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)

N alpha-Phosphoryl-L-alanyl-L-proline is a reversible competitive inhibitor of angiotensin converting enzyme with a Ki of 1.4 nM. Alkylation of one phosphate oxygen with methyl, ethyl, or benzyl does not change the Ki. The high activity of the O-alkylated inhibitors demonstrates that the two phosphate oxygen anions do not constitute a bidentate ligand of the active site zinc ion. Substitution of valyltryptophan, glycylglycine, or delta-aminovaleric acid for alanylproline in the phosphoramidate raises the Ki to 12 nM, 25 microM, and 178 microM, respectively. Methylation of the alanine nitrogen in phosphorylalanylproline raises the Ki to 29 microM. Polyphosphates inhibit converting enzyme with the following Ki's: phosphate, approximately 300 mM; pyrophosphate, 2 mM; tripolyphosphate, 18 microM; tetrapolyphosphate, 150 microM. The inhibition by tripolyphosphate appears to be competitive and is unaffected by the addition of excess zinc ion. Since the Ki of tripolyphosphate is nearly 10-fold lower than that of N-phosphoryl-delta-aminovaleric acid and is near that of N alpha-phosphorylglycylglycine, its terminal phosphates may bind the zinc site and the cationic site on the enzyme, thus spanning the S1' and S2' sites.
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PMID:Inhibition of angiotensin converting enzyme by phosphoramidates and polyphosphates. 629 38

ACE is a function of the endothelial cell that appears vital to integrative homeostatic physiology in stress. The endothelial cell, both in the lung and in systemic tissues, is uniquely situated to detect changes in ambient oxygen tension; thereafter, as exemplified by the effects of altered oxygen tension on ACE, the cell is capable of initiating changes that modulate its functions to reflect the altered physiologic state. Based upon extensive studies of endothelial cells propagated in tissue culture, these altered functions are rapid in onset, rapidly reversible, and quite closely correlated to PO2. Integrity of the endothelial cell membrane is necessary for the modulating changes to occur, and indeed, ACE purified from the cell is insensitive to changes in oxygen tension: it is the cell, not the enzyme, that responds to changes in oxygen tension (FIGURE 5). It is important to emphasize the interdependent nature of the several vasoactive systems. The kallikrein-kinin system, in addition to its putative role in blood pressure regulation, is an intimate component of both the coagulation and fibrinolysis plasma protease cascades. The sympathetic nervous system has multiple points of interdigitation in both the kallikrein-kinin and the renin-angiotensin systems; high levels of epinephrine stimulate renin release and activate both plasma and tissue kallikrein. In turn, both of the vasoactive peptides of these systems, bradykinin and angiotensin II, stimulate epinephrine production from the adrenal medulla. Angiotensin II enhances the potency of norepinephrine released from postganglionic sympathetic nerve endings, increasing alpha-adrenergic tone. In addition, multiple interactions have been described between angiotensin II and bradykinin and the formation of prostaglandins by endothelial cells. Preliminary data indicate that the potency of these peptides in causing prostanoid release is, as might be expected, closely correlated to ACE activity, which itself is a function of ambient PO2. These multiple interactions are diagrammed in FIGURE 9. It is noteworthy that the two fundamental regulators of the circulation, pH and PO2, can be shown to interact at the most basic level with endothelial cell function.
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PMID:Endothelial cell functions in the hemodynamic responses to stress. 630 25

Exposure of mice to normobaric 100% oxygen for 72 hr has been shown to damage lung capillary endothelial cells and to markedly alter the pulmonary disposition and metabolism of endogenous serotonin (5-HT) and exogenous [3H]5-HT in a time-dependent manner. We have extended these studies to examine the reparative changes occurring in lung following moderate oxygen-induced injury. Pulmonary angiotensin converting enzyme (ACE) activity, a biochemical marker of endothelial cell injury, was decreased after a 72-hr oxygen exposure and progressively increased above control levels during the recovery period (130%, 168 hr) and paralleled lung protein content. The pulmonary disposition of [3H]5-HT also provided an index of endothelial cell function. Lung levels of [3H]5-HT were elevated 183% (0 hr) and 200% (24 hr) and returned to control values by 72 hr of air recovery. Pulmonary edema followed a similar time-course that corresponded to reported ultrastructural changes. The circulating platelet concentration progressively decreased from control values at 0 hr to 68% of control of 168 hr. In contrast to lung where 5-HT was significantly elevated during the early reparative period, platelet 5-HT content was significantly decreased and, like lung, returned to control values by 72 hr. The two forms of lung monoamine oxidase (MAO) showed different responses during the reparative phase. Type A MAO was slightly elevated throughout the recovery period. In contrast, type B MAO was decreased at 0 hr but increased throughout the reparative phase, being significantly elevated 128% at 72 hr and 139% at 168 hr. These data suggest that the lung is capable of readily recovering from moderate oxygen-induced injury and that certain biochemical parameters described herein provide useful indices of pulmonary microvascular function.
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PMID:Reparative changes following oxygen-induced lung injury: effect on serotonin disposition and metabolism. 631 29

