Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(1-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system.
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PMID:In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. 131 52

Experiments were performed in anaesthetized dogs to characterize the renal effects of the selective dopamine DA1-receptor agonist, fenoldopam. Intrarenal artery infusion of fenoldopam (0.01-10 micrograms/kg per min) caused dose-related renal vasodilation. At low doses (0.01-0.3 micrograms/kg per min), renal vasodilation occurred without concomitant falls in blood pressure but was accompanied by increased urine output. This diuresis was most probably a result of reduced tubular reabsorption since glomerular filtration rate was not increased. Both fenoldopam-induced renal vasodilation and diuresis were blocked to a similar extent by the selective dopamine DA1-receptor antagonist, SCH 23390 (30 micrograms/kg, intravenously), suggesting that both effects were mediated by dopamine DA1-receptors. In the presence of the angiotensin converting enzyme inhibitor, captopril (1 mg/kg, intravenously, + 20 micrograms/kg per min, intrarenal artery), fenoldopam (0.01-0.3 micrograms/kg per min) significantly increased fractional excretion of sodium, despite reducing blood pressure; neither of these effects were observed in captopril-free dogs. These observations support the view that the inhibitory effect of fenoldopam on tubular function, and its vasodepressor activity, may be opposed by angiotensin II resulting from fenoldopam-induced renin release.
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PMID:Effects of dopamine DA1-receptor blockade and angiotensin converting enzyme inhibition on the renal actions of fenoldopam in the anaesthetized dog. 168 41

The effects of the angiotensin converting enzyme (ACE) inhibitor captopril and the neutral endopeptidase (NEP) inhibitors thiorphan and SCH 32615 on the changes in airway opening pressure (PaO) and the recovery of offered peptide were studied after intratracheal administration of substance P (SP) and neurokinin A (NKA) in isolated guinea pig lungs superfused through the trachea. Pao changes and the recovery of offered peptide were significantly greater in NEP inhibitor-treated lungs than in control lungs. Captopril did not cause a significant change in the physiological effects or the recovery of SP and NKA. HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action. We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides.
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PMID:Peptidase modulation of the pulmonary effects of tachykinins in tracheal superfused guinea pig lungs. 168 68

SCH 33844 is a new, potent and long-acting inhibitor of angiotensin converting enzyme (ACE). Antihypertensive, hemodynamic and autonomic actions of SCH 33844 were examined in the present series of experiments. Oral administration of 0.3-30 mg/kg reduced blood pressure of spontaneously hypertensive rats. The magnitude of the response was significantly enhanced by pretreatment of the animals with hydrochlorothiazide. Blood pressure remained significantly depressed 24 hr following doses of 3 and 10 mg/kg. Administration of SCH 33844 (3 mg/kg) twice daily to nonpretreated rats or once daily to diuretic-pretreated animals for 5 days resulted in a progressive decrease in blood pressure. The compound did not reduce blood pressure in nephrectomized rats demonstrating the dependence of its action on renal renin. SCH 33844 (1-10 mg/kg orally) also produced dose-related decreases in pressure in diuretic-pretreated conscious normotensive dogs. However, only a small fall in pressure occurred in non-pretreated dogs. Hemodynamic actions were examined in anesthetized dogs. SCH 33844 (1 mg/kg i.v.) reduced blood pressure, increased cardiac output and caused a large fall in peripheral resistance. Autonomic actions were assessed in pithed rats. The compound (10 mg/kg orally) tended to decrease pressor responses to sympathetic activation and to i.v. norepinephrine. This profile is probably due, at least in part, to vasorelaxation following suppression of angiotensin II generation. In conclusion, SCH 33844 is a potent, long-lasting antihypertensive agent which reduces peripheral vascular resistance and possesses only slight autonomic effects.
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PMID:Antihypertensive, hemodynamic and autonomic profile of a new angiotensin converting enzyme inhibitor, SCH 33844 (spirapril). 288 41

Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly (p less than 0.05) decreased and the blood urea nitrogen was slightly but significantly (p less than 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.
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PMID:Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor. 300 64

SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.
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PMID:Angiotensin converting enzyme inhibitory activity of SCH 33844 (spirapril) in rats, dogs and monkeys. 303 28

The antihypertensive activity of SCH 33844, a new angiotensin converting enzyme inhibitor, was investigated in conscious spontaneously hypertensive rats during a 3-week treatment regimen and for 1 week following drug withdrawal. SCH 33844 was given once daily at 2 dose levels (1 and 5 mg/kg orally) and its effects were compared with those of captopril (60 mg/kg orally). Systolic blood pressure was recorded twice weekly just before administration and at varying time intervals up to 6 hr after dosing; recordings were continued for 1 week after drug withdrawal. SCH 33844 was found to produce dose-related antihypertensive effects. Given at 1 mg/kg, the compound elicited small but significant blood pressure changes during the treatment. After drug withdrawal, systolic blood pressure returned to pre-drug levels within 1 week. SCH 33844 at 5 mg/kg, and captopril at 60 mg/kg, both reduced blood pressure markedly and to a similar extent. After each administration the effect was rapid in onset, lasted for over 6 hr and was not subject to tolerance. Drug withdrawal resulted in a gradual return of systolic blood pressure toward pre-treatment levels within 1 week, with no evidence of rebound phenomena. These results indicate that SCH 33844, like captopril, produces an effective antihypertensive action throughout a repeated dosing.
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PMID:Antihypertensive activity of a new ACE-inhibitor, SCH 33844, during repeated administration in spontaneously hypertensive rats. 303 29

SCH 33861 (7- N- 1(S)-(Carboxy)-3-phenylpropyl -(S)-alanyl 1,4-dithia-7-azaspiro 4.4 nonane-8(S)-carboxylic acid) is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor with marked topical ocular hypotensive activity. The present study evaluated the degree of systemic ACE inhibition resulting from topical administration of 0.01 and 0.1% concentrations (10 and 100-fold greater than needed to lower IOP) of SCH 33861 in conscious rabbits. For reference purposes, captopril, a prototype ACE inhibitor, was examined at concentrations 5 and 20-fold greater than needed to lower IOP. Neither 0.01 nor 0.1% topical SCH 33861 led to inhibition of pressor responses to 0.3 micrograms/kg iv challenges with angiotensin I (AI) over a 4 hr period. Captopril, in contrast, caused significant attenuation of AI pressor responses. The magnitude and duration of systemic ACE inhibition following captopril administration was concentration related. Intravenous administration of the same dose administered topically did not cause any systemic ACE inhibition with 0.01% SCH 33861. Following iv 0.1% SCH 33861, 0.5 or 2.0% captopril, AI responses were inhibited 60-70% indicating the ability to inhibit ACE if any systemic absorption took place. Topical administration of 0.01% SCH 33861 twice daily for five days also did not produce systemic ACE inhibition. These findings indicate that topical amounts of SCH 33861 greatly in excess of those needed to effect reductions in IOP have an exceptionally low potential for producing systemic effects.
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PMID:Systemic effects resulting from topical ocular administration of SCH 33861, a novel ACE inhibitor ocular hypotensive agent. 304 62

SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.
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PMID:Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. 316 88

We studied the effects of a new topical angiotensin converting enzyme inhibitor, SCH 33861, in lowering intraocular pressure in 20 patients with ocular hypertension or primary open-angle glaucoma. In a double-masked, four-way crossover study with placebo and timolol, SCH 33861 was well tolerated and effective in lowering intraocular pressure. The magnitude of the drug's effect in lowering intraocular pressure was less than that of timolol 0.5%.
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PMID:Use of an angiotensin converting enzyme inhibitor in ocular hypertension and primary open-angle glaucoma. 328 43


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