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)

Single doses of the angiotensin converting enzyme (ACE) inhibitor quinapril were administered to salt replete normotensive men to investigate pharmacokinetics and dose responses. Maximal ACE inhibition was produced by the 2.5, 5, and 20 mg doses (but not by 0.5 mg), but there was evidence of dose-dependency only for the duration of ACE inhibition. Quinaprilat was detectable in plasma up to 72 hours after all doses and the terminal phase half-life was calculated at 26 +/- 7 hours. Although there were dose-related increases in area under the curve (AUC), the relationships between dose and both AUC and maximum concentration were nonlinear. These findings suggest that quinapril displays the same prolonged terminal phase half-life that is characteristic of other ACE inhibitor drugs. The failure of doses above 2.5 mg to produce any further increase in the magnitude of ACE inhibition is consistent with an maximum effect dose-response relationship, with the obvious implication that higher doses will increase only the duration not the magnitude of response.
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PMID:Dose responses and pharmacokinetics for the angiotensin converting enzyme inhibitor quinapril. 131 2

The effect of experimentally-induced hypertension on the angiotensin converting enzyme (ACE) activity in the endothelium and smooth muscle cum adventitia of the Sprague Dawley rats was investigated. The ACE activity in both tissues of the 1-clip 2-kidney renovascular hypertensive rats and the deoxycorticosterone acetate/salt hypertensive rats were significantly higher than those of the normotensive control. These findings (i) support the suggestion that the 1-clip 2-kidney renovascular hypertensive rat represents a model of renin- and angiotensin-dependent hypertension and that the increased vascular ACE activity could play a role in the maintenance of hypertension (ii) provide new information regarding the association of increased vascular ACE activity and hypertension in the mineralocorticoid/salt treated hypertensive rats which may account for the finding by others that captopril is effective in preventing the development of hypertension in this low renin model of hypertension. On the other hand, the data also bring forth the possibility that the observed increase in vascular ACE activity could be the result of hypertension.
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PMID:Effect of experimentally-induced hypertension on angiotensin converting enzyme activity in the aortic endothelium and smooth muscle cum adventitia of the Sprague Dawley rat. 131 37

Diuretics have long been used to lower blood pressure in hypertensive patients or to control body fluid and electrolyte homeostasis in diseases such as congestive heart failure, chronic renal failure or cirrhosis. The initial response to diuretics is a negative sodium and fluid balance. The diuretic-induced loss of salt and water activates several hormonal systems such as vasopressin, the renin-angiotensin-aldosterone system or the sympathetic nervous system which tend to compensate for the changes in sodium and water balance. This neurohormonal response may have important clinical implications. Thus, the activation of the renin-angiotensin-aldosterone cascade appears to be partially responsible for the flat dose-blood pressure response curve of thiazides in hypertensive patients. It may also be responsible for the difference between responders and non-responders to diuretic therapy and for the development of side-effects such as hypokalaemia, metabolic alkalosis or hyponatraemia. There are several ways to prevent the undesirable consequences of the neurohormonal responses to diuretics. The first is to use low doses of these agents. It is also possible to combine them with agents that block the activity of the renin-angiotensin-aldosterone system such as ACE inhibitors or in combination with drugs that reduce aldosterone secretion such as calcium antagonists. The development of drugs able to enhance urinary sodium excretion and to reduce simultaneously the activity of the renin-angiotensin-aldosterone system may offer a new interesting alternative. This might perhaps be achieved in the future with the administration of neutral endopeptidase inhibitors which interfere with the enzymatic degradation of atrial natriuretic peptide.
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PMID:Neurohormonal consequences of diuretics in different cardiovascular syndromes. 136 43

We have evaluated the genes for angiotensin converting enzyme (ACE) and guanylyl cyclase A/atrial natriuretic peptide receptor (GCA) for genetic effects on blood pressure response to high salt diet. In F2 rats derived from Milan normotensive and Dahl salt-hypertension sensitive (S) rats, both ACE and GCA cosegregated with blood pressure, and rats that were homozygous for the S allele at both the ACE and GCA loci had inordinately high blood pressure. In F2 derived from Wistar Kyoto (WKY) and S rats, GCA revealed positive cosegregation with blood pressure, but ACE did not. We conclude that certain alleles at the GCA and ACE loci (or at loci closely linked to them) have a significant genetic impact on blood pressure response to high salt in specific rat strains.
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PMID:Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats. 136 13

