UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II, the principal effector of the renin-angiotensin cascade, stimulates a variety of physiological responses that support blood pressure and renal function. Abnormal generation of angiotensin II also contributes to the pathogenesis of hypertension, arterial diseases, cardiac hypertrophy, heart failure and proteinuric progressive renal diseases. It is well recognized that angiotensin-converting enzyme inhibitors effectively limit the progression of diabetic and non-diabetic proteinuric renal diseases towards end-stage renal disease, a capacity not necessarily shared by other blood pressure lowering agents. Whether angiotensin II type 1 receptor antagonists have the same renoprotective effect as angiotensin-converting enzyme inhibitors in progressive renal diseases remains ill defined. Angiotensin II type 1 receptor antagonists as antiproteinuric agents have been used originally in animal models of renal disease progression. Results have shown that angiotensin II type 1 receptor blockers are as effective as angiotensin-converting enzyme inhibitors in normalizing proteinuria in models of renal disease. Studies in humans are very few, but those that have been undertaken report consistent antiproteinuric effects of angiotensin II type 1 receptor antagonists that are similar to those with angiotensin-converting enzyme inhibitors. Long-term studies, however, are required to examine whether the antiproteinuric effects of angiotensin II type 1 receptor antagonists can be translated into renoprotection.
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PMID:Angiotensin II receptor antagonists and treatment of hypertension and renal disease. 981 6

Most antihypertensives have advantages and disadvantages. The ideal antihypertensive drug should be effective in lowering blood pressure, well tolerated, safe in the long term, and easy to use. Ideally, it should be relatively inexpensive. Most importantly it should reduce the risk of the adverse effects of high blood pressure, such as myocardial infarction, sudden death, stroke, heart failure, renal damage, and retinal changes. Most antihypertensive drugs effectively reduce blood pressure, are available as once daily preparations, and are safe long-term. Unfortunately, most antihypertensive drugs cause adverse effects in some patients and for few drugs is there good evidence that they protect the heart, the brain, the kidney, and the eye? Reducing the effects of Angiotensin II (using an ACE inhibitor) has been shown to reduce the incidence of coronary events, sudden death, heart failure, renal damage, and fundal changes. AT1 blocking drugs offer the same pharmacological advantages but also very good tolerability, in particular no cough. Therefore, they have the potential to meet all the criteria for an ideal antihypertensive drug.
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PMID:Therapeutic advantages of AT1 blockers in hypertension. 983 62

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.
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PMID:Angiotensin II and coronary artery disease, congestive heart failure, and sudden cardiac death. 983 71

The purpose of this study was to determine whether Angiotensin II (Ang II) contributes to the regulation of resting hemodynamics via Ang II type 1 (AT1) receptors in awake dogs with coronary microembolization-induced heart failure. Six dogs were surgically instrumented for measurement of systemic hemodynamics and for coronary microembolization. The acute hemodynamic effects of a selective AT1-receptor antagonist, GR138950 (1 mg/kg, i.v.), were determined before and after congestive heart failure (CHF). GR138950 had no effects on hemodynamics before CHF Daily coronary microembolizations (through the previously implanted coronary catheter) resulted in CHF, as documented by hemodynamic measurements, a slight but significant increased Ang II plasma level (17.4 +/- 1.6 vs. 23 +/- 1.0 pg/ml; p < 0.05), and characteristic clinical signs of CHF. After CHF, GR138950 significantly increased left ventricular dP/dt(max) (LVdP/dt(max)) from 1,754 +/- 68 to 2,347 +/- 114 mm Hg/s and decreased LV systolic pressure (LVSP) from 118 +/- 5 to 101 +/- 7 mm Hg; meanwhile, heart rate (from 132 +/- 4 to 102 +/- 6 beats/min) and LV end-diastolic pressure (LVEDP; from 17 +/- 3 to 9 +/- 1.5 mm Hg) were significantly decreased. Mean arterial pressure (MAP) was not affected. The peak effects occurred 90 min after administration. Thus Ang II contributes significantly to resting hemodynamics via AT1 receptors in this CHF model; that is, the specific AT1 blocker inhibits the negative inotropic actions of Ang II in the CHF state.
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PMID:The role of angiotensin II AT1 receptor in the maintenance of hemodynamics in a canine model of coronary microembolization-induced heart failure. 1002 45

