In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. II. Implementation and application

We measured pulmonary angiotensin-converting enzyme (ACE) kinetics with fluorine-18 captopril and positron emission tomographic (PET) imaging in five control dogs and in five dogs after 20–30 min of left caudal lobe (LCL) hypoxic ventilation. Time-activity data obtained with PET were interpreted with a compartmental receptor model relating changes in tissue and blood activity to one another within the region. In control dogs, the mean ratio of regional blood flow (measured by PET) between left and right dorsal lung regions was 0.90 +/- 0.16 (SD) vs. 0.54 +/- 0.24 (P < 0.05) in LCL hypoxic dogs. In control dogs, the amount of perfused unbound enzyme normalized to regional extravascular water concentration (Bmax/EVLW) averaged 13.3 +/- 8.9 x 10(-6) mmol ACE/ml EVLW; the ratio of regional values between the left and right sides was 1.02 +/- 0.18. In the LCL hypoxic dogs, Bmax/EVLW was 9.7 +/- 11.3 x 10(-6) mmol/ml hypoxic lung region and the ratio was 0.47 +/- 0.31 (P < 0.05). In control dogs, the coefficient of variation for Bmax/EVLW among regions was only 19 +/- 10%, although the between-dog variation was greater (64 +/- 4%). We conclude that this completely noninvasive method appears to be a promising approach for evaluating the expression of pulmonary ACE in vivo.

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In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. I. Theory and error analysis

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.3.1158 ◽

1995 ◽

Vol 78 (3) ◽

pp. 1158-1168 ◽

Cited By ~ 9

Author(s):

J. Markham ◽

T. J. McCarthy ◽

M. J. Welch ◽

D. P. Schuster

Keyword(s):

Angiotensin Converting Enzyme ◽

Enzyme Kinetics ◽

Kinetic Parameters ◽

Converting Enzyme ◽

Activity Data ◽

Time Activity ◽

Fast Kinetics ◽

Trans Conformer ◽

Kinetics Of

We developed a procedure for measuring pulmonary angiotensin-converting enzyme kinetics with fluorine-18 fluorocaptopril and positron emission tomography (PET). The method is based on the application of a compartmental receptor model that represents the kinetics of two species of ligand, presumably the trans and cis conformers of captopril. The input function was characterized and includes corrections for the labeled metabolites of fluorocaptopril. Application of the procedure to lung time-activity data obtained with PET produced estimates of kinetic parameters demonstrating fast kinetics for one conformer and slower kinetics for the other. Simulation studies were performed to evaluate the sensitivity of the estimated parameters to errors in the model assumptions and in measured values for variables required for analysis of the PET data. Estimates for two of the kinetic parameters, the amount of perfused unbound functional enzyme normalized to regional lung volume and the association rate constant for the trans conformer, were relatively stable even with large errors in the input data, varying < 30% from true values for all perturbations. Thus, the procedure produces reliable estimates of the kinetics of the trans conformer of captopril as well as theoretical curves that are close to the observed data.

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Transport, In Vivo Antihypertensive Effect, and Pharmacokinetics of an Angiotensin-Converting Enzyme (ACE) Inhibitory Peptide LVLPGE

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.0c07048 ◽

2021 ◽

Vol 69 (7) ◽

pp. 2149-2156

Author(s):

Jingyan Pei ◽

Ying Hua ◽

Tingyi Zhou ◽

Xinchang Gao ◽

Yali Dang ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Antihypertensive Effect ◽

Converting Enzyme ◽

Inhibitory Peptide ◽

Ace Inhibitory Peptide ◽

Ace Inhibitory

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Voxelwise Principal Component Analysis of Dynamic [S-Methyl-11C]Methionine PET Data in Glioma Patients

Cancers ◽

10.3390/cancers13102342 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2342

Author(s):

Corentin Martens ◽

Olivier Debeir ◽

Christine Decaestecker ◽

Thierry Metens ◽

Laetitia Lebrun ◽

...