The pyruvate dehydrogenase complex (PDC) from muscle of the adult parasitic nematode Ascaris suum plays a unique role in its anaerobic mitochondrial metabolism. Resolution of the intact complex in high salt dissociates the pyruvate dehydrogenase subunit but leaves the dihydrolipoyl dehydrogenase subunit (E3) and two other proteins with apparent M(r)s of 45 and 43 kDa bound to the dihydrolipoyl transacetylase (E2) core. These proteins are not observable on Coomassie brilliant blue-stained gels of other eukaryotic PDCs, but the 45-kDa protein is similar in apparent M(r), pI, and sensitivity to trypsin to the Kb subunit of the bovine kidney PDH alpha kinase. Acetylation of the ascarid PDC with [2-14C]pyruvate under conditions designed to maximize the incorporation of label into protein yielded only a single radiolabeled subunit, E2. These results confirm earlier reports that the ascarid PDC lacks protein X, an integral component recently identified in other eukaryotic PDCs. About 1.6 to 1.8 mol of 14C was incorporated/mole of E2, suggesting that the ascarid E2 contained two lipoly-bearing domains. Domain mapping of the 14C-acetylated ascarid E2 by limited tryptic digestion identified two lipoyl-bearing fragments with apparent M(r)s of 50 and 34 kDa and two core fragments with apparent M(r)s of 46 and 30 kDa. The ascarid E2 domain structure appears to be similar to that of other E2s. However, it appears that the subunit-binding domain (E2B) of the ascarid E2 may be significantly larger or be flanked by larger than normal interdomain regions. An enlarged E2B domain may be necessary to accommodate the additional binding of E3 to the E2 subunit in the ascarid complex, in the absence of protein X.
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PMID:The pyruvate dehydrogenase complex from the parasitic nematode Ascaris suum: novel subunit composition and domain structure of the dihydrolipoyl transacetylase component. 137 97

Isolated systolic hypertension (ISH) is generally defined as a systolic pressure of 160 mmHg or more, with a diastolic pressure cut-off point below 95 mmHg in some studies and 90 mmHg in others. Its prevalence and incidence vary from 3 to 30% depending on the definition applied, methodology of measurement, as well as the population and the age and sex of the patients. Mechanisms that could lead to the development of isolated systolic hypertension are discussed, especially the role of atherosclerosis and sodium intake. Comparing results from different countries, the Intersalt study showed that the age related rise in systolic pressure was positively related to the mean sodium excretion in that country. A post-hoc analysis of data from 4 Belgian groups could not show such a correlation within our country. The risks of systolic hypertension on mortality and morbidity in the elderly are considered. The need for further studies to quantify the risk and to establish the effect of treatment is emphasized. Three such studies in patients above the age of 60 years with ISH were started. The studies are double-blind, placebo-controlled trials and the main purpose is to examine the influence of treatment on morbidity, mortality, and general well-being. In the American SHEP study the patients of the actively treated group received a diuretic and possibly a beta-blocker or reserpine. The results indicate a significant reduction in non fatal stroke, heart failure and myocardial infarction without a significant reduction in fatal stroke, fatal myocardial infarction, cardiovascular or all cause mortality. Studies in other continents are still in progress, such as the Syst-Chin in China and the Syst-Eur trial in Europe. They may indicate whether the results obtained in the U.S.A. can be extrapolated to other continents and whether the use of other drugs without metabolic disturbances, such as calcium entry blockers and angiotensin converting enzyme inhibitors, produce a similar reduction in events. Additional studies are needed to establish the effect of reducing salt intake in younger age groups on the prevalence of ISH and of the related morbidity and mortality.
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PMID:[Isolated systolic hypertension in persons older than 60]. 141 81

