Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progression of lung fibrosis induced in rabbits by intratracheal bleomycin (BLM, 10 mg/kg) was monitored by biochemical and morphological measurements. These indicated that the evolution of fibrosis in the rabbit was slower than in other experimental animals. Histology revealed cellular and fibrocellular lesions 4 weeks after BLM. At 8 weeks these lesions still predominated, indicating continuing active disease accompanied by a progression to fibrosis. The gradual progression of the response was reflected in alterations in lung composition. Changes in lung content of collagen, protein and DNA were evident at 8 weeks after BLM, at which time concentration (micrograms/mg dry weight) of collagen and protein were also elevated (P less than 0.05). Plasma angiotensin converting enzyme (ACE), a marker of endothelial injury, decreased 1 week after BLM (P less than 0.01) and then returned to normal, indicating that endothelial injury does not parallel the fibrotic response. In summary, the continuing active inflammation and slow progress of fibrosis induced by i.t. BLM in the rabbit suggests that this model has advantages over others for the serial study of the cellular and biochemical evolution of lung fibrosis.
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PMID:Progress of bleomycin-induced lung fibrosis in rabbits. 242 99

The murine retina provides an ideal model for the study of vascular development. In this investigation we have examined the development of blood vessels in flat-mounted whole retinas from C57B6 mice ranging from birth to 4 months of age. Basement membrane components of blood vessels were visualized by indirect immunofluorescence with antibodies against type IV collagen and laminin. Endothelial cells (EC) were labeled with a plant lectin, Ricinus communis agglutinin I (RCA), and antibodies against angiotensin converting enzyme. Results show three stages of vascular differentiation. During the first stage (postnatal days P0-P10), vessels develop radially from optic disc to ora serrata within the presumptive nerve fiber layer. In the second stage beginning P4, vessels form within deeper retinal layers. In the third stage beginning P7, a capillary network develops as branches of radial vessels in the nerve fiber layer. The entire vascular system begins as a polygonal network of capillary-like vessels. Selective regression of various segments of these polygons leads to the ultimate arborous pattern of arteries, arterioles, veins, venules, and capillaries seen in the adult. Some individual EC appear to be left behind during this retraction process and pericytes may have a role in determining which vessel segments regress. This combination of flat-mounted whole retinas and probes specific for vascular elements provides an ideal system for the study of retinal vascularization and the characterization of vasculogenesis in general.
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PMID:Characterization of vascular development in the mouse retina. 246 91

1. From a morphologic standpoint, the myocardium has three compartments: cardiac myocytes; intramyocardial coronary arteries with a microcirculation; and an interstitium composed largely of fibrillar collagen. As long as intercompartmental equilibrium exists, myocardial mechanics and energetics and myocyte viability will each be preserved. 2. The hypertrophic process seen with left ventricular pressure overload secondary to renovascular hypertension alters this equilibrium because of the adverse remodelling of intramural coronary arteries and fibrillar collagen. The pathogenetic mechanism(s) responsible for the observed myocardial fibrosis, having reactive and reparative components, remains to be elucidated. 3. Attractive circumstantial evidence, however, has been obtained to incriminate circulating angiotensin II in this process. Five lines of evidence favouring the role of angiotensin II in promoting the reactive perivascular and interstitial fibrosis and the reparative fibrosis are presented, including the potential cardioprotective effects of angiotensin converting enzyme inhibitors.
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PMID:Angiotensin and the remodelling of the myocardium. 269 Sep 5

The effects of hypertension and its treatment on the function and structure of arteries have been extensively studied, but no data are yet available on the effect of hypotensive drugs on the large arteries in normotensive rats. Two groups of 11-month-old normotensive breeder male rats were treated for 5 months, one with an angiotensin converting enzyme (ACE) inhibitor (MK-421, 2 mg/kg per day; n = 10) and the other with dihydralazine (15 mg/kg per day; n = 8). A group of 14 rats served as controls. Blood pressure was recorded every 14 days by the tail-cuff method. At the end of the treatment period (5 months), the rats were killed under anaesthesia and the descending thoracic aorta was removed and fixed. The different components of the aorta were assessed by automated morphometric image analysis after specific coloration of elastin (orceine), collagen (sirius red) and nuclei (haematoxylin after periodic acid oxidation. Both the ACE inhibitor and dihydralazine caused similar decreases in systolic blood pressure (SBP) compared with controls. This hypotensive effect was associated with a reduction in medial thickness, from 120 +/- 15 microns in controls to 104 +/- 9 microns in ACE inhibitor-treated and 103 +/- 10 microns in dihydralazine-treated normotensive rats. Elastin density significantly increased in the two treatment groups but the greatest increase was in the dihydralazine-treated group (P less than 0.001). Elastin fibre thickness increased significantly in the dihydralazine-treated group only. Collagen density was not significantly modified by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of vasodilatators on the structure of the aorta in normotensive ageing rats. 283 73

