by speeding and increasing the growth of the mold cells, it was also possible to speed and increase the production of the enzymes; (2) efforts to cultivate the mold Pleurotus ostreatus in the same culture with Trichoderma reesei were successful. When the two molds were cultured on an enriched cellulose media, it was discovered that the reesei produced large amounts of the beta glucosidase. Reesei produces very small amounts of this enzyme under normal conditions but this high production under coculture conditions may be due to the fact that Pleurotus ostreatus removes the glucose formed from the cellulose breakdown. Trichoderma reesei produces cellulases which convert cellulose into cellobiose and cellobiose is converted to glucose by the enzyme beta-glucosidase. In the presence of glucose the gene producing beta-glucosidase is repressed by the feedback mechanism. These surplus enzymes can then be used for saccharifying cellulose from wastepaper, wood pulp, cornstalks, wheat straw and other cellulosic materials and eventually produce alcohol; (3) efforts to produce mutants of the Trichoderma reesei by using the uv irradiation were unsuccessful; and (4) Zymomonas mobilis is capable of faster fermentation. The only drawback is that only low concentrations of glucose can be used. Mutants of Zymomonas resistant to higher alcohol levels would help in this process and are being looked into.

  4. Protein Kinase C Regulates the Cell Surface Activity of Endothelin-Converting Enzyme-1.

    PubMed

    Smith, A Ian; Lew, Rebecca A; Thomas, Walter G; Tochon-Danguy, Nathalie

    2006-09-01

    The potent vasoconstrictor endothelin is a 21 amino acid peptide whose principal physiological function is to regulate vascular tone. The generation of endothelin is crucially dependent on the local presence and activity of endothelin converting enzyme-1 (ECE-1) expressed on the surface of vascular endothelial cells. In this study, we have shown in endothelial cells that the enzyme is phosphorylated, and that phosphorylation is increased by phorbol ester stimulation of protein kinase C (PKC). Furthermore, by monitoring specific ECE-1 activity on the surface of live cells, we also show that following PKC activation, enzyme activity is significantly increased at the cell surface, where it is positioned to catalyse the generation of active endothelin. We believe this novel finding is unprecedented for a peptide processing enzyme. Indeed, this new knowledge regarding the control of endothelin production by regulating ECE-1 activity at the cell surface opens up a new area of endothelin biology and will provide novel insights into the physiology and pathophysiology of endothelin and endothelin-associated diseases. In addition, the information generated in these studies may provide valuable new insights into potential extra- and intracellular targets for the pharmacological and perhaps even therapeutic regulation of endothelin production and thus vascular tone. PMID:19617920

  5. Regional circulatory response to converting-enzyme inhibition in congestive heart failure

    PubMed Central

    Faxon, D. P.; Creager, M. A.; Halperin, J. L.

    1982-01-01

    1 To determine the distribution of flow, the regional haemodynamic response to 100 mg of captopril was determined in 36 patients with refractory cardiac heart failure. Measurements included forearm blood flow by venous occlusion plethysmography (eight patients), splanchnic blood flow by indocyanine green clearance (10 patients), and coronary blood flow by thermodilution (12 patients). 2 Cardiac index significantly rose in one hour (1.9 ± 0.1 to 2.2 ± 0.1 l/m/m2, p < 0.01) while forearm blood flow rose slightly (2.9 ± 0.8 to 3.2 ± 0.3 ml/100 ml/min). Renal blood flow rose significantly by 30% (344 ± 48 to 533 ± 82 ml/min, p < 0.02). Despite a fall in rate pressure product (8.8 ± 0.7 to 7.1 ± 0.5 mm Hg bt × 103, p < 0.02), coronary blood flow did not significantly change (160 ± 20 to 133 ± 12 ml/min), indicating an improved supply-demand relationship. 3 External myocardial efficiency improved (19 ± 3 to 26 ± 6%, p < 0.05). Coronary blood flow is unaffected and converting-enzyme inhibitor improves myocardial efficiency. This strategic reduction in vascular impedence distinguishes converting-enzyme inhibitors as a unique class of vasodilators in the treatment of coronary heart failure. PMID:6753899

  6. Usefulness of plasma renin activity in predicting haemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chronic heart failure. Experience in 100 consecutive patients.