1. Intravenous ACE inhibitor therapy is of increasing importance in the treatment of patients with unstable heart failure after myocardial infarction. Available pharmacokinetic and concentration effect data with this route of administration are limited. 2. The pharmacokinetics and blood pressure responses to perindoprilat were studied during prolonged low dose (1 mg) infusions in eight normotensive salt replete male volunteers. 3. Subjects received randomised, single (subject) blinded therapy with saline placebo (30 ml) over 3 h or active treatment (1 mg in 30 ml) over 1 h, 3 h or 6 h by constant rate infusion. 4. Significant falls in blood pressure greater than placebo were noted with active infusions without changes in heart rate. Mean maximal plasma perindoprilat concentrations reflected the rate of infusion (1 h, 51.5 +/- 11.4 ng ml-1; 3 h, 30.4 +/- 8.4 ng ml-1; 6 h 19.0 +/- 4.0 ng ml-1) and mean maximal plasma ACE inhibition was less with slower infusions (1 h, 95.7 +/- 0.5%; 3 h 92.3 +/- 2.7%; 6 h 87.4 +/- 5.1%, P less than 0.013). 5. Concentration-time profiles showed a sigmoid drug accumulation profile with delay in the early accumulation of drug particularly during the 3 h and 6 h infusions. The pharmacokinetic data was assessed by statistical comparison of a hierarchy of standard compartmental models and non linear saturable binding models. A non linear model incorporating elements to describe both tissue and plasma binding of the drug provided the best fit to observed data. 6. Low dose constant rate infusions are a means of optimising intravenous ACE inhibitor therapy to allow individual dose titration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers. 141 73

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.
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PMID:Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats. 142 16

The ability of centrally administered angiotensin converting enzyme (ACE) inhibitors to lower mean arterial pressure (MAP) has been demonstrated in numerous animal models of hypertension. In the present study, we assessed the effect of intracerebroventricular (i.c.v.) injection of the ACE inhibitor captopril (10 micrograms) on MAP in conscious, freely moving hypertensive inbred Dahl salt-sensitive (DS/JR) rats and their normotensive control inbred Dahl salt-resistant (DP/JR) rats. Both DS/JR and DR/JR rats were maintained on an 8% salt diet from 4 weeks of age until experimentation at 7-8 weeks of age, at which time DS/JR pressures were significantly elevated as compared to DR/JR rats (185 +/- 6 vs. 99 +/- 2 mm Hg, respectively). Following i.c.v. administration of captopril, a significant depressor response lasting for several hours was observed in DS/JR rats, with a maximum reduction of 17.6 +/- 4.1 mm Hg. The same treatment had no effect on the MAP of DR/JR rats. Mean arterial pressures in both groups were not significantly affected by i.c.v. administration of vehicle alone or by intravenous (i.v.) administration of 100 micrograms of captopril. These findings indicate that i.c.v. captopril lowers MAP in hypertensive DS/JR rats. Further studies will be necessary to elucidate the mechanism of this antihypertensive effect.
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PMID:The antihypertensive effect of acute intracerebroventricular administration of captopril in Dahl salt-sensitive rats. 146 97

As the major regulator of arterial blood pressure and sodium balance, the renin axis supports normotension or hypertension via angiotensin-mediated vasoconstriction and angiotensin plus aldosterone-induced renal sodium retention. In this endocrine servo control, renal renin is released by hypotension or salt depletion; conversely, with hypertension or volume excess, plasma renin activity falls to zero. Accordingly, any renal renin secretion is abnormal in the face of arterial hypertension. Human hypertensive disorders comprise a spectrum of abnormal vasoconstriction-volume products (renin-sodium profiles). Excess plasma renin activity for the sodium balance is created by nephron heterogeneity in which a subpopulation of ischemic nephrons hypersecretes renin and retains sodium. This excess renin impairs adaptive natriuresis of neighboring normal nephrons. Research defining the pivotal role of vascular cytosolic calcium for transducing sodium or renin-mediated vasoconstriction explains the selective value of calcium antagonists for correcting the sodium-volume-mediated, and beta-blockers or angiotensin converting enzyme inhibitors for correcting renin-mediated, arteriolar vasoconstriction. The renin precursor prorenin appears to be physiologically active, causing selective vasodilation that offsets renin-mediated vasoconstriction. Overactivity of prorenin may be involved in the hyperperfusion vascular injuries of diabetes mellitus and toxemias. Prorenin underactivity may facilitate renin-mediated ischemic vascular injury. In essential hypertension, undue plasma renin activity is powerfully and independently associated with heart attack risk. Conversely, patients with low renin activity are protected from heart attack despite higher blood pressures and greater age. Also, renin or angiotensin administration consistently causes vascular injury in the heart, brain, and kidneys of animals. These data suggest new potentials for the prevention of cardiovascular sequelae (heart attack and stroke) by using explicit strategies to curtail plasma renin activity.
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PMID:Lewis K. Dahl Memorial Lecture. The renin system and four lines fo hypertension research. Nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack. 151 45


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