The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.
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PMID:Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. 299 75

Male rats were killed 2 months (early fibrosis) or 6 months (peak fibrosis) after a range of single doses of 60Co gamma rays to the right hemithorax. Pulmonary arterial perfusion scans were performed at 2 months on animals scheduled for autopsy at 6 months. Lung angiotensin converting enzyme (ACE) activity was used to monitor endothelial function, and hydroxyproline (HP) concentration served as an index of interstitial collagen accumulation (fibrosis). ACE activity also was measured in right lung bronchoalveolar lavage (BAL) fluid and blood serum, to determine whether information obtained from a minimally invasive procedure might serve as an index or predictor of the severity of lung damage. Linear dose-response curves (r = 0.92-0.99) were obtained for right lung arterial perfusion, ACE activity and HP concentration. At 2 months, perfusion decreased 2.7% per Gy, ACE activity (per lung, per mg wet weight, or per mg protein) decreased 3.0-4.2% per Gy, and HP concentration (per g dry weight) increased 1.7% per Gy. At 6 months, the slopes of the response curves were virtually identical to those at 2 months; the Y intercept of the response curve for ACE activity was unchanged, whereas that for HP concentration was 50% higher at 6 than at 2 months. ACE activity and protein concentration in the BAL increased with increasing dose, but the variation within groups was too large, and the sensitivity was too low to serve as a reliable index of lung status. Serum ACE activity was independent of radiation dose at both autopsy times. Thus in rat lung, arterial perfusion, endothelial dysfunction and interstitial fibrosis exhibit similar but not identical radiosensitivities. The dose-effect curves for these three responses of the lung in situ change less than 5% per Gy over the dose range of 10-30 Gy, a smaller variation than would be predicted from endothelial cell survival data based on clonogenic assays in vitro or in vivo.
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PMID:The relationship between endothelial dysfunction and collagen accumulation in irradiated rat lung. 299 91

A versatile, convenient assay for vertebrate collagenases has been developed using the fluorescent peptide substrate dansyl-Pro-Gln-Gly-Ile-Ala-Gly-D-Arg. This sequence resembles that of collagen at the site of cleavage but includes modifications designed to eliminate nonspecific hydrolysis by contaminating peptidases. Both human skin fibroblast and bovine corneal cell collagenases cleave the substrate specifically at the Gly-Ile bond. Plasmin, thrombin, trypsin, alpha-chymotrypsin, carboxypeptidase B, and bacterial collagenase do not cleave the substrate. Elastase and angiotensin converting enzyme display 20- and 400-fold less activity than the vertebrate collagenases, respectively, and cleave the peptide at different positions. The assay is performed by incubating a 5- to 25-microliters aliquot of trypsin-activated sample with an equal volume of 2 mM substrate overnight at 33 degrees C and pH 7.5. Thin-layer chromatography then separates the fluorescent product from the substrate in less than 20 min and allows the detection of subnanogram levels of collagenase. The assay is applicable to the screening of large numbers of samples under different conditions of pH and ionic strength and is readily adaptable for use in a variety of collagenase-dependent systems, such as assays for collagenase activating and/or inducing factors.
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PMID:A convenient fluorescent assay for vertebrate collagenases. 301 20