    PubMed Central

    Packer, M; Medina, N; Yushak, M; Lee, W H

    1985-01-01

    The relation between plasma renin activity before treatment and the haemodynamic and clinical responses to converting enzyme inhibition was determined in 100 consecutive patients with severe chronic heart failure who were treated with captopril or enalapril. Initial doses of captopril produced significant increases in cardiac index and decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure, heart rate, and systemic vascular resistance that varied linearly with the pretreatment value for plasma renin activity. In contrast, there was no relation between the pretreatment activity and the magnitude of haemodynamic improvement after 1-3 months of treatment with the converting enzyme inhibitors, and, consequently, a similar proportion of patients with a high (greater than 6 ng/ml/h; greater than 4.62 mmol/l/h), intermediate (2-6 ng/ml/h; 1.54-4.62 mmol/l/h), and low (less than 2 ng/ml/h; less than 1.54 mmol/l/h) pretreatment value improved clinically during long term treatment (64%, 60%, and 64% respectively). Long term survival after one, two, and three years was similar in the three groups. Estimating the degree of activation of the renin-angiotensin system by measuring pretreatment plasma renin activity fails to predict the long term haemodynamic or clinical responses to converting enzyme inhibitors in patients with severe chronic heart failure, and thus appears to be of limited value in selecting those patients likely to benefit from treatment with these drugs. PMID:2994697

  7. Mutational Analysis of the Ras Converting Enzyme Reveals a Requirement for Glutamate and Histidine Residues

    PubMed Central

    Plummer, Lisa J.; Hildebrandt, Emily R.; Porter, Stephen B.; Rogers, Victoria A.; McCracken, Jay; Schmidt, Walter K.

    2010-01-01

    The Ras converting enzyme (RCE) promotes a proteolytic activity that is required for the maturation of Ras, the yeast a-factor mating pheromone, and certain other proteins whose precursors bear a C-terminal CAAX tetrapeptide motif. Despite the physiological importance of RCE, the enzymatic mechanism of this protease remains undefined. In this study, we have evaluated the substrate specificity of RCE orthologs from yeast (Rce1p), worm, plant, and human and have determined the importance of conserved residues toward enzymatic activity. Our findings indicate that RCE orthologs have conserved substrate specificity, cleaving CVIA, CTLM, and certain other CAAX motifs, but not the CASQ motif, when these motifs are placed in the context of the yeast a-factor precursor. Our mutational studies of residues conserved between the orthologs indicate that an alanine substitution at His194 completely inactivates yeast Rce1p enzymatic activity, whereas a substitution at Glu156 or His248 results in marginal activity. We have also determined that residues Glu157, Tyr160, Phe190, and Asn252 impact the substrate selectivity of Rce1p. Computational methods predict that residues influencing Rce1p function are all near or within hydrophobic segments. Combined, our data indicate that yeast Rce1p function requires residues that are invariably conserved among an extended family of prokaryotic and eukaryotic enzymes and that these residues are likely to lie within or immediately adjacent to the transmembrane segments of this membrane-localized enzyme. PMID:16361710

  8. Palmitoylation of the three isoforms of human endothelin-converting enzyme-1.

    PubMed Central

    Schweizer, A; Löffler, B M; Rohrer, J

    1999-01-01

    Endothelin-converting enzyme-1 (ECE-1) is a membrane-bound metalloprotease that catalyses the conversion of inactive big endothelins into active endothelins. Here we have examined whether the three isoforms of human ECE-1 (ECE-1a, ECE-1b and ECE-1c) are modified by the covalent attachment of the fatty acid palmitate and have evaluated a potential functional role of this modification. To do this, wild-type and mutant enzymes were expressed and analysed by metabolic labelling with [3H]palmitate, immunoprecipitation and SDS/PAGE. All three ECE-1 isoforms were found to be palmitoylated via hydroxylamine-sensitive thioester bonds. In addition, the isoforms showed similar levels of acylation. Cys46 in ECE-1a, Cys58 in ECE-1b and Cys42 in ECE-1c were identified as sites of palmitoylation and each of these cysteines accounted for all the palmitoylation that occured in the corresponding isoform. Immunofluorescence analysis demonstrated further that palmitoylated and non-palmitoylated ECE-1 isoforms had the same subcellular localizations. Moreover, complete solubility of the three isoforms in Triton X-100 revealed that palmitoylation does not target ECE-1 to cholesterol and sphingolipid-rich membrane domains or caveolae. The enzymic activities of ECE-1a, ECE-1b and ECE-1c were also not significantly affected by the absence of palmitoylation. PMID:10359648

