Lung Angiotensin Converting Enzyme Research Articles

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury.

Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats. Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response. Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors. Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

Exploring the Mechanism of Periplogenin in the treatment of Lung Cancer Based on Network Pharmacology and Molecular Biology

Lung cancer (the 5-year survival rate is only about 16%) has a low survival rate, and more-effective drugs are urgently needed. Our team discovered that cortex Periplocae Radicis has obvious toxic effects on various cancer cells, including lung cancer cells. However, the mechanism is not clear. Therefore, we used the PubChem database to obtain periplogenin as the target of therapeutic drugs and the TCGA database to obtain differential genes of lung cancer. The results showed that MMP9, PPARG, BMP2, and TGFB2 were the core proteins of periplogenin acting on lung adenocarcinoma (LUAD), and MMP9, angiotensin-converting enzyme (ACE), BMP2, PPARG, MMP13, MMP3, and TGFB2 were the core proteins of periplogenin acting on lung squamous cell carcinoma (LUCS). Through gene ontology (GO) enrichment analysis, it was found that periplogenin mainly acted on LUAD via fatty acid binding, metallopeptidase activity, and monocarboxylic acid binding, and mainly acted on lung squamous carcinoma (LUSC) via endopeptidase activity, metallopeptidase activity, and serine-type peptidase activity. Kyoto Encyclopedia of Genes, and Genomes (KEGG) analysis revealed that the IL-17 signaling pathway, fluid shear stress, atherosclerosis, hepatocellular carcinoma, and so on, were the main signaling pathways of periplogenin acting on LUSC, whereas glycolysis/gluconeogenesis, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were major signaling pathways of periplogenin acting on LUAD. This shows that treatment of lung cancer can be achieved through multi-targeted, and multi-channel periplogenin activity.

Human Tissue Angiotensin Converting Enzyme (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and Heart.

Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman’s p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman’s Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.

The duration of embryo culture after mouse IVF differentially affects cardiovascular and metabolic health in male offspring.

