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)

The development of pharmacological agents that block the renin-angiotensin system (RAS) specifically have helped to define all the components of the system and their contribution to blood-pressure control and to the pathogenesis of hypertension, congestive heart failure and chronic renal failure. The angiotensin converting-enzyme inhibitors (ACEi) are among all available drugs that interfere with the RAS, the most efficient, so far, in the treatment of several cardiovascular diseases, with comfortable posologic schemes and an acceptable safety profile. The most important difference between them are more related to pharmacokinetic profile rather than to pharmacodynamic characteristics. With the use of ACEi the interference with other neurohumoral systems is unavoidable and the controversy has been pharmacologically and clinically installed. With the advent of oral selective AT1 angiotensin II receptor blockers (ARB) the pharmacological interference became eventually much more selective. Their antihypertensive efficacy is identical and their tolerability is better than that showed by ACEi. The ARBs differ mainly in their pharmacokinetics and in their binding capacity to the AT1 angiotensin receptor. The results of several ongoing clinical trials will show if the ARBs as ACEi will be capable to protect target-organs and to promote a significant reduction in cardiovascular morbility and mortality. In parallel there is an intense experimental and clinical research with other groups of drugs which also markedly interfere with RAS: renin inhibitors, chymase inhibitors and simultaneous inhibitors of vasopeptidases (ACE, endothelin converting-enzyme, neutral endopeptidase). From the pharmacological point of view, it is now possible to block effectively RAS with some relevant clinical results that will be certainly widen in the near future.
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PMID:[Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists. Pharmacologic features]. 1130 8

Hypertension is found among 1 to 6% of young women. Treatment aims to decrease cardiovascular risk, the magnitude of which is less dependent on the absolute level of blood pressure (BP) than on associated cardiovascular risk factors, hypertension-related target organ damage and/or concomitant disease. Lifestyle modifications are recommended for all hypertensive individuals. The threshold of BP at which antihypertensive therapy should be initiated is based on absolute cardiovascular risk. Most young women are at low risk and not in need of antihypertensive therapy. All antihypertensive agents appear to be equally efficacious; choice depends on personal preference, social circumstances and an agent's effect on cardiovascular risk factors, target organ damage and/or concomitant disease. Although most agents are appropriate for, and tolerated well by, young women, another consideration remains that of pregnancy, 50% of which are unplanned. A clinician must be aware of a woman's method of contraception and the potential of an antihypertensive agent to cause birth defects following inadvertent exposure in early pregnancy. Conversely, if an oral contraceptive is effective and well tolerated, but the woman's BP becomes mildly elevated, continuing the contraceptive and initiating antihypertensive treatment may not be contraindicated, especially if the ability to plan pregnancy is important (e.g. in type 1 diabetes mellitus). No commonly used antihypertensive is known to be teratogenic, although ACE inhibitors and angiotensin receptor antagonists should be discontinued, and any antihypertensive drugs should be continued in pregnancy only if anticipated benefits outweigh potential reproductive risk(s). The hypertensive disorders of pregnancy complicate 5 to 10% of pregnancies and are a leading cause of maternal and perinatal mortality and morbidity. Treatment aims to improve pregnancy outcome. There is consensus that severe maternal hypertension (systolic BP > or = 170mm Hg and/or diastolic BP > or = 110mm Hg) should be treated immediately to avoid maternal stroke, death and, possibly, eclampsia. Parenteral hydralazine may be associated with a higher risk of maternal hypotension, and intravenous labetalol with neonatal bradycardia. There is no consensus as to whether mild-to-moderate hypertension in pregnancy should be treated: the risks of transient severe hypertension, antenatal hospitalisation, proteinuria at delivery and neonatal respiratory distress syndrome may be decreased by therapy, but intrauterine fetal growth may also be impaired, particularly by atenolol. Methyldopa and other beta-blockers have been used most extensively. Reporting bias and the uncertainty of outcomes as defined warrant cautious interpretation of these findings and preclude treatment recommendations.
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PMID:Treating hypertension in women of child-bearing age and during pregnancy. 1136 52

