Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Ventricular remodeling following nonfatal myocardial infarction includes an excentric hypertrophy of the surviving myocardium, associated with hemodynamic overload. Disseminated cardiomyocyte apoptosis and phenotype changes of the surviving myocardium, such as a labile calcium homeostasis of the hypertrophied cardiomyocytes, impaired beta-adrenergic signal transduction, interstitial fibrosis, and reduced coronary reserve are typical features of the overloaded, distended ventricular wall. They are considered as relevant for the myocardial dysfunction progressing to overt cardiac failure and for the enhanced mortality risk. Hemodynamic load and trophic angiotensin effects are assumed to cause this excentric hypertrophy, since systemic and local angiotensin formation in the overloaded myocardium is activated. In isolated rat cardiomyocytes, cultured on distensible membranes, overload is mimicked by distension, and causes enhanced formation and release of angiotensin II, which results in AT1 receptor mediated trophic reactions of distended neonatal cardiomyocytes and in AT1-mediated apoptosis in distended adult cardiomyocytes. In experimental models of postinfarct remodeling, therapy with ACE inhibition or with AT1 blockade similarly normalizes myocardial hypertrophy, interstitial fibrosis, and impaired coronary reserve. In patients with terminal heart failure, a reduction of apoptotic signs and a normalization of antiapoptotic gene expression is obtained by myocardial unloading under ventricular assist devices or by treatment with ACE inhibitors, and the latter therapy has been shown to improve survival. In contrast to general assumptions and to predictions from data in vitro, the improvements obtained by AT1 blocker therapy in vivo are mediated by bradykinin, as are those obtained under ACE inhibitors. Under AT1 blockade, bradykinin is probably activated due to stimulation of AT2 and other AT receptors.
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PMID:Role of ACE inhibition or AT1 blockade in the remodeling following myocardial infarction. 983 70

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

At the present time we cannot assume that the proven benefits of ACEI on renal disease will be reproduced by using AT1-ra. With potentially differing modes of activity of these drugs, they cannot be seen as interchangeable and ACEI should remain the drug of choice in patients with progressive renal disease unless they are not tolerated. It is possible that AT1-ra may offer additional advantages in some patients or that synergy exists between the two agents, but this view will remain entirely speculative unless proper trials are conducted. Despite the results of the ELITE study [22], the uncertainty regarding the use AT1-ra in cardiovascular disease mirrors that of renal disease. This issue is obviously of relevance to the nephrologist in view of the spectrum of cardiac disease that accompanies chronic renal failure, such as left ventricular hypertrophy and cardiac failure, which provide multiple indications for manipulation of RAS. Despite their renoprotective effect, previous studies on ACEI [3,4] have not shown an overall reduction in mortality and this issue needs to be addressed in addition to renoprotection in studies comparing AT1-ra and ACEI.
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PMID:Angiotensin converting enzyme inhibitors and angiotensin receptor (AT1) antagonists: either or both for primary renal disease? 1005 68

The objective of the present study was to determine the effects of early long-term monotherapy with the angiotensin II AT1-receptor antagonist valsartan on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Studies were performed in 30 dogs with moderate HF produced by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction was 30-40%. Two weeks after the last embolization, dogs were randomized to 3 mo of oral therapy with low-dose valsartan (400 mg twice daily, n = 10), to high-dose valsartan (800 mg twice daily, n = 10), or to no treatment at all (control, n = 10). Treatment with valsartan significantly reduced mean aortic pressure and LV end-diastolic pressure compared with control. In untreated dogs, LV ejection fraction decreased (37 +/- 1 vs. 29 +/- 1%, P = 0.001) and end-systolic volume (ESV) and end-diastolic volume (EDV) increased (81 +/- 5 vs. 92 +/- 5 ml, P < 0.001; 51 +/- 3 vs. 65 +/- 3 ml, P = 0.001, respectively) after 3 mo of follow-up compared with those levels before follow-up. In dogs treated for 3 mo with low-dose valsartan, ejection fraction was preserved (37 +/- 1 vs. 38 +/- 2%, pretreatment vs. posttreatment) as was ESV but not EDV. In dogs treated for 3 mo with high-dose valsartan, ejection fraction decreased (35 +/- 1 vs. 31 +/- 2%, P = 0.02) and ESV and EDV increased in a manner comparable to those levels in controls. Valsartan had no significant effects on cardiomyocyte hypertrophy or on the extent of interstitial fibrosis. We conclude that, for dogs with moderate HF, early long-term therapy with the AT1-receptor blocker valsartan decreases preload and afterload but has only limited benefits in attenuating the progression of LV dysfunction and chamber remodeling.
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PMID:Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure. 1019 66

Blockade of the renin-angiotensin system is recognized as an effective approach for the treatment of hypertension and congestive heart failure. It is possible to antagonize the effects of angiotensin II (AngII) by blocking its receptors, using nonpeptide receptor antagonists. Six angiotensin receptor blockers (ARB) have been approved for the treatment of hypertension: losartan, valsartan, irbesartan, candesartan, telmisartan, and eprosartan. These new drugs are highly selective for the AT1 receptor subtype and induce dose-dependent inhibition of the BP response to exogenous AngII. Numerous double-blind, placebo-controlled studies have demonstrated that ARB are efficacious for treating mild, moderate, and severe hypertension. When compared with other classes of antihypertensive agents, ARB are as effective as angiotensin-converting enzyme inhibitors, calcium antagonists, thiazide diuretics, and beta-blockers. One advantage of ARB as a class is their excellent tolerability and side effect profile. Several large clinical trials of ARB are now under way to demonstrate their benefits in hypertension, heart failure, and type II diabetic nephropathy.
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PMID:Comparative antihypertensive effects of angiotensin II receptor antagonists. 1020 83

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, i.v.) or enalaprilat (1 mg/kg, i.v.) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 +/- 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 +/- 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure.
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PMID:Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure. Differential acute effects according to the renin-angiotensin system activation. 1032 61

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non-angiotensin-converting enzyme (non-ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end-organ damage in these conditions.
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PMID:Practical considerations of the pharmacology of angiotensin receptor blockers. 1035 58

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

Losartan is a potent non-peptide, selective angiotensin II (AngII) type 1 (AT1) receptor antagonist. Losartan has been worldwide marketed as the first orally active AT1 receptor antagonist with once-daily dosing for treatment of hypertension. In a study of patients with heart failure, the mortality appeared to be lower with losartan than with the ACE inhibitor captopril. In healthy subjects, losartan produced a dose-dependent reduction in serum uric acid. The mechanism of action is considered to be the inhibition of reabsorption of uric acid in the proximal tubules of the kidney. Furthermore, it was recently reported that losartan has moderate affinity for the thromboxane (TX) A2 receptor in a competitive-inhibition manner in the platelets and vascular smooth muscle. The efficacy of losartan with regard to not only AT1 receptor blockade, but also the reduction of serum uric acid and the blockade of TXA2 receptors, may be advantageous to patients with hypertension having these cardiovascular risk factors.
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PMID:[Pharmacological properties and its significance in clinical practice]. 1036 45


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