STUDY QUESTIONDo the long-term health outcomes following IVF differ depending upon the duration of embryo culture before transfer?SUMMARY ANSWERUsing a mouse model, we demonstrate that in male but not female offspring, adverse cardiovascular (CV) health was more likely with prolonged culture to the blastocyst stage, but metabolic dysfunction was more likely if embryo transfer (ET) occurred at the early cleavage stage.WHAT IS KNOWN ALREADYART associate with increased risk of adverse CV and metabolic health in offspring, and these findings have been confirmed in animal models in the absence of parental infertility issues. It is unclear which specific ART treatments may cause these risks. There is increasing use of blastocyst, versus cleavage-stage, transfer in clinical ART which does not appear to impair perinatal health of children born, but the longer-term health implications are unknown.STUDY DESIGN, SIZE, DURATIONFive mouse groups were generated comprising: (i) natural mating (NM)—naturally mated, non-superovulated and undisturbed gestation; (ii) IV-ET-2Cell—in-vivo derived two-cell embryos collected from superovulated mothers, with immediate ET to recipients; (iii) IVF-ET-2Cell—IVF generated embryos, from oocytes from superovulated mothers, cultured to the two-cell stage before ET to recipients; (iv) IV-ET-BL—in-vivo derived blastocysts collected from superovulated mothers, with immediate ET to recipients; (v) IVF-ET-BL—IVF generated embryos, from oocytes from superovulated mothers, cultured to the blastocyst stage before ET to recipients. Both male and female offspring were analysed for growth, CV and metabolic markers of health. There were 8–13 litters generated for each group for analyses; postnatal data were analysed by multilevel random effects regression to take account of between-mother and within-mother variation and litter size.PARTICIPANTS/MATERIALS, SETTINGS, METHODSC57/BL6 female mice (3–4 weeks old) were used for oocyte production; CBA males for sperm with human tubal fluid medium were used for IVF. Embryos were transferred (ET) to MF1 pseudo-pregnant recipients at the two-cell stage or cultured in synthetic oviductal medium enriched with potassium medium to the blastocyst stage before ET. Control in-vivo embryos from C57BL6 × CBA matings were collected and immediately transferred at the two-cell or blastocyst stage. Postnatal assays included growth rate up to 27 weeks; systolic blood pressure (SBP) at 9, 15 and 21 weeks; lung and serum angiotensin-converting enzyme (ACE) activity at time of cull (27 weeks); glucose tolerance test (GTT; 27 weeks); basal glucose and insulin levels (27 weeks); and lipid accumulation in liver cryosections using Oil Red O imaging (27 weeks).MAIN RESULTS AND THE ROLE OF CHANCEBlastocysts formed by IVF developed at a slower rate and comprised fewer cells that in-vivo generated blastocysts without culture (P < 0.05). Postnatal growth rate was increased in all four experimental treatments compared with NM group (P < 0.05). SBP, serum and lung ACE and heart/body weight were higher in IVF-ET-BL versus IVF-ET-2Cell males (P < 0.05) and higher than in other treatment groups, with SBP and lung ACE positively correlated (P < 0.05). Glucose handling (GTT AUC) was poorer and basal insulin levels were higher in IVF-ET-2Cell males than in IVF-ET-BL (P < 0.05) with the glucose:insulin ratio more negatively correlated with body weight in IVF-ET-2Cell males than in other groups. Liver/body weight and liver lipid droplet diameter and density in IVF-ET-2Cell males were higher than in IVF-ET-BL males (P < 0.05). IVF groups had poorer health characteristics than their in-vivo control groups, indicating that outcomes were not caused specifically by background techniques (superovulation, ET). No consistent health effects from duration of culture were identified in female offspring.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONResults from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models, in this case, in the absence of confounding parental infertility, in assessing the safety of ART manipulations.WIDER IMPLICATIONS OF THE FINDINGSThe study indicates that longer duration of embryo culture after IVF up to blastocyst before ET leads to increased dysfunction of CV health in males compared with IVF and shorter cleavage-stage ET. However, the metabolic health of male offspring was poorer after shorter versus longer culture duration. This distinction indicates that the origin of CV and metabolic health phenotypes after ART may be different. The poorer metabolic health of males after cleavage-stage ET coincides with embryonic genome activation occurring at the time of ET.STUDY FUNDING/COMPETING INTEREST(S)This work was supported through the European Union FP7-CP-FP Epihealth programme (278418) and FP7-PEOPLE-2012-ITN EpiHealthNet programme (317146) to T.P.F., the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F007450/1) to T.P.F., and the Saudi government, University of Jeddah and King Abdulaziz University to A.A. The authors have no conflicts of interest to declare.

Improving efficiency of an angiotensin converting enzyme inhibitory peptide as multifunctional peptides

Bioactive peptides have been defined as specific protein fragments that have numerous biological activities. The aim of this study was to introduce three multifunctional peptides. Hence, we used rabbit lung angiotensin converting enzyme (ACE) inhibitor peptide AFKDEDTEEVPFR to prepare two analogous peptides KDEDTEEVP and KDEDTEEVH. ACE inhibitory, antioxidant, and antimicrobial activities of three synthetic peptides were investigated. Among the three peptides, KDEDTEEVP exhibited the highest ACE inhibitory activity with IC50 value of 69.63 ± 2.51 μM. Furthermore, the results of fluorescence spectroscopy and molecular modeling showed that KDEDTEEVP had more affinity to ACE than other peptides. The peptide of KDEDTEEVH showed the strongest antioxidant scavenging capacity on DPPH radicals (EC50 = 135 ± 9.62 μM), hydroxyl radicals (EC50 = 144 ± 8.73 μM), and ABTS radicals (EC50 = 62 ± 4.52%). Moreover, it showed the highest activity in iron-chelating test (EC50 = 226 ± 14.13 μM) and could also effectively inhibit the peroxidation of linoleic acid. The antimicrobial activity results showed that KDEDTEEVH had higher efficiency against Gram-positive than Gram-negative bacteria with MIC values of higher than 205 ± 10.75 μM. Although there was not a direct correlation between ACE inhibitor and antioxidant activity for analogous peptides, both analogous peptides exhibited more efficiency than the mother peptide. Thus, they can be considered as multifunctional peptides and would be beneficial ingredient to be used in food and drug industry.