Angiotensin II plays an important role in blood pressure control and in water and salt homeosthasis. It is involved in the pathogenesis of hypertension and structural alterations of the vasculature, kidney, and heart, including nephrosclerosis, post infarction remodelling and left ventricular hypertrophy. At least two subtypes of receptors have been identified, angiotensin type 1 (AT1) and type 2 (AT2). The AT1 receptor is responsible for all the known effects of Ang II on blood pressure, osmoregulation, and cell growth and consequently for the contribution to cardiovascular and renal pathology. Research has indicated that the AT1 receptor modulates cardiac and vascular hypertrophy, cellular growth and ventricular remodelling. Evidence suggests that, on the other hand, the AT2 receptor is involved in growth inhibition, inhibits cell proliferation, induces vasodilatation and reverses the AT1 induced hypertrophy. The accumulating evidence appears to demonstrate therefore that the function of these receptor subtypes may exerts opposite effects while stimulated by AngII. The angiotensin receptor antagonists are able to inhibit the renin angiotensin system by blocking selectively the AT1 receptor. It is supposed that AT1 receptor antagonists may provide end organ protection by blocking angiotensin II effects via the AT1 receptor leaving the AT2 receptor unopposed: it is conceivable that the stimulation of AT2 receptors may prevent the hypertropic effects seen in conditions such as LVH, hypertrophy, postinfarction remodeling and repair after injury. For this, the AT1/AT2 selectivity associated to these drugs may be important for their effects and to differentiate them from ACE inhibitors.
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PMID:[The role of the selective blocking of angiotensin II receptors in the treatment of cardiovascular diseases]. 1144 21

Improvements in the death rate from coronary heart disease and in the control of hypertension have leveled off in recent years, reversing a trend toward steady improvement that began in 1972. Of the roughly 20% of Americans who suffer from hypertension, only 29% achieve adequate control (<140/90 mm Hg) with treatment and nearly half receive no treatment at all. Poor adherence to therapy doubtless plays a key role in this failure. As a major cause of poor adherence, tolerability becomes an extremely important element in any discussion of effective antihypertensive treatment. Despite their efficacy in treating hypertension, diuretics, beta-blockers, and calcium channel blockers have all been associated with numerous side effects, including increased serum lipid levels, insulin resistance, and edema. With the introduction of the angiotensin converting enzyme (ACE) inhibitors, patients were able to achieve blood pressure goals with fewer side effects. These agents, however, cause an irritating cough in up to 19% of patients. A newer class of drugs, the angiotensin receptor blockers (ARB), have similar effects to the ACE inhibitors, but their highly selective nature produces even fewer side effects. Eprosartan is a structurally unique ARB. Like the other ARB, this promising new agent has a side effect profile similar to placebo, and its response rate rivals or exceeds that of enalapril. Although it remains to be seen whether the ARB can significantly reduce morbidity and mortality from cardiovascular disease, preliminary data from the Evaluation of Losartan in the Elderly (ELITE) trial appear to be promising.
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PMID:Issues in hypertension: drug tolerability and special populations. 1145 11

The role of the renin-angiotensin system (RAS) in the regulation of blood pressure and the pathogenesis of both hypertension and renal complications involves an intricate interplay of genetic and environmental factors. In the case of diabetic nephropathy, the genes governing the RAS are an obvious choice in the search for contributing factors. These genetic components can reflect polygenetic mechanisms or a major gene effect. During recent years, polymorphisms of the genes governing both angiotensin converting enzyme (ACE) and angiotensinogen have been studied, with varying outcomes. Investigation of the interaction between ACE inhibition and the glycemic state yields equally interesting results. In healthy subjects on a high salt diet, the hyperglycemic state produced significant increases in renal plasma flow (RPF) in response to administration of the ACE inhibitor captopril. A similar study using the angiotensin receptor blocker (ARB) eprosartan demonstrated again that the agent had little effect on RPF in subjects in a normal glycemic state; however, when administered during a hyperglycemic state, a marked increase in RPF occurred. Implications for the prevention of nephropathy and endstage renal disease (ESRD) in diabetics with hypertension are significant. Until recently, pharmacologic intervention in the RAS has focused on the ACE step, with documented success being reported in the prevention of diabetic nephropathy and ESRD using ACE inhibitors. Despite this success, data suggest that greater therapeutic benefit might be accomplished by blocking the deleterious effects of angiotensin II at the receptor site. From a renoprotective perspective, the ARB appear to have tremendous potential in the management of hypertension.
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PMID:Renal implications of angiotensin receptor blockers. 1145 12

