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)

Endothelial dysfunction is emerging as an important factor in the early development of acute and chronic renal disease. Drugs aimed specifically at rectifying this aberration are being developed, although other established agents such as calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and HMG CoA reductase inhibitors also have beneficial effects in this setting. Calcium antagonists are particularly effective at ameliorating acute renal ischaemia associated with endothelial dysfunction. Combination therapy with a calcium antagonist and an ACE inhibitor might optimise the beneficial effects of calcium channel blockade on the sequelae of endothelial dysfunction in chronic renal failure.
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PMID:Endothelial function and the kidney. An emerging target for cardiovascular therapy. 903 51

A large number of drug trials for prevention of restenosis have been conducted with many showing little or conflicting benefit. Antiplatelets such as aspirin, ticlopidine and thromboxane A2 receptor inhibitors have not shown a clear benefit. Similarly, antithrombotics, either acting indirectly such as heparin, or as direct thrombin inhibitors such as hirudin and hirulog, do not prevent restenosis. Trials with ACE inhibitors, HMG-CoA reductase inhibitors and fish-oil supplements have yielded inconclusive results. The antiproliferatives, angiopeptin, trapidil and tranilast have shown some benefit in small-scale studies. Other drug classes of potential benefit include the glycoprotein IIb/IIIa receptor antagonists, inhibitors of the early coagulation cascade, calcium channel blockers and nitric oxide donors. Drug research into restenosis prevention has been hampered by problems with the definition of restenosis and the applicability in humans of animal models. Although no single drug has conclusively proven effective yet, the promise of a number of agents, together with other nonpharmacological strategies will likely result in further reductions in the incidence of restenosis.
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PMID:Pharmacological approaches for the prevention of restenosis after percutaneous coronary intervention. 932 30

Coronary heart disease and other vascular diseases account for approximately half of all deaths in women. Although the underlying pathophysiological processes (atherosclerosis and thrombosis) are similar, deaths and other clinical end-points are significantly delayed compared to men. The reason for this sex-related delay in the expression of vascular disease remains a matter of debate but may be largely attributable to the actions of endogenous oestrogens: coronary heart disease manifestations are extremely rare in premenopausal women but increase after the menopause. These observations have lead to speculation that oestrogen-replacement therapy might continue to retard the development of cardiovascular disease in the post-menopausal years (primary prevention). The cardioprotective benefits of oestrogens include a favourable impact on plasma lipids, anti-platelet effects, preservation of endothelium-mediated vasodilatation and antioxidant effects. Several observational studies support this thesis but the results of prospective randomised controlled trials are still awaited. Secondary preventative measures such as aspirin, beta-blockade, ACE inhibition and HMG-CoA reductase inhibitors seem to be equally effective for women as men. However, there remains evidence that physicians are less likely to use such interventions in women at high risk.
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PMID:Women and heart disease. 983 68

The increased risk of cardiovascular disease in diabetic patients is well documented. A greater appreciation for the importance of this fact and regular use of secondary prevention strategies, including aggressive use of HMG-CoA reductase inhibitors or other lipid-lowering agents to reduce cholesterol levels, are clearly indicated for diabetic patients with CAD. If no contraindications exist, ACE inhibitors, beta blockers, and aspirin also should be considered for these high-risk patients.
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PMID:Coronary artery disease and diabetes. 1002 4

Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10(-7) M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P < 0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [3H]acetate into cholesterol) by up to 90% (P < 0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM's cholesterol synthesis by up to 70% (P < 0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10(-7) M Ang II for 18 h at 37 degrees C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10(-5) M), an AT1 blocker, but not PD 123319 (10(-5) M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.
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PMID:Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. 1053 81

Adjunctive therapy is critical in treating acute coronary syndromes. Aspirin, nitrates, beta-blockers, ACE inhibitors, HMG-CoA reductase inhibitors (statins), and intra-aortic balloon pumps all have important roles and should be considered on a case-by-case basis.
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PMID:Adjunctive medical therapy for acute coronary syndromes. 1074 8

Based on the data from large single and multi-center clinical trials, including the Heart Outcomes Prevention Evaluation (HOPE) study, it is clear that the presence of microalbuminuria is a signal from the kidney that cardiovascular risk is increased and that vascular responses are altered. This is exemplified by studies that have demonstrated that the compensatory vasodilation seen following relief from prolonged ischemia or infusion of vasodilators such as nitroglycerin is blunted in people with microalbuminuria. Thus, the presence of between 30 and 299 mg/day of albumin in the urine is associated with abnormal vascular responsiveness, which may be the result of more advanced atherosclerosis and not necessarily related to the presence of hypertension or renal disease. Agents known to reduce the rise in microalbuminuria or actually reduce the level of microalbuminuria, such as ACE inhibitors, angiotensin receptor blockers, HMG-CoA reductase inhibitors, beta blockers, non-dihydropyridine calcium channel blockers and diuretics, have all been shown to reduce cardiovascular mortality and in some cases preserve renal function. This article will present an overview of the data that support the assertion that a reduction in the rise of microalbuminuria is a significant consideration in the selection of agents to treat a given risk factor (cholesterol or blood pressure) to a recommended target goal. Achieving such a goal with agents that also impact microalbuminuria will provide for a more complete cardiovascular risk reduction.
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PMID:Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. 1208 33