  9. Effect of renin-angiotensin system on sodium intake.

    PubMed Central

    Chiaraviglio, E

    1976-01-01

    1. Water and saline intake was measured in rats depleted of Na by I.P. dialysis. Na intake was prevented 180 min but not 60-90 min after bilateral nephrectomy. Unilateral nephrectomy as well as ureteral ligature had no effect on Na intake. 2. Renin (3u.) injected I.P. re-established the Na appetite abolished by nephrectomy. 3. Angiotensin I (5 ng) or II (5-40 ng) injected into the 3rd ventricle, also restored the Na intake and this effect was dose-dependent. 4. The angiotensin converting-enzyme inhibitor Sq 20,881 (1 mg/kg) inhibited the effect of AI but not that of AII in restoring Na intake. 5. It is concluded that the kidneys might play a role in the regulation of Na intake through the renin-angiotensin system. PMID:1255521

  10. Monocyte Tumor Necrosis Factor-α–Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation*

    PubMed Central

    O’Callaghan, David J. P.; O’Dea, Kieran P.; Scott, Alasdair J.; Takata, Masao

    2015-01-01

    Objectives: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α–converting enzyme baseline and inducible activity profiles. Design: Observational clinical study. Setting: Mixed surgical/medical teaching hospital ICU. Patients: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. Interventions: None. Measurements and Main Results: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α–converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients’ monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α–converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α–converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α–converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α–converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α–converting enzyme activity could

  11. Mitochondrial uncoupling proteins regulate angiotensin‐converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies

    PubMed Central

    Maubaret, Cecilia; Pedersen‐Bjergaard, Ulrik; Brull, David J.; Gohlke, Peter; Payne, John R.; World, Michael; Thorsteinsson, Birger; Humphries, Steve E.; Montgomery, Hugh E.

    2015-01-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.

  12. Long-Term Regulation of the Local Renin-Angiotensin System in the Myocardium of Spontaneously Hypertensive Rats by Feeding Bioactive Peptides Derived from Spirulina platensis.

    PubMed

    Pan, Huanglei; She, Xingxing; Wu, Hongli; Ma, Jun; Ren, Difeng; Lu, Jun

    2015-09-01

    This study investigated the long-term (8 weeks) anti-hypertensive effects of 10 mg/kg tripeptides isolated from Spirulina platensis, Ile-Gln-Pro (IQP) and Val-Glu-Pro (VEP), and S. platensis hydrolysates (SH) on spontaneously hypertensive rats. The treatment period was 6 weeks, and observation continued for another 2 weeks. After treatment, weighted systolic blood pressure, weighted diastolic blood pressure, left ventricular mass index, and right ventricular mass index of groups treated with IQP, VEP, and SH were significantly lower than those of the group treated with distilled water, even when the treatments had been withdrawn for 2 weeks. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting showed the mRNA expression levels and protein/peptide concentrations of the main components of the renin angiotensin system in myocardium were significantly affected by treatment: angiotensin converting enzyme, angiotensin II, and angiotensin type 1 receptor were down-regulated, whereas angiotensin type 2 receptor, angiotensin converting enzyme 2, angiotensin-(1-7), and Mas receptor were up-regulated. PMID:26245714

  13. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

  14. Hypotensive effects and angiotensin-converting enzyme inhibitory peptides of reishi (Ganoderma lingzhi) auto-digested extract.

    PubMed

    Tran, Hai-Bang; Yamamoto, Atsushi; Matsumoto, Sayaka; Ito, Hisatomi; Igami, Kentaro; Miyazaki, Toshitsugu; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2014-01-01

    Reishi (Ganoderma lingzhi) has been used as a traditional medicine for millennia. However, relatively little is known about this mushroom's proteins and their bioactivities. In this study, we used reishi's own proteases to hydrolyze its protein and obtained auto-digested reishi (ADR) extract. The extract was subjected to in vitro assays and administered to spontaneous hypertensive rats (SHRs) to determine its potential for use as a hypotensive medication. Bioassay-guided fractionation and de novo sequencing were used for identifying the active compounds. After 4 h administration of ADR, the systolic pressure of SHRs significantly decreased to 34.3 mmHg (19.5% change) and the effect was maintained up to 8 h of administration, with the decrease reaching as low as 26.8 mmHg (15% reduction-compare to base line a decrease of 26.8 mmHg is less than a decrease of 34.3 mmHg so it should give a smaller % reduction). Eleven peptides were identified and four of them showed potent inhibition against ACE with IC50 values ranging from 73.1 μM to 162.7 μM. The results showed that ADR could be a good source of hypotensive peptides that could be used for antihypertensive medication or incorporation into functional foods. PMID:25178067

  15. T-lymphocyte induction of human monocyte angiotensin converting enzyme (ACE) is not dependent upon T-lymphocyte proliferation

    SciTech Connect

    Vuk-Pavlovic, Z.; Rohrbach, M.S.