ACE phenotyping in human heart.

AimsAngiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs.Methods and resultsWe performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10–15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. “Conformational fingerprint” of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles.ConclusionsSignificant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

AN IN VITRO STUDY OF CINNAMOMUM ZEYLANICUM AS NATURAL INHIBITOR OF ANGIOTENSIN-CONVERTING ENZYME (ACE) ON SHEEP (OVIS ARIES) TISSUES

ABSTRACTObjective: The present study was aimed to find the angiotensin-converting enzyme (ACE) inhibitory activity using the methanolic extract ofCinnamomum zeylanicum (as a natural inhibitor) on sheep tissues as the enzyme source.Methods: Hippuryl-histidyl-leucine (HHL) as a substrate, tissue ACE activity was measured spectrophotometrically at 228 nm. For an incubationperiod of 30 minutes at 37°C, the linearity of ACE activity of kidney, lung, and testis enzyme was established. A known medicinal plant C. zeylanicumwas used as natural inhibitor of ACE. In this enzyme assay, inhibitory effect of methanolic extract of C. zeylanicum on kidney, lung and testicular ACEwas determined. ACE activity was confirmed by captopril, a standard inhibitor of ACE.Results: In the presence of a methanolic extract of C. zeylanicum (10:1), ACE activity was determined and this has inhibited ACE activity verysignificantly. C. zeylanicum leaves extract has reduced sheep kidney, lung, and testis ACE activity by 70.06%, 12.63%, and 20.23%, respectively.Conclusion: Significant inhibition was observed in the kidney ACE than in lung and testis ACE activity. This can propose that there may be a possiblerole in controlling blood pressure or reduction in cardiovascular diseases. Some plants with the great medicinal property may be considered aspromising sources of natural inhibitors of ACE for medicine and commercial uses. This comprehensive study may show numerous beneficial effects asa potential therapeutic agent for lowering blood pressure.Keywords: Angiotensin-converting enzyme, Natural angiotensin-converting enzyme inhibitor, Kinetic assay, Hippuryl-histidyl-leucine, Cinnamomumzeylanicum, Cardiovascular diseases.

Tissue Specificity of Human Angiotensin I-Converting Enzyme

BackgroundAngiotensin-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 FindingsWe 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.ConclusionsDramatic 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.

Acute Cadmium Exposure Reduces the Local Angiotensin I Converting Enzyme Activity and Increases the Tissue Metal Content.

Cadmium exposure causes health problems that may result from increased oxidative stress and from changes in enzyme metalloproteases activities as angiotensin-converting enzyme (ACE). In fact, cadmium produces inhibition of serum ACE but is not known how cadmium acts on tissue ACE activity and whether following acute exposure tissue cadmium content is increased. In order to elucidate these issues, a cadmium bolus was injected intravenously in Wistar rats, and the cadmium content and the ACE activity were measured in the serum, lungs, aorta and kidneys. Moreover, in order to clarify if the cadmium affects directly tissue ACE activity, acute metal exposure in vitro was performed. Our results demonstrated that 120min following cadmium administration, blood and organ cadmium content were both increased. Serum and lung ACE activity were reduced following acute cadmium exposure, but aortic and kidney ACE activities were not affected. The inhibitory effects induced by cadmium on ACE activity were also observed in the serum, as well as the lungs and the aorta, but not in the kidneys following in vitro exposure. Moreover, the inhibitory effects induced by cadmium on ACE activity were partially restored in vitro by zinc supplementation, suggesting a possible interaction or competition between cadmium and zinc by at the active site of ACE. Summarising, our results suggest that acute cadmium exposure promotes an increase in the tissue metal content that was accompanied by direct inhibition of serum, aorta and lung ACE activity, an effect that is cadmium concentration-dependent and is partially reversed by zinc.