Teprotide, a nonapeptide isolated from the venom of a Brazilian pit viper, Bothrops jararaca, was the first angiotensin converting enzyme (ACE) inhibitor to be discovered and tested. It was found to be an effective, non-toxic antihypertensive agent as well as an afterload-reducing agent for patients with congestive heart failure (CHF). The primary activity of teprotide resulted from blockade of the angiotensin I converting enzyme--the pivotal step in the renin-angiotensin-aldosterone system (RAAS), and consequent reductions in angiotensin II levels. There was limited clinical testing for teprotide because of: its scarcity; the need for parenteral administration; and the subsequent discovery and synthesis of captopril, the first orally active angiotensin converting enzyme inhibitor. Captopril is the prototype oral angiotensin converting enzyme inhibitor and has been extensively studied since the initiation of formal studies in 1976. Perhaps one of the most closely researched drugs in modern times, the experience with captopril now includes more than 12,000 patients studied in formalized trials and over 4,000,000 patients treated world-wide by physicians for hypertension and congestive heart failure. Enalapril (MK421) is the first of what appears to be a growing number of analogues which are structurally and pharmacodynamically different from captopril; yet, they possess the same capacity for inhibiting the activity of angiotensin converting enzyme. The side effect profile of enalapril (and presumably future) angiotensin converting enzyme inhibitors appears to be similar to captopril, though clearly more experience is needed with newer agents. The initial use of captopril was troubled by a relatively high incidence of side effects which will form the focus of this discussion. Partially the result of incomplete pharmacokinetic information, captopril was administered in early studies at dosages now recognised to be far in excess of those necessary for drug action. In addition, dosages were given without regard for deficiencies of renal function, now known to be the main excretory route of captopril. The population of those patients studied frequently had chronic, treatment-resistant hypertension, often associated with concomitant end-organ disease (especially renal disease); and many additional factors further complicating the clinical setting, e.g. a relatively high incidence of collagen vascular disease and immunosuppressive treatments.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. 302 83

Male rats were sacrificed 2 or 6 months after a range of single doses of gamma rays (0-30 Gy) to the right hemithorax. Half of each dose group consumed control feed continuously after irradiation, and half consumed feed containing the collagen antagonist D-penicillamine (10 mg/rat/day). Four markers of pulmonary endothelial function were monitored: angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Bronchoalveolar lavage (BAL) fluid also was obtained from the right lung, and was analyzed for macrophage number, and PGI2 and TXA2 concentration. Right lung ACE and PLA activities decreased linearly with increasing dose at both 2 and 6 months postirradiation, and penicillamine had no significant effect on either response. In contrast, PGI2 and TXA2 production by the right lung increased linearly with increasing radiation dose at both autopsy times. Penicillamine significantly ameliorated the increase in PGI2 production at 2 months, and the increase in TXA2 production at both 2 and 6 months postirradiation. Penicillamine dose-reduction factors (DRF) for PGI2 and TXA2 production were 1.3-1.4, and the response curve slope ratios were 1.7-2.5 (p less than 0.05). Penicillamine also ameliorated the dose-dependent increase in TXA2 concentration in the BAL fluid at 2 months. These data indicate that the four "markers" of radiation-induced pulmonary endothelial dysfunction do not respond identically to penicillamine dose-modification. Of the four markers, TXA2 production exhibits the most significant and widespread penicillamine sparing. TXA2 is a potent vasoconstrictor, promoter of platelet aggregation, and mediator of inflammation, and partial prevention of the radiation-induced hyperproduction of this eicosanoid may account in part for penicillamine's therapeutic action in this model.
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PMID:Functional responses of the pulmonary endothelium to thoracic irradiation in rats: differential modification by D-penicillamine. 304 Jun 46

When captopril was first introduced, it was used in high doses for severe hypertension, often in the presence of renal insufficiency, and side effects such as proteinuria, rash, neutropenia, and altered taste sensation were noted. Upon analysis, these effects were most commonly seen in patients with renal disease, autoimmune disease, or collagen vascular disease. These complications usually reversed rapidly upon discontinuation of treatment. In contrast, the growing use of the angiotensin converting enzyme inhibitors, captopril and enalapril, for treating mild to moderate hypertension and the trend toward the use of lower doses has shown these agents to be well tolerated with a low frequency of troublesome adverse effects. In fact, the original spectrum of adverse effects has virtually disappeared with the use of lower doses in patients with uncomplicated hypertension. In low doses, the converting enzyme inhibitors produce remarkably few incidences of symptomatic discomfort; the most common is skin rash, which often responds to dosage reduction. Cough and rare occurrences of angioedema have also been reported. Moreover, evidence is evolving that indicates that the converting enzyme inhibitors may sometimes decrease proteinuria and improve renal function; these effects may be especially important in diabetic hypertensive patients. Of note, these drugs can also attenuate the unwanted metabolic side effects of concurrent diuretic treatment.
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PMID:Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitors. 306 5


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