    1986-03-05

    Human peripheral blood monocytes cultured in serum free media for seven days show a basal activity of the ectoenzyme ACE which is augmented 2-3 times by the presence of autologous peripheral blood T-lymphocytes. Since these two cell types are also involved in autologous mixed lymphocyte reaction if serum is present, the authors compared the ability of T-cells to stimulate ACE activity in the presence or absence of proliferation (measured by /sup 3/H-thymidine incorporation). By the seventh day, cultures with 5% AB/sup +/ serum showed significant increase in proliferation but no increase in ACE activity compared to the serum free cultures. Even higher proliferation rate achieved by co-culturing T-lymphocytes with allogeneic monocytes did not increase ACE production; on the contrary, ACE activity remained at the basal level. Monocyte-T-cell co-cultures stimulated with increasing concentrations of ConA or PHA showed dose dependent increases in proliferation but parallel decreases in ACE activity. Addition of soluble antigen (Candida albicans) also enhanced proliferation but not ACE synthesis. They conclude that T-lymphocyte induction of monocyte ACE is a result of cooperation between autologous cells which is not dependent upon T-cell proliferation.

  16. Pilot scale production of angiotensin I-converting enzyme (ACE) inhibitory peptides from aflatoxin contaminated peanut meal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peanut meal (PM) is the high protein (45-50%) by-product remaining after commercial extraction of peanut (Arachis hypogaea L.) oil. Applications of PM are limited to feeds and fertilizers because it typically contains a high concentration of aflatoxin. Recently, our lab has developed a process to r...

  17. Regional differences in endothelin converting enzyme activity in rat brain: inhibition by phosphoramidon and EDTA.

    PubMed Central

    Warner, T. D.; Budzik, G. P.; Matsumoto, T.; Mitchell, J. A.; Förstermann, U.; Murad, F.

    1992-01-01

    1. It has been demonstrated previously that conversion of big endothelin-1 (bET-1) to endothelin-1 (ET-1) is inhibited in vitro and in vivo by phosphoramidon. In addition, ET-1 binding sites and mRNA have been shown within the brain. Here we expand upon our previous observation that rat brain contains phosphoramidon-inhibitable endothelin converting enzyme (ECE) and show that this activity is not uniformly distributed throughout the brain. 2. ECE activity was detected by a bioassay which depended upon the 10,000 fold difference in potency between bET-1 and ET-1 as stimulants of guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in kidney epithelial (PK1) cells of the pig. Data were confirmed by specific enzyme-linked immunosorbent assay (ELISA) employing antibody directed against ET-1/3(17-21). 3. Following homogenization of the whole brain and ultracentrifugation the 100,000 g pellet contained greater than 4 times more ECE activity than the cytosol. Washing of the pellet with KCl (1 M) and extraction with the detergent CHAPS (20 mM) revealed a phosphoramidon-inhibitable ECE within the residual particulate fraction (nominally classified as the cytoskeletal fraction). Phosphoramidon (IC50, approx. 5 microM) or EDTA inhibited the conversion of bET-1 to ET-1 by the cytoskeletal fraction of rat brain by more than 60%.2+ 4. Following dissection of rat brain into olfactory bulb, cerebral cortex, striatum, hippocampus, cerebellum, midbrain (including thalamus), hypothalamus and medulla oblongata (including pons) the greatest ECE was detected in the hypothalamus and medulla oblongata.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393292

  18. Characterization of Two Streptomyces Enzymes That Convert Ferulic Acid to Vanillin

    PubMed Central

    Yang, Wenwen; Tang, Hongzhi; Ni, Jun; Wu, Qiulin; Hua, Dongliang; Tao, Fei; Xu, Ping

    2013-01-01

    Production of flavors from natural substrates by microbial transformation has become a growing and expanding field of study over the past decades. Vanillin, a major component of vanilla flavor, is a principal flavoring compound used worldwide. Streptomyces sp. strain V-1 is known to be one of the most promising microbial producers of natural vanillin from ferulic acid. Although identification of the microbial genes involved in the biotransformation of ferulic acid to vanillin has been previously reported, purification and detailed characterization of the corresponding enzymes with important functions have rarely been studied. In this study, we isolated and identified 2 critical genes, fcs and ech, encoding feruloyl-CoA synthetase and enoyl-CoA hydratase/aldolase, respectively, which are involved in the vanillin production from ferulic acid. Both genes were heterologously expressed in Esc