Inhibitory Efficacy and Biological Variability of Tryptophan Containing Dipeptides on Human Plasma Angiotensin Converting Enzyme Activity

Background: Hypertension remains a major unsolved health problem with life threatening consequences. A potential innovative prophylactic approach against its development may be supplementation of daily food with natural antihypertensive compounds. In our work we tested the efficacy of novel tryptophan containing dipeptides from whey protein with respect to their inhibitory potency on the angiotensin converting enzyme (ACE) as well as their stability in human plasma. Methods: ACE activity from rabbit lung and human plasma as well as recombinant human ACE activity were measured using benzoyl-glycyl-histidyl-leucine as a substrate. Product formation of hippuric acid and histidyl-leucine was assessed by UV-HPLC. The stability of the peptides was quantified in human plasma and, in case of incubation with recombinant human angiotensin converting enzyme, in buffer. Variability of ACE inhibiting activity of peptides was assessed via analysis of coefficient of variation with particular reference to true inter-individual variability corrected for methodological and analytical errors. Results: Isoleucine-tryptophan (IW) had a stronger ACE inhibiting potency (IC50 of 1.9 and 38.8 μmol/l with rabbit lung and human plasma ACE, respectively) than other tested peptides, i.e. glutamic acid-tryptophan (EW), tryptophanleucine (WL) and tryptophan-glutamic acid (WE). However, stability of IW showed a high degree of variability in plasma of different volunteers. In contrast EW, WL, WE were relatively stable in plasma and no major inter-individual variability was observed. Inhibition of plasma proteases extended plasma half-life of IW significantly. ACE did not contribute to peptide elimination. Conclusion: Milk whey protein represents a valuable source for bioactive peptides with ACE inhibitory potency that can be used as a food supplement to prevent, or in combination with other pharmaceutical agents to treat hypertension. However, in addition to the ACE inhibitory efficacy the stability of these peptides must be considered for in vivo ACE inhibition.

In vitro effects of ultra-low and low doses of radiation produced by sources of different nature and power on enzymes

The effects of low and ultra-low doses of X-ray radiation and neutron fluxes produced by continuous-wave and pulsed sources of different nature and power on the activity of plant peroxidases and the bovine lung angiotensin-converting enzyme were studied. Certain ranges of doses (including ultra-low), the exposure to which under particular conditions causes the in vitro activation and/or inactivation of the enzymes, were found. Possible factors responsible for this phenomenon are discussed.

GW24-e0025 Endothelial blockade induced RAAS expression up-regulation and blood pressure regulation

ObjectivesTo compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure...

GW24-e0020 The effect of dual blockade of RAAS and endothelin system in blood pression control

ObjectivesTo compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure...

The Role of Angiotensin II on Sodium Appetite After a Low‐Sodium Diet

The present study aimed to investigate the role of angiotensin II (AngII) on sodium appetite in rats subjected to a normal or a low-sodium diet (1% or >0.1% NaCl) for 4days. During sodium restriction, a reduction in water intake, urinary volume and sodium excretion was observed. After a low-sodium diet, we observed decreased plasma protein concentrations and haematocrit associated with a slight reduction in arterial pressure, without any significant changes in heart rate, natraemia, corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus and corticosterone levels. After providing hypertonic saline, there was an increase in saline intake followed by a small increase in water intake, resulting in an enhanced saline intake ratio and the recovery of arterial pressure. Sodium deprivation increased plasma but not brain Ang I and II concentrations. A low-sodium diet increased kidney renin and liver angiotensinogen mRNA levels but not lung angiotensin-converting enzyme mRNA expression. Moreover, Ang II type 1a receptor mRNA expression was increased in the subfornical organ and the dorsal raphe nucleus and decreased in the medial preoptic nuclei, without changes in the paraventricular nucleus and the nucleus of solitary tract after a low-sodium diet. Blockade of AT(1) receptors or brain Ang II synthesis led to a reduction in sodium intake after a low-sodium diet. Intracerebroventricular injection of Ang II led to a similar increase in sodium and water intake in the control and low-sodium diet groups. In conclusion, the results of the present study suggest that Ang II is involved in the increased sodium appetite after a low-sodium diet.

