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)

The acute and subacute toxicities of N-[8-amino-1(S)-carboxyoctyl]-L- alanyl-L-proline (AB-47, CAS 120008-53-9), which is a non-sulfhydryl angiotensin converting enzyme inhibitor, were studied in male and female Fischer 344 rats. In the acute study, male and female rats were orally given 5000 mg/kg of AB-47. No rats were dead during the observation period (14 days) after the administration. The LD50 values of AB-47 were more than 5000 mg/kg in both male and female rats. Although only diarrhoea as toxic sign was observed 2 to 7 h after the administration, this sign disappeared within 24 h after the administration. Necropsy at the termination of observations revealed no macroscopic lesions in any rats. In the subacute study, male and female Fischer 344 rats were orally given 40, 200 or 1000 mg/kg/d of AB-47 for 4 weeks. Neither toxic signs nor death due to drug effects were observed at any dosage levels of AB-47. Furthermore, AB-47 did not influence body weight, food consumption, food efficiency, urinalytical and hematological parameters in both male and female rats. The minor changes of serum parameters, which consisted of very slight increases in serum potassium and decreases in serum albumin/globulin ratio, occurred in male rats given 200 and 1000 mg/kg/d of AB-47. Serum urea nitrogen values were elevated in both male and female rats given 1000 mg/kg/d of AB-47. Slight decreases of heart weight and heart weight/body weight ratios were observed at all dosage levels of AB-47.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity studies of the non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline in rats. 128 6

The hemodynamic effects of imidapril, a novel nonsulfhydryl angiotensin-converting enzyme inhibitor, were examined in anesthetized dogs by the intravenous injection of its active metabolite 6366A ((4S)-3-((2S)-2-[N-((1S)-1-carboxy-3- phenylpropyl)amino]propionyl)-1-methyl-2-oxoimidazolidine-4-carboxylic acid, CAS 89371-44-8) and were compared to those of enalaprilat. 6366A (1-100 micrograms/kg) reduced the blood pressure and total peripheral resistance in a dose-dependent manner, while causing no marked changes in heart rate, LV dp/dtmax, and pulmonary arterial pressure. The cardiac output and stroke volume were slightly increased. Blood flow in the common carotid artery, the vertebral artery, and the femoral artery was reduced or tended to decrease, while the superior mesenteric arterial blood flow was increased. These effects were similar to those of enalaprilat. 6366A did not inhibit the pressor response of angiotensin II, but markedly inhibited that of angiotensin I, and the effects of 6366A on regional blood flow were opposite to those of angiotensin II. Thus, 6366A appears to produce its hemodynamic effects by angiotensin converting enzyme inhibition, as does enalaprilat. 6366A also tended to decrease myocardial oxygen consumption. These results suggested that the hemodynamic effects of imidapril on the heart and on regional blood flow are similar to those of enalapril.
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PMID:Acute hemodynamic effects of the active metabolite of imidapril, (4S)-3-((2S)-2-[N-((1S)-1-carboxy-3-phenyl-propyl)amino]propionyl)-1- methyl-2-oxoimidazolidine-4-carboxylic acid, and enalaprilat in anesthetized dogs. 133 27

Effects of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), a new prodrug type angiotensin converting enzyme (ACE) inhibitor, and 6366 A (CAS 89371-44-8), an active metabolite of imidapril, on isolated vascular preparations were studied. 6366 A inhibited angiotensin I (AT-I)-induced contraction of the rabbit thoracic aorta at 3 x 10(-10) mol/l or more and augmented bradykinin (BK)-induced relaxation of the dog renal artery precontracted with prostaglandin F2 alpha PGF2 alpha at 10(-9) mol/l or more, whereas imidapril at 10(-7) mol/l did not affect these responses. However, 6366 A, like imidapril, had no effect on angiotensin II (AT-II), norepinephrine, serotonin-, KCl- and PGF2 alpha-induced contractions. The inhibitory effect of 6366 A on AT-I-induced contraction was attenuated by denudation of the endothelium, but it was still maintained even after washing out the aorta that had been previously exposed to the medium containing 6366 A. This suggests that 6366 A persistently inhibits the angiotensin I converting enzyme located preferentially in the endothelium. Therefore, the antihypertensive action of imidapril is mainly attributable to the vasodilation through the inhibitory effects of 6366 A on AT-II synthesis and BK degradation in the vasculature.
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PMID:Effects of the new angiotensin-I-converting enzyme inhibitor imidapril on the responses of isolated vascular preparations to various agonists. 164 67