The treatment of hypertension has become increasingly refined during the past decade. Although a variety of antihypertensive medication classes exist, drugs that interrupt the renin-angiotensin axis have gained a favored position in the treatment of hypertension and its attendant end-organ complications. In this regard, two drug classes, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are most commonly used. Angiotensin receptor blockers have proven highly effective in the management of hypertension. This class is fairly heterogeneous with individual class members having somewhat distinctive pharmacologic properties. Eprosartan is a recent entry into this class. This compound compares favorably to others in this class relative to blood pressure reduction. In addition, preliminary studies indicate that this compound may uniquely interrupt the sympathetic nervous system and thereby preferentially reduce systolic blood pressure.
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PMID:Pharmacology and clinical efficacy of angiotensin receptor blockers. 1145 13

Despite major advances many cardiovascular disorders remain poorly controlled. As a result the search for newer agents goes on. Anti-neurohormonal agents have been the most successful agents: beta-blockers, ACE inhibitors and angiotensin receptor blockers. To these we now add anti-aldosterone strategies with the phenomenal success of spironolactone in reducing mortality in severe heart failure. A more recent and more selective aldosterone receptor antagonist has been developed, eplerenone, and it shows considerable promise in managing and preventing the complications of hypertension. It may have a role both being anti-fibrotic and anti-neurohormonal in mild to moderate heart failure, in post-MI left ventricular dysfunction and in progressive renal disease. The EPHESUS trial which randomised patients with heart failure due to impaired left ventricular systolic function aims to randomise 6,200 patients to eplerenone or placebo on top of standard therapy and follow subjects until 1,012 deaths have occurred (approx. 2.5 years of follow up). This and other trials with the novel strategy of selective aldosterone antagonism are eagerly awaited. The beneficial effects established by the earliest anti-neurohormonal agents give us confidence that further benefits could be obtained by this intellectual strategy.
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PMID:Exciting new drugs on the horizon - eplerenone, a selective aldosterone receptor antagonist (SARA). 1153 39

Meta-analysis has become a very popular tool to compare the efficacy of different antihypertensive regimens. Combining results from various outcome studies may provide evidence to guide the therapeutic approach even before results from large prospective studies are available. However, meta-analysis may be misleading if it is not done meticulously. Some meta-analyses that received broad news media coverage in the recent years were misleading. One analysis suggested that the use of short-acting nifedipine in moderate to high doses in patients with coronary disease increased mortality. This claim was refuted later by observational studies. Based on another meta-analysis, it was claimed that diuretics and beta-blockers are equally effective in reducing cardiovascular morbidity and mortality. Another more careful meta-analysis, omitting one study in which most patients were on combination therapy and not on beta-blocker monotherapy, showed the superiority of diuretic versus b-blocker treatment in the elderly. Calcium antagonists were recently blamed for increasing the rate of myocardial infarction and congestive heart failure in hypertensive patients, and therefore their use was not recommended as first-line therapy in hypertension. This recommendation was based on a meta-analysis subject to major drawbacks and was misleading. Another notion based on meta-analysis was that angiotensin converting enzyme inhibitors reduce left ventricular mass more than diuretics. This notion was refuted by three large randomized studies. A recent meta-analysis, which showed a similar blood pressure lowering effect for all angiotensin receptor blockers, was refuted by head-to-head studies. Thus, when performed correctly, meta-analysis can be an important tool, but when uncritically employed, it is prone to be misleading.
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PMID:Meta-analyses of antihypertensive therapy: Are some of them misleading? 1155 71

Recent clinical trials clearly demonstrate that patients with diabetes and hypertension, and patients with renal disease and hypertension, should have their blood pressure lowered intensively. A recent analysis of long-term clinical trials over the past 8 years clearly demonstrates that the lower the blood pressure over a range of values, the greater the preservation of renal function. It is also readily apparent that monotherapy does not suffice in attaining these more intensified goals. A review of five clinical trials in the recent National Kidney Foundation consensus report demonstrates that patients randomized to the lower level of blood pressure required an average of 3.2 different antihypertensive medications taken daily. Consequently, it is evident that the question is no longer what the initial preferred monotherapy should be, but rather what should be the optimal drug to add to an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. In this paper we review data from several recent studies clearly indicating that to achieve goal blood pressure in the clinical setting of metabolic disarray and hyperglycemia, long-acting calcium antagonists constitute an excellent add-on agent for enhancing efficacy. We anticipate that the data that will accrue from the IDNT and RENAAL studies will further delineate the renal effects of dihydropyridine calcium antagonists.
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PMID:What is the optimal strategy to intensify blood pressure control and prevent progression of renal failure? 1155 78

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.
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PMID:Differential subcellular actions of ACE inhibitors and AT(1) receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats. 1156 13


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