Patients with acute myocardial infarction and evidence of heart failure or left ventricular dysfunction during the acute phase have an excessive mortality risk. Therapy with angiotensin-converting enzyme inhibitors attenuates the detrimental effects of angiotensin II and has been shown to substantially reduce morbidity and mortality in this population. Selective, angiotensin type 1 receptor antagonism with losartan, which inhibits the effects of angiotensin II regardless of its source at the receptor level, may provide more complete blockade of the renin-angiotensin system. The Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study is a multicenter, double-blind, randomized, parallel, captopril-controlled trial. The primary hypothesis is that, compared with captopril, losartan will decrease the risk for all-cause mortality by 20% in high-risk patients after acute myocardial infarction. The study population will consist of 5,000 patients, > or = 50 years of age, with heart failure during the acute phase or with a new Q-wave anterior infarction or reinfarction. Patients will be randomized to treatment with either losartan or captopril. All patients will be followed until 937 deaths occur (event-driven). The primary end point is total mortality (all-cause mortality). The secondary and tertiary end points are sudden death (and/or resuscitated cardiac death) and fatal/nonfatal reinfarction. Based on the assumed event rate, treatment effect and a 95% power to detect a 20% reduction in all-cause mortality at the 4.3% significance level (2-sided, adjusted for 2 interim analyses), the trial will enroll at least 5,004 patients and continue until a total number of 937 events has been reached (intention-to-treat analysis).
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PMID:Comparison of the effects of losartan and captopril on mortality in patients after acute myocardial infarction: the OPTIMAAL trial design. Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan. 1007 46

Angiotensin II (AII) participates in regulation of arterial blood pressure through its binding to AII receptors distributing among its target organs. In addition, locally produced AII appears to play a major role in the pathogenesis of cardiovascular hypertrophy via mechanism not related to blood pressure. Two subtypes of AII receptors, AT1 and AT2, are recognized as distinct in both molecular and pharmacological basis. In adult, AT1 is a dominant subtype in cardiovascular system, and mediates virtually all the previously known actions of AII, including vasoconstriction, production of growth factors, hypertrophy of smooth muscle and cardiomyocyte, proliferation of smooth muscle and fibroblast, production of extracellular matrix and so on. Recently, upregulation of AT2 expression is revealed under certain pathological conditions, such as vascular injury, myocardial infarction, and heart failure. Biological significance of AT2 are still under investigation, however, countering actions against AT1 are often suggested.
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PMID:[Distribution and function of angiotensin receptor subtypes in cardiovascular system]. 1036 30

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.
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PMID:Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. 1036 49

Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia. The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hearts were perfused by the Langendorff method and were exposed to ischemia, hypoxia, H(2)O(2), or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms alpha, beta(2), gamma, and zeta, and H(2)O(2) translocated PKC isoforms alpha, beta(2), and zeta. Angiotensin II produced translocation of alpha, beta(2), epsilon, gamma, and zeta isoforms. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (alpha, beta(2), and zeta) and angiotensin II-induced (alpha, beta(2), gamma, and zeta) translocation of PKC isoforms. Inhibition of tyrosine kinase with genistein blocked translocation of PKC isoforms by hypoxia (beta(2) and zeta) and by angiotensin II (beta(2)). By contrast, neither D609 nor genistein blocked H(2)O(2)-induced translocation of any PKC isoform. We conclude that hypoxia-induced activation of PKC isoforms is mediated through pathways involving phospholipase C and tyrosine kinase, but oxidative stress may activate PKC isoforms independently of Galphaq-phospholipase C coupling and tyrosine kinase signaling. Because oxidative stress may directly activate PKC, and PKC activation appears to be involved in human heart failure, selective inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.
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PMID:Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. 1043 69