Inhibition of glucose-6-phosphate dehydrogenase (G6-PDH) by dithranol (anthralin, CAS 480-22-8) has been studied in the presence of catalase, superoxide dismutase (SOD) and various scavengers of active oxygen species. Most scavengers were found to be either inhibitors of G6-PDH by themselves or simply without effect. The combined addition of catalase and SOD as well as the heat-denatured enzymes and the oxygen radical scavengers alpha-tocopherol and salicylic acid markedly reduced the inhibitory effect of dithranol. The direct exposure of G6-PDH to active oxygen species led to different results. When liberated from a water-soluble naphthalene endoperoxide, singlet oxygen was without effect whereas photosensitization with methylene blue resulted in a total loss of enzyme activity. Experiments under anaerobic conditions revealed that this inhibition was accomplished by the triplet state of the sensitizer. Superoxide anion radical was highly effective at concentrations corresponding to the amount of that produced by a 10 mumol/l dithranol solution. In contrast, hydroxyl, alkylperoxyl and alkoxyl radicals were all less efficient. H2O2 and alkylhydroperoxides did not alter the enzyme activity. The results suggest that .O2- is the potent species towards G6-PDH, if dithranol acts through formation of active oxygen species.
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PMID:Dithranol, glucose-6-phosphate dehydrogenase inhibition and active oxygen species. 181 Feb 65

To study the effects of a novel angiotensin I converting enzyme inhibitor (ACEI) on hypertension-induced cardiac hypertrophy, benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4) at the dose of 3 and 10 mg/kg/d p.o. was administered to spontaneously hypertensive rats from 4 to 16 weeks of age. In addition to suppression of developing blood pressure, benazepril hydrochloride reduced both the wet weights of whole heart and left ventricle dose-dependently and significantly. Benazepril hydrochloride had no effect on hydroxyproline concentration and content or protein concentration in the left ventricle, whereas is reduced the total protein content dose-dependently. Serum ACE activity was significantly reduced at 10 mg/kg/d of benazepril hydrochloride, but renin activity, aldosterone and noradrenaline concentration in serum were not changed. From the microscopic findings of the left ventricle, benazepril hydrochloride reduced the myocardial hypertrophy significantly. From these results, benazepril hydrochloride seems to suppress the increase in volume load by acting through the renin-angiotensin-aldosterone system, and dose not seem to cause a significant reflex of catecholamine which often occurs with peripheral vessels dilation. Thus, benazepril hydrochloride may be expected to suppress cardiac hypertrophy in patients with hypertension.
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PMID:Effect of benazepril hydrochloride on cardiac hypertrophy in spontaneously hypertensive rats. 183 66

In the present study, the efficacy of cilazapril (Ro 31-2848/006, CAS 88768-40-5), a new angiotensin converting enzyme (ACE) inhibitor, was examined in 7 essential hypertensive patients by monitoring ambulatory blood pressure for 24 h. Oral cilazapril, given once a day in the morning, lowered systolic and diastolic blood pressure without affecting heart rate. Daily profiles of blood pressure and heart rate, however, were not different from those prior to cilazapril in these patients. Percentages of high blood pressure values (more than 160/95 mmHg), both systolic and diastolic decreased, following cilazapril administration. Ambulatory blood pressure monitoring revealed that cilazapril did not cause a dangerous fall in blood pressure even in the night time. From these results, cilazapril could be an effective and useful antihypertensive drug for the treatment of essential hypertensive patients.
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PMID:Antihypertensive effect of cilazapril in essential hypertensive patients. Clinical study with 24 h ambulatory blood pressure monitoring. 183 65

The effects of angiotensin converting enzyme inhibitors (ACEIs), CGS 14831 (CAS 86541-78-8) and captopril, on the mechanical function and energy metabolism were studied in isolated rat hearts using global ischemia-reperfusion model. The myocardial tissue levels of ATP, creatine phosphate (CP) and pH were determined with 31P-nuclear magnetic resonance (31P-NMR). Global ischemia was induced by cross-clamping of the inflow line for 40 min. While thiol containing ACEI, captopril, significantly inhibited the ATP depletion and pH fall produced by ischemia, non-thiol compound, CGS 14831, did not have any influence on the ATP degradation and pH fall during ischemia. Both CGS 14831 (20 micrograms/ml) and captopril (80 micrograms/ml) have little influence on the mechanical function during the ischemia-reperfusion period. L-Cysteine (44.6 micrograms/ml) inhibited the pH fall significantly during the ischemia without exerting influence on the ATP degradation. These data suggest that local renin-angiotensin-aldosterone system does not play an important role in maintenance of the myocardial mechanical function during ischemia-reperfusion. The thiol residue of captopril is not responsible for the inhibitory effect of this compound on ischemia-induced ATP degradation. Some specific effect of captopril may play a role in the protective effect.
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PMID:Effects of two angiotensin converting enzyme inhibitors on the mechanical function and energy metabolism of isolated rat hearts. A nuclear magnetic resonance study with an active form of benazeprilat and captopril. 229 44