Mitigation of radiation induced pulmonary vascular injury by delayed treatment with captopril

A single dose of 10 Gy radiation to the thorax of rats results in decreased total lung angiotensin-converting enzyme (ACE) activity, pulmonary artery distensibility and distal vascular density while increasing pulmonary vascular resistance (PVR) at 2 months post-exposure. In this study, we evaluate the potential of a renin-angiotensin system (RAS) modulator, the ACE inhibitor captopril, to mitigate this pulmonary vascular damage. Rats exposed to 10 Gy thorax only irradiation and age-matched controls were studied 2 months after exposure, during the development of radiation pneumonitis. Rats were treated, either immediately or 2 weeks after radiation exposure, with two doses of the ACE inhibitor, captopril, dissolved in their drinking water. To determine pulmonary vascular responses, we measured pulmonary haemodynamics, lung ACE activity, pulmonary arterial distensibility and peripheral vessel density. Captopril, given at a vasoactive, but not a lower dose, mitigated radiation-induced pulmonary vascular injury. More importantly, these beneficial effects were observed even if drug therapy was delayed for up to 2 weeks after exposure. Captopril resulted in a reduction in pulmonary vascular injury that supports its use as a radiomitigator after an unexpected radiological event such as a nuclear accident.

DUAL BLOCKADE OF RAAS & ET SYSTEM IN BLOOD PRESSURE REGULATION

ObjectivesTo compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure...

Losartan exerts no protective effects against acute pulmonary embolism-induced hemodynamic changes

The acute obstruction of pulmonary vessels by venous thrombi is a critical condition named acute pulmonary embolism (APE). During massive APE, severe pulmonary hypertension may lead to death secondary to right heart failure and circulatory shock. APE-induced pulmonary hypertension is aggravated by active pulmonary vasoconstriction. While blocking the effects of some vasoconstrictors exerts beneficial effects, no previous study has examined whether angiotensin II receptor blockers protect against the hemodynamic changes associated with APE. We examined the effects exerted by losartan on APE-induced hemodynamic changes. Hemodynamic evaluations were performed in non-embolized lambs treated with saline (n = 4) and in lambs that were embolized with silicon microspheres and treated with losartan (30 mg/kg followed by 1 mg/kg/h, n = 5) or saline (n = 7) infusions. The plasma and lung angiotensin-converting enzyme (ACE) activity were assessed using a fluorometric method. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 21 ± 2 mmHg and 375 ± 20 dyn s cm⁻⁵ m⁻², respectively (P < 0.05). Losartan decreased MPAP significantly (by approximately 15%), without significant changes in PVRI and tended to decrease cardiac index (P > 0.05). Lung and plasma ACE activity were similar in both embolized and non-embolized animals. Our findings show evidence of lack of activation of the renin-angiotensin system during APE. The lack of significant effects of losartan on the pulmonary vascular resistance suggests that losartan does not protect against the hemodynamic changes found during APE.