Stroke is a major cause of morbidity and mortality. Full assessment of stroke or transient ischaemic attack (TIA) patients is required to identify all risk factors and apply appropriate secondary preventative strategies. Antiplatelet therapies are effective in the secondary prevention of ischaemic stroke and can be justified despite adverse effects such as gastrointestinal haemorrhage. Aspirin (acetylsalicylic acid), aspirin plus dipyridamole, ticlopidine and clopidogrel are all of value but their adverse effect profiles vary significantly. Combinations of antiplatelet agents may offer additional benefit but not all combinations have been studied in stroke patients. Anticoagulation with agents such as warfarin is effective with coexisting atrial fibrillation and other conditions predisposing to cardioembolic stroke. Antihypertensive agents have been extensively studied in the primary prevention of stroke; however, relatively few trials of antihypertensive agents in the secondary prevention of stroke are available. The incidence of adverse effects of antihypertensive agents is relatively low and the benefit-risk profile would tend to favour their use in the secondary prevention of stroke. Recent studies of ACE inhibitors have identified an important role for these agents in the secondary prevention of stroke even in those who are normotensive and in those who have had a haemorrhagic stroke. The incidence of serious adverse effects with ACE inhibitors appears relatively low. Lipid-lowering agents may have a role to play in certain groups of patients with stroke. The incidence of adverse effects is relatively low with HMG-CoA reductase inhibitors. Cigarette smoking is an important risk factor for stroke and evidence is available that smoking cessation does reduce the individual's risk of stroke. Pharmacological agents are available to help smoking cessation. In patients with diabetes mellitus, intensive regimens with insulin and oral hypoglycaemic agents have so far not definitively been shown to reduce the incidence of macrovascular complications such as stroke. Tight glycaemic control has been shown to improve microvascular complications such as retinopathy, nephropathy and neuropathy and hence this is reason enough to advocate the use of these agents. Future developments in the treatment of diabetes may help. Secondary prevention of stroke has improved greatly over the past decade and hopefully will continue to improve. The use of pharmacological agents available currently and in the future will be clarified and refined as further clinical trials report.
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PMID:A benefit-risk assessment of agents used in the secondary prevention of stroke. 1238 Dec 15

Recent progress in molecular biological research has revealed that many types of transporters are expressed in the liver. Such xenobiotic transporters have a wide range of substrate specificity, which allows them to act as a barrier to protect the body from potentially harmful xenobiotics. Most of them mediate active transport of the substrates, leading to concentrative uptake and excretion into the hepatocytes and bile. Transport properties such as these may play a role in the toxicity of certain types of substrates. For example, anticancer agents such as methotrexate and irinotecan are efficiently excreted into the bile and such excretion has been suggested to account for their toxic gastrointestinal side-effects. A similar hypothesis has also been proposed for NSAIDs. Considering their tissue-specific expression, these transporters also appear to be a promising target for the delivery of small molecules, while simultaneously minimizing their side-effects. For example, transporters involved in the oral absorption, hepatic uptake, and biliary excretion of pravastatin, an HMG-CoA reductase inhibitor, ensure its enterohepatic circulation giving it an important pharmacokinetic advantage since its pharmacological target is the liver. Of the major ACE inhibitors currently available, temocaprilat is a substrate of hepatic transporters. Since the major elimination route for other ACE inhibitors is via urinary excretion, their plasma concentrations exhibit a high degree of inter-patient variability over a wide range of renal function whereas the concentrations of temocaprilat exhibit a much lower degree of inter-patient variability due to its elimination into the bile. Thus, the hepatobiliary transporters are involved in some aspects of toxicology and, therefore, a rational strategy for regulating the recognition by such transporters may be required for optimum drug design. This presentation will discuss the possible role of hepatic transporters from a toxicological point of view.
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PMID:Toxicological implications of hepatobiliary transporters. 1250 27

Coronary artery disease (CAD) is prevalent in the elderly and often leads to disability. Consequently, strategies for optimising the prevention and treatment of CAD in the elderly are important from both the individual and societal perspectives. Although it is common knowledge that the elderly are heavy consumers of drugs, there is evidence to show that there is under-prescribing of evidence-based medical therapies in the home-dwelling elderly coronary patient and there may be overuse of some non-evidence-based (antioxidants) and purely symptomatic treatments. In particular, aspirin (acetylsalicylic acid), beta-adrenoceptor antagonists, ACE inhibitors and HMG-CoA reductase inhibitors are under-utilised. Although the evidence base is largely drawn from trials including patients younger than 75 years, it is reasonable to assume that the data applies to patients aged over 75 years and that better use of evidence-based medicines would provide benefits to the home-dwelling aged patient. Evidence from the few multifactorial studies available suggest possible benefits including reduction of cardiovascular events, less disability and better quality of life in old age. At the societal level, this would be reflected in fewer hospitalisations and institutionalisations, which means decreased cost of elderly care.
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PMID:Benefits of optimising drug treatment in home-dwelling elderly patients with coronary artery disease. 1279 26


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