A three-months toxicity study of an angiotensin converting enzyme (ACE) inhibitor, rentiapril (CAS 80830-42-8), was performed in Sprague-Dawley rats by oral administration. The dose levels of 0, 30, 125, 500 and 1000 mg/kg were tested in both sexes, in which each experimental group comprised 10 rats. Another ACE inhibitor, captopril, was used as a reference compound. Rentiapril at the highest dose of 1000 mg/kg caused low food consumption and death of some animals with signs of bloody feces and anemia. In males and females receiving 500 and 1000 mg/kg, there were low body weight gain, increases in water intake, urine volume and serum BUN level, and decreases in levels of various erythrocytic parameters. Kidney weight was increased dose-dependently in both sexes. Histopathologically, renal changes in the 500 and 1000 mg/kg groups consisted of proximal tubular degeneration, juxtaglomerular cell hyperplasia and interstitial cell infiltration. Similar, but mild, changes in proximal tubules were present in the female 125 mg/kg group. Dead animals from the highest dose groups further showed gastrointestinal hemorrhagic erosion and/or ulcer, decreased bone marrow erythropoiesis and hepatocytic vacuolar degeneration. There was no pathological alteration in rats from other rentiapril-treated groups, as well as in controls. These results indicate that the no-effect dose of rentiapril in rats by three months oral administration is 30 mg/kg in female and 125 mg/kg in male, and suggest that, like other ACE-inhibitors, this compound also has a toxic potential to affect renal tissues.
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PMID:Toxicity study of the angiotensin converting enzyme inhibitor rentiapril in rats. 789 62

The effects of N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline (AB-47, CAS 120008-53-9), an orally active angiotensin converting enzyme inhibitor, on the central nervous, respiratory and cardiovascular, autonomic systems, isolated smooth muscles and other functions were investigated in various experimental animals. AB-47 had no effect on central nervous, autonomic systems and isolated smooth muscles. AB-47 (10 and 30 micrograms/kg i.v.) significantly lowered femoral blood pressure without affecting respiration and heart rate in anesthetized rats. However, AB-47 had no effect on the contractile tension of mammalian isolated atrium and aorta. AB-47 had no effect on gastrointestinal transit in mice. Very slight injury of gastric mucosa was observed 4 h after the oral administration of AB-47 in rats but AB-47 did not damage the small intestinal mucosa. AB-47 had no effect on the contraction of rat phrenic nerve-diaphragm preparation induced by electrical stimulation. AB-47 did not affect the incidence of acetic acid-induces writhings. AB-47 potentiated carrageenan-induced hind paw edema in rats. The potentiation of edema may be due to an accumulation of bradykinin induced by the inhibition of angiotensin converting enzyme (ACE), because ACE is the identical enzyme with kinase II. The pretreatment of AB-47 for 7 days (1, 3, 10 mg/kg/d p.o.) inhibited the cardiac hypertrophy induced by isoproterenol (isoprenaline). This result suggests that the renin-angiotensin-aldosterone system directly or indirectly participates in the cardiac hypertrophy induced by isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of the non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline. 829 59

Angiotensin II has a plethora of different actions in the heart including, for instance, also slight positive inotropic effects. Thus cardiotonic therapy with angiotensin converting enzyme (ACE) inhibitors should possibly be complemented by positive inotropic drug therapy. With this respect, novel cardiotonic drugs that increase calcium sensitivity of myofilaments such as pimobendan (CAS 118428-36-7) might be particularly useful, as they will increase force with little, if any concomitant increase in myoplasmic free calcium. These drugs mimic mechanistically the Frank-Starling-Mechanism or alpha-adrenergic effects which also involve, at least partly, calcium sensitization of the myofilaments. The latter may therefore be a useful therapeutic principle, in particular in cases where myofibrillar calcium responsiveness is pathologically depressed such as for instance in the stunned myocardium or under hypoxic conditions.
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PMID:[Modulation of calcium sensitivity in the heart muscle--physiology, pathophysiology and pharmacology]. 838 86


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