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Radical scavenging and angiotensin converting enzyme inhibitory activities of standardized extracts of Ficus racemosa stem bark

The present study evaluated the radical scavenging and angiotensin converting enzyme (ACE) inhibitory activity of cold and hot aqueous extracts of Ficus racemosa (Moraceae) stem bark. The extracts were standardized using HPLC. Radical scavenging activity was determined using 1,1-diphenyl-2-picrylhydrazyl radical and angiotensin converting enzyme inhibitory activity using rabbit lung and partially purified porcine kidney ACE. HPLC profiles of cold aqueous extract (FRC) showed the presence of bergenin, an isocoumarin, while hot aqueous extract (FRH) was found to contain ferulic acid, kaempferol and coumarin in addition to bergenin. FRH showed significantly higher (p ≤ 0.01) radical scavenging activity than FRC and butylated hydroxytoluene (BHT), consequently resulting in a significantly lower (p ≤ 0.01) IC₅₀ value than FRC and BHT. Both the extracts exhibited a dose dependent inhibition of porcine kidney and rabbit lung ACE. FRH showed significantly higher (p ≤ 0.01) activity than FRC with lower IC(50) values of 1.36 and 1.91 μg/mL respectively, for porcine kidney and rabbit lung ACE, compared with those of FRC (128 and 291 μg/mL). Further, a significant correlation (r = 0.893; p ≤ 0.05) was observed between radical scavenging activity and ACE-inhibitory activity. This is the first report on the ACE-inhibitory activity of F. racemosa stem bark suggesting its potential to be utilized as a therapeutic alternative for hypertension.

Expression of angiotensin converting enzyme and angiotensin converting enzyme 2 gene in lung of paraquat poisoning rats and protection of sodium dimercaptopropane sulfonate

To investigate the expression of angiotensin converting enzyme (ACE) and ACE2 Gene in lung of paraquat poisoning rats and the protection of sodium dimercaptopropane sulfonate (Na-DMPS). One hundred SD male rats were randomly equally divided into 4 groups:normal control group (10 rats), drug control group (40 rats), paraquat poisoning group (40 rats) and drug intervention group(40 rats). The paraquat poisoning and drug intervention group rats were injected intraperitoneally by paraquat (20 mg/kg). The rats in drug intervention group rats were protected by intraperitoneal injection with Na-DMPS (200 mg/kg) 15 min before exposure of paraquat. Behavioral changes of the rats and histological changes of lung tissues under light microscope were observed. And the expression of ACE and ACE2 mRNA in lung tissues of rats both in paraquat poisoned group and drug intervention group were measured by RT-PCR at different time of 6 h, 24 h, 3 and 7 d after poisoning. The poisoning symptoms of shortness of breath, cramps appeared and deteriorated progressively in rats after paraquat exposure and the protection of NA-DMPS could delay and reduce these symptoms significantly. Histological appearance of disorganization of pulmonary capillary and alveolus, exudation in alveolar space, pulmonary edema, severe bleeding, and inflammatory cells infiltration were obvious in lungs of rats after paraquat poisoning, whereas the histological changes were extenuated by protection of NA-DMPS. As compared with normal control group (NC group), the expressions of ACE, ACE2 mRNA in lung tissue decreased, and the lowest level of ACE mRNA expressions appeared at 24 h (0.457 +/- 0.262), on 3 d (0.385 +/- 0.179) after Paraquat exposure (P < 0.05), while lowest level of ACE2 mRNA expressions appeared on 3 d (0.415 +/- 0.247), 7 d (0.365 +/- 0.215) (P < 0.05). As compared with paraquat poisoned group, the expressions of ACE mRNA in lung tissue of rats in NA-DMPS protected group increased significantly at 24 h (0.739 +/- 0.558) and 3 d (0.749 +/- 0.414) (P < 0.05), while the expressions of ACE2 mRNA increased markedly on 3 d (0.584 +/- 0.345) and 7 d (0.493 +/- 0.292) (P < 0.05). But the expression of ACEmRNA and ACE2 mRNA in lungs had no statistical significance between normal control group and drug intervention group (P > 0.05). The expressions of ACE and ACE2 mRNA in lung tissue of the rats with paraquat poisoning are decreased. Na-DMPS can effectively improve the balance of RAS in local lung tissue and reduce the pathological changes of lung tissue, delay the poisoning symptoms and show protective effects for acute lung injury induced by paraquat.