Isolated rat hearts were perfused according to Langendorff and as a working heart preparation with glucose as the only exogenous substrate under nonrecirculating conditions to avoid accumulation of heart metabolites and, thereby, changes in the composition of the perfusion medium. In the absence of insulin or at low work, oxidation of endogenous substrates as glycogen is of importance for myocardial energy metabolism. Accordingly, about 1/3 of the glucose oxidized by the heart was derived from myocardial glycogen. Lipolysis of endogenous triglycerides and oxidation of the fatty acids produced were, however, low in normal rat hearts. By contrast, in the presence of insulin or at high work load endogenous substrates play a minor role for energy provision. About 80% of the total oxygen consumption could be attributed to the oxidation of exogenous glucose. Furthermore, insulin exerted its major effect in accelerating glucose uptake and glycolysis, but had little influence on PDH-activity. Insulin increased lipolysis in control hearts, however, changes in the endogenous triglycerides were less than valves calculated from the rate of lipolysis. Thus, glycerol release can be taken as a measure for lipolysis, but not as a measure for fatty acid oxidation, since the produced fatty acids were partly reesterified to glycerides. On the basis of the metabolic data obtained, the oxygen and energy balance was calculated. We conclude that a sufficient energy provision is only warranted if the rat heart is perfused either in the presence of insulin or at higher--more physiological--work load.
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PMID:Glycolysis and glucose oxidation in the rat heart under nonrecirculating perfusion conditions. 638 35

The Warburg method was used to study the action of adenosine on several phases of rat cerebral cortex metabolism, using cortex slices or homogenates. In the presence of exogenous glucose in vitro, oxygen consumption and lactate production are not affected by adenosine in sections. In vivo, there is an increase of oxygen consumption and of lactate production but which are not significant. Adenosine may activate metabolic pathways, since the observed metabolic changes remain constant during the period of activity of adenosine (30 to 60 min) and disappear concomitantly with adenosine. The action of adenosine is much more evident in sections from the brains of injected animals, where the increase of lactate production becomes significant. This suggests that in this case adenosine favors a better utilization of glycogen via an activation of adenylate cyclase. The increased activity of G-6-PDH was observed in vitro but was not significant in vivo. These observations were confirmed with homogenates from the in vivo series by the significant decrease of inorganic phosphate levels, consistent with an increased formation of nucleotide phosphates. The increased cerebral glucose concentration is perhaps a result of increased blood glucose levels, in turn resulting from the known depression of insulin release by adenosine, or from a preferential utilization of glycogen, resulting from the activation of adenylate cyclase.
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PMID:Action of adenosine on energy metabolism and on glucose-6-phosphate dehydrogenase in rat brains. 672 44

Exercise intolerance is one of the primary characteristics of chronic congestive heart failure (CHF). Therefore, exercise testing has been widely used in the assessment of CHF patients, both to define the severity of the disease and to assess the efficacy of pharmaceutical agents in clinical trials. A number of different exercise tests can be used, although maximal exercise testing is the most common. Maximal exercise capacity can be determined by measuring exercise duration during incremental exercise, or maximal oxygen (O2) consumption, or it can be estimated by anaerobic threshold. While baseline exercise testing in CHF patients accurately identifies and quantifies cardiac failure and determines prognosis, it is of limited value in assessing changes that occur as a result of drug therapy. A key drawback of exercise testing as a measurement of drug effect is the fact that exercise changes produced by drug intervention do not correlate well with changes in the mortality rate. Several examples of the lack of correlation between exercise testing and mortality rates have been observed in clinical trials with angiotensin converting enzyme (ACE) inhibitors and vasodilators. ACE inhibitors have a modest effect on maximal exercise capacity but they improve survival. It is thought that neuroendocrine activation more closely reflects mortality rates and also the changes in survival observed with pharmacological intervention compared with other modes of evaluation.
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PMID:Exercise testing in heart failure. A critical review. 752 58