Keyword(s):

Principal Component Analysis ◽

Principal Component ◽

Component Analysis ◽

Added Value ◽

Time Activity ◽

Positron Emission ◽

Activity Curve ◽

The Mean ◽

Mean Time ◽

Met Pet

Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11C]methionine ([11C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11C]MET PET in gliomas.

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Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82

Journal of Neurosurgery ◽

10.3171/jns.1996.84.3.0494 ◽

1996 ◽

Vol 84 (3) ◽

pp. 494-502 ◽

Cited By ~ 21

Author(s):

Bernhard Zünkeler ◽

Richard E. Carson ◽

Jeffrey Olson ◽

Ronald G. Blasberg ◽

Mary Girton ◽

...

Keyword(s):

Positron Emission Tomography ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Emission Tomography ◽

Brain Barrier ◽

Blood Brain ◽

Positron Emission ◽

The Mean ◽

Rubidium 82

✓ Hyperosmolar blood-brain barrier (BBB) disruption remains controversial as an adjuvant therapy to increase delivery of water-soluble compounds to extracellular space in the brain in patients with malignant brain tumors. To understand the physiological effects of BBB disruption more clearly, the authors used positron emission tomography (PET) to study the time course of BBB permeability in response to the potassium analog rubidium-82 (82Rb, halflife 75 seconds) following BBB disruption in anesthetized adult baboons. Mannitol (25%) was injected into the carotid artery and PET scans were performed before and serially at 8- to 15-minute intervals after BBB disruption. The mean influx constant (K1), a measure of permeability-surface area product, in ipsilateral, mannitol-perfused mixed gray- and white-matter brain regions was 4.9 ± 2.4 µl/min/ml (± standard deviation) at baseline and increased more than 100% (ΔK1 = 9.4 ± 5.1 µl/min/ml, 18 baboons) in brain perfused by mannitol. The effect of BBB disruption on K1 correlated directly with the total amount of mannitol administered (p < 0.005). Vascular permeability returned to baseline with a halftime of 24.0 ± 14.3 minutes. The mean brain plasma volume rose by 0.57 ± 0.34 ml/100 ml in ipsilateral perfused brain following BBB disruption. This work provides a basis for the in vivo study of permeability changes induced by BBB disruption in human brain and brain tumors.

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Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00001.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. L162-L169 ◽

Cited By ~ 40

Author(s):

Kai Nowak ◽

Sandra Weih ◽

Roman Metzger ◽

Ronald F. Albrecht ◽

Stefan Post ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Dry Weight ◽

Serum Levels ◽

Converting Enzyme ◽

Pulmonary Endothelium ◽

Preferential Expression

Limitation of reactive oxygen species-mediated ischemia-reperfusion (I/R) injury of the lung by vascular immunotargeting of antioxidative enzymes has the potential to become a promising modality for extension of the viability of banked transplantation tissue. The preferential expression of angiotensin-converting enzyme (ACE) in pulmonary capillaries makes it an ideal target for therapy directed toward the pulmonary endothelium. Conjugates of ACE monoclonal antibody (MAb) 9B9 with catalase (9B9-CAT) have been evaluated in vivo for limitation of lung I/R injury in rats. Ischemia of the right lung was induced for 60 min followed by 120 min of reperfusion. Sham-operated animals (sham, n = 6) were compared with ischemia-reperfused untreated animals (I/R, n = 6), I/R animals treated with biotinylated catalase (CAT, n = 6), and I/R rats treated with the conjugates (9B9-CAT, n = 6). The 9B9-CAT accumulation in the pulmonary endothelium of injured lungs was elucidated immunohistochemically. Arterial oxygenation during reperfusion was significantly higher in 9B9-CAT (221 ± 36 mmHg) and sham (215 ± 16 mmHg; P < 0.001 for both) compared with I/R (110 ± 10 mmHg) and CAT (114 ± 30 mmHg). Wet-dry weight ratio of I/R (6.78 ± 0.94%) and CAT (6.54 ± 0.87%) was significantly higher than of sham (4.85 ± 0.29%; P < 0.05), which did not differ from 9B9-CAT (5.58 ± 0.80%). The significantly lower degree of lung injury in 9B9-CAT-treated animals compared with I/R rats was also shown by decreased serum levels of endothelin-1 (sham, 18 ± 9 fmol/mg; I/R, 42 ± 12 fmol/mg; CAT, 36 ± 11 fmol/mg; 9B9-CAT, 26 ± 9 fmol/mg; P < 0.01) and mRNA for inducible nitric oxide synthase (iNOS) [iNOS-GAPDH ratio: sham, 0.15 ± 0.06 arbitrary units (a.u.); I/R, 0.33 ± 0.08 a.u.; CAT, 0.26 ± 0.05 a.u.; 9B9-CAT, 0.14 ± 0.04 a.u.; P < 0.001]. These results validate immunotargeting by anti-ACE conjugates as a prospective and specific strategy to augment antioxidative defenses of the pulmonary endothelium in vivo.