Angiotensin II plays a significant role in cell growth and proliferation in model systems and in humans. In addition, angiotensin II appears to facilitate sympathetic activation and the release of endothelin-1, and also to promote apoptosis. The use of angiotensin-converting enzyme (ACE) inhibitors has provided beneficial effects on left ventricular hypertrophy (LVH) regression and on cardiac remodelling in the presence of heart failure. Data from experimental models as well as studies in humans suggest that the increase of bradykinin mediated by ACE inhibitors provides most of the beneficial effects of ACE inhibitors. The new class of angiotensin receptor blocker appears to provide cardioprotective effects that are similar to those of the ACE inhibitors. Most of the beneficial effects provided by these agents appear to be related to a more complete blockade of angiotensin II type 1 (AT1) receptor. However, costimulation of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and thus to cause some bradykinin-like effects. Evidence for the role of angiotensin II in promoting LVH and cardiac failure as well as for abnormal regulations of the angiotensin signal transduction pathways in model systems and in humans are reviewed. Second, the mechanisms for the beneficial effects of angiotensin II modulation by ACE inhibitors versus angiotensin II antagonists studied in model systems are presented. Finally, results from pivotal phase II studies such as Evaluation of Losartan In The Elderly (ELITE), as well as an overview of the ongoing phase III trials involving the use of ARB in high risk patients are presented.
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PMID:Cardioprotective effect of angiotensin II receptor antagonists. 1057 47

Angiotensin II plays a central role in the regulation of systemic arterial pressure through its systemic synthesis via the renin-angiotensin-aldosterone cascade. It acts directly on vascular smooth muscle as a potent vasoconstrictor. In addition, it affects cardiac contractility and heart rate through its action on the sympathetic nervous system. Angiotensin II also alters renal sodium and water absorption through its ability to stimulate the zona glomerulosa cells of the adrenal cortex to synthesize and secrete aldosterone. Furthermore, it enhances thirst and stimulates the secretion of the antidiuretic hormone. Consequently, angiotensin II plays a critical role in both the acute and chronic regulation of blood pressure through its systemic endocrine regulation. A potent neurohormone that regulates systemic arterial pressure, angiotensin II also affects vascular structure and function via paracrine and autocrine effects of local tissue-based synthesis. This alternate pathway of angiotensin II production is catalyzed in tissues via enzymes such as cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme, and chymase. Intratissue formation of angiotensin II plays a critical role in cardiovascular remodeling. Upregulation of these alternate pathways may occur through stretch, stress, and turbulence within the blood vessel. Similar processes within the myocardium and glomeruli of the kidney may also lead to restructuring in these target organs, with consequent organ dysfunction. Additionally, angiotensin II may increase receptor density and sensitivity for other factors that modulate growth of vascular smooth muscle, such as fibroblast growth factor, transforming growth factor beta-1, platelet-derived growth factor, and insulin-like growth factors. Atherosclerosis may also be related, in part, to excessive angiotensin II effect on the vessel wall, which causes smooth muscle cell growth and migration. It also activates macrophages and increases platelet aggregation. Angiotensin II stimulates plasminogen activator inhibitor 1 and directly causes endothelial dysfunction. Other postulated effects of angiotensin II on vascular structure that could promote atherogenesis include inhibition of apoptosis, increase in oxidative stress, promotion of leukocyte adhesion and migration, and stimulation of thrombosis. Inhibition of angiotensin II synthesis with an angiotensin-converting enzyme inhibitor has been demonstrated to be beneficial in modifying human disease progression. This is clearly apparent in clinical trials involving patients with diabetic nephropathy, postmyocardial infarction, or advanced degrees of systolic heart failure. Thus, angiotensin II is an excellent target for pharmacologic blockade. Not only does it play a pivotal role in both the acute and chronic regulation of systemic arterial pressure, but it also is an important modulator of cardiovascular structure and function and may be specifically involved in disease progression. Modification of angiotensin II effect may therefore serve a dual purpose. Not only will blood pressure reduction occur with less stretch, stress, and turbulence of the vascular wall, but there will also be less stimulation, either directly or indirectly, for restructuring and remodeling of the cardiovascular tree.
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PMID:The renin-angiotensin-aldosterone system: a specific target for hypertension management. 1061 73

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