To determine whether neutral endopeptidase (NEP) and kininase II (angiotensin-converting enzyme, ACE) influence coronary hemodynamics, we compared the effects of inhibiting NEP, ACE, or both before and after isoproterenol (50 mg/kg ip). We measured flow and resistance using radioactive microspheres in 90 anesthetized rats which received the NEP inhibitor phosphoramidon (2.5 mg/kg), the ACE inhibitor captopril (2.5 mg/kg), both combined, or vehicle alone. Before isoproterenol, inhibiting NEP, ACE, or both increased left ventricular blood flow by 48 +/- 10 (SE), 33 +/- 9, and 10 +/- 6%, respectively, and decreased left ventricular vascular resistance by 26 +/- 6, 31 +/- 10, and 10 +/- 6%, respectively. After isoproterenol, NEP inhibition augmented the decrease in left ventricular vascular resistance (25 +/- 6% decrease within 90 s of isoproterenol vs. 8 +/- 5% in controls). ACE inhibition did not augment the decrease in resistance but inhibiting both enzymes did so to a lesser extent than inhibiting NEP. These effects cannot be explained by vascular responses secondary to changes of myocardial oxygen consumption. We conclude that NEP and ACE are regulators of myocardial blood flow.
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PMID:Effects of inhibiting neutral endopeptidase and kininase II on coronary and systemic hemodynamics in rats. 757 97

In order to clarify the preventive action of Dai-Saiko-to (Da-Chai-Hu-Tang) extract (TJ-8) on the progression of acute liver injury in rats intoxicated with carbon tetrachloride (CCl4), we examined the effect of post-oral TJ-8 administration on hepatic active oxygen metabolism following the progression of this liver damage. When TJ-8 (1.0 g/kg body weight) was administered orally to male Wistar rats aged five weeks 2 hrs after i.p. injection of CCl4 (1.0 ml/kg body weight), an apparent liver injury occurred. Significant prevention against the progression of liver injury was found at 24 hrs after injection, judging from the activities of serum transaminases, indexes of liver cell damage. Liver cytosolic superoxide dismutase (SOD) activity decreased 2 and 24 hrs after CCl4 injection, while liver cytosolic catalase and glutathione reductase (GSSG-R) activities decreased 24 hrs after the injection. At 2 and 24 hrs after CCl4 treatment, liver cytosolic Se-containing glutathione peroxidase (GSH-px) activity did not change and liver cytosolic glucose-6-phosphate dehydrogenase (G-6-PDH) activity increased. Post-oral TJ-8 administration significantly ameliorated decreases in liver SOD, catalase, and GSSG-R activities at 24 hrs after CCl4 injection, but did not affect liver Se-GSH-px and increased liver G-6-PDH activities at 24 hrs after the injection. Although increased liver lipid peroxide level and decreased liver reduced glutathione and ascorbic acid levels were observed 2 and 24 hrs after CCl4 injection, post-oral TJ-8 administration significantly prevented these changes found at 24 hrs after injection. These results indicate that post-oral TJ-8 administration can prevent the progression of acute liver injury in CCl4-injected rats by inhibiting enhanced lipid peroxidation and by improving disrupted active oxygen metabolism in the injured liver.
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PMID:Preventive effect of dai-saiko-to (da-chai-hu-tang) extract on disrupted hepatic active oxygen metabolism in rats with carbon tetrachloride-induced liver injury. 759 92

We studied 14 patients who had exercise-induced ventricular arrhythmias after a previous Q-wave myocardial infarction. All had symptomatic mild heart failure in New York Heart Association class II and a maximal oxygen consumption between 16 and 20 ml/kg/min. They were treated with the angiotensin converting enzyme inhibitor benazepril (20 mg) and hydrochlorothiazide (50 mg) for 3 months in a double-blind randomized cross-over study. Benazepril improved the maximal oxygen uptake by 15% and exercise time by 18%. Hydrochlorothiazide slightly increased exercise time (5%) and the respiratory exchange ratio but not oxygen consumption. The arrhythmias were nonsustained and reproducible in two baseline recordings. Compared with baseline, benazepril reduced the mean number (3.5 +/- 2.5) (+/- SD) of episodes of ventricular tachycardia by 66%, and total (47.4 +/- 40.9) and paired (5.2 +/- 4.5) premature ventricular contractions by 61% and 62%, respectively. Hydrochlorothiazide did not reduce the number of arrhythmias. Thus an improved cardiac function induced by benazepril is associated with a reduction in exercise-induced ventricular arrhythmias in patients with symptomatic mild heart failure after infarction.
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PMID:Reduction of exercise-induced ventricular arrhythmias in mild symptomatic heart failure by benazepril. 767 69

This study attempted to research the protective effects of cilazapril, a new ACE inhibitor, on chronic hypoxic pulmonary hypertension and hypoxemia in rats. The mean pulmonary arterial pressure (mPAP) of the rats after hypoxia and injection with 1% Fecl3 via the tail veins for 4 weeks increased significantly but its PaO2 decreased separately. Cilazapril effectively protected mPAP increase and PaO2 decrease in rats treated with Cilazapril (0.5 mg/d) by suppressing the lung injury of TNF and oxygen free radical.
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PMID:[The protective effects of cilazapril of chronic hypoxic pulmonary hypertension and hypoxemia in rats]. 771 84


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