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Dual inhibition of angiotensin converting enzyme and neutral endopeptidase by omapatrilat in rat in vivo

Pharmacological Research ◽

10.1006/phrs.2001.0875 ◽

2001 ◽

Vol 44 (5) ◽

pp. 411-418 ◽

Cited By ~ 20

Author(s):

Tom Bäcklund ◽

Eeva Palojoki ◽

Tina Grönholm ◽

Anders Eriksson ◽

Olli Vuolteenaho ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Neutral Endopeptidase ◽

Converting Enzyme ◽

Dual Inhibition

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Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide

Biochemical Journal ◽

10.1042/bj2620125 ◽

1989 ◽

Vol 262 (1) ◽

pp. 125-130 ◽

Cited By ~ 39

Author(s):

P Dubreuil ◽

P Fulcrand ◽

M Rodriguez ◽

H Fulcrand ◽

J Laur ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Chloride Ion ◽

Peptide Bond ◽

Major Product ◽

Enzyme Hydrolysis ◽

Ion Concentration ◽

Converting Enzyme ◽

Rabbit Lung ◽

Hydrolysis Of

ACE (angiotensin-converting enzyme; peptidyl dipeptidase A; EC 3.4.15.1), cleaves C-terminal dipeptides from active peptides containing a free C-terminus. We investigated the hydrolysis of cholecystokinin-8 [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and of various gastrin analogues by purified rabbit lung ACE. Although these peptides are amidated at their C-terminal end, they were metabolized by ACE to several peptide fragments. These fragments were analysed by h.p.l.c., isolated and identified by comparison with synthetic fragments, and by amino acid analysis. The initial and major site of hydrolysis was the penultimate peptide bond, which generated a major product, the C-terminal amidated dipeptide Asp-Phe-NH2. As a secondary cleavage, ACE subsequently released di- or tri-peptides from the C-terminal end of the remaining N-terminal fragments. The cleavage of CCK-8 and gastrin analogues was inhibited by ACE inhibitors (Captopril and EDTA), but not by other enzyme inhibitors (phosphoramidon, thiorphan, bestatin etc.). Hydrolysis of [Leu15]gastrin-(14-17)-peptide [Boc (t-butoxycarbonyl)-Trp-Leu-Asp-Phe-NH2] in the presence of ACE was found to be dependent on the chloride-ion concentration. Km values for the hydrolysis of CCK-8, [Leu15]gastrin-(11-17)-peptide and Boc-[Leu15]gastrin-(14-17)-peptide at an NaCl concentration of 300 mM were respectively 115, 420 and 3280 microM, and the catalytic constants were about 33, 115 and 885 min-1. The kcat/Km for the reactions at 37 degrees C was approx. 0.28 microM-1.min-1, which is approx. 35 times less than that reported for the cleavage of angiotensin I. These results suggest that ACE might be involved in the metabolism in vivo of CCK and gastrin short fragments.

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