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

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
 ...
PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

The nonpeptide angiotensin II (AII) subtype-1 (AT1) receptor antagonist candesartan cilexetil is completely converted to its active form, candesartan, during gastrointestinal absorption. In in vitro studies, candesartan has been found to act as an insurmountable antagonist at the AT1 receptor that dose-dependently reduces the maximal contractions induced by AII and, at high concentrations, virtually eliminates the AT1-receptor-mediated effects of AII. Receptor binding studies suggest that insurmountable antagonism may be due to tight binding to the AT1 receptor and slow dissociation from it. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension. Candesartan cilexetil exerts a long-lasting antihypertensive action in spontaneously hypertensive rats in the low dose range of 0.1-10 mg/kg. The long-lasting antihypertensive effect of candesartan cilexetil is confirmed by the trough/peak ratio in hypertensive patients. It has been demonstrated that administration of AII receptor antagonists is followed by a rise in AII levels, and the increased AII levels result in competition with the antagonist for binding to the receptor. Insurmountable antagonists would seem to be more advantageous since they would block more efficiently in the presence of increasing AII levels than surmountable antagonists. A growing number of studies indicate that candesartan cilexetil provides end-organ protection in addition to lowering blood pressure. The utility of AT1 antagonists may extend beyond treatment of hypertension, chronic heart failure and renal diseases, as suggested by the potential usefulness of ACE inhibitors in the treatment or prevention of many other cardiovascular diseases.
 ...
PMID:[Candesartan cilexetil: pharmacological properties and protective effects against organ damage of a novel nonpeptide angiotensin II-receptor antagonist]. 1087

An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11beta-hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV reduces total mortality by 30%.
 ...
PMID:Induction of cardiac fibrosis by aldosterone. 1088 42

The pathogenesis of hypertension in haemodialyzed uraemic patients is multifactorial. The following are involved: sodium and water retention as a result of the impaired excretory capacity of the kidneys, excessively increased activity of the RAAS and sympathetic nerve, increased levels of the vascular constrictor endothelin-1, cumulation of endogenous inhibitors of NO synthesis and reduced formation of vasodepressor factors. As to other factors in the development of hypertension raised intracellular calcium associated with hyperparathyroidism may participate, the stiffness of calcified arteries, erythropoietin treatment and preexisting essential hypertension. Treatment comprises salt restriction below 5 g/day, systematic control of the volume of extracellular fluid by ultrafiltration during every haemodialysis to the level of so-called dry weight and pharmacological treatment in patients where volume control dos not suffice. All drug groups are used. In their selection contraindications are taken into consideration as well as co-morbidity, the dialyzability of antihypertensive drugs and compelling evidence. In patients with a preserved residual diuresis furosemide is administered--125-750 mg/day. Beta-blockers are indicated in patients with IHD, in particular after IM. Calcium blockers are recommended in ventricular hypertrophy and diastolic dysfunction, when beta-blockers are contraindicated and in elderly patients. ACEI indicated in congestive heart failure and left ventricular hypertrophy with systolic dysfunction. Inhibitors of AT1 receptors are an alternative in case of undesirable effects od ACEI. Alpha-blockers and central alpha agonists are used mainly in combinations. In case of failure the haemodialyzation method can be altered or changing the patients to CAPD may be considered. The relationship between BP and the survival of haemodialyzed patients is bimodal. An adverse effect is exerted by a high as well as low BP and in particular by interdialyzation hypotension. The target BP for the haemodialyzed population has not been defined so far. There is, however, evidence that a high BP is independently associated with the de novo development of IHD and MAP above 106 mm Hg with de novo development of cardiac failure. MAP below 98 mm Hg minimalizes the development and progression of left ventricular hypertrophy and MAP below 106 mm Hg the development of heart failure. Long-term survival for 15 and more years is statistically significantly associated with MAP lower than 99 mm Hg.
 ...
PMID:[Hypertension in hemodialyzed uremic patients]. 1095 54

Angiotensin II AT1-receptor blockers (AT1-s) prolong survival in experimental postischemic (coronary artery ligation) heart failure (CHF) in rats. The goal of this study was to investigate whether potential beneficial effects of short- and/or long-term treatment with AT1-s on coronary dynamics, function, and structure develop along with the drug-induced survival prolongation in this model. Coronary blood flow was measured (fluorescent microspheres) in conscious sham, untreated, and irbesartan-treated (50 mg/kg daily for 6 weeks or 6 months, starting 8 days after surgery) CHF rats at baseline and at maximal vasodilatation induced by dipyridamole, and coronary dilatation reserve (CDR) was calculated as the ratio of maximal to baseline coronary flow. Coronary endothelial function was assessed in vitro by measuring the coronary relaxant responses to acetylcholine in the three groups of animals. Finally, cardiac hypertrophy and pericoronary fibrosis also were investigated. In CHF rats, left (LV) and right (RV) ventricular CDR were markedly depressed at both 7 weeks and 6 months after ligation, whereas coronary endothelial function was significantly impaired only after 6 months. Short-term AT1-receptor blockade with irbesartan did not prevent CDR deterioration at 7 weeks, nor did it significantly oppose cardiac hypertrophy and pericoronary fibrosis development. Prolonged AT1-receptor blockade prevented both RV CDR deterioration and coronary endothelial function impairment. It also limited significantly the increase in LV end diastolic pressure and the development of cardiac hypertrophy and pericoronary fibrosis. In conclusion, in postischemic CHF in rats, alterations of CDR precede those of coronary endothelial function. Long-, but not short-term AT1-receptor blockade prevents endothelial function degradation, opposes RV CDR impairment, prevents pericoronary fibrosis development, and improves systemic hemodynamics. These effects of AT1-s on coronary dynamics, function, and structure (i.e., on myocardial perfusion) may contribute to the drug-induced survival prolongation in this model.
 ...
PMID:Effects of angiotensin II AT1-receptor blockade on coronary dynamics, function, and structure in postischemic heart failure in rats. 1097 90

The aim of the study was to investigate the effect of angiotensin-converting enzyme inhibitor enalapril and non-peptide blocker of AT1 receptors losartan on endothelial function of the shoulder artery in patients with congestive cardiac insufficiency. The examination covered 96 patients (mean age 46.71 +/- 4.13) with stable effort angina (functional class II-III) and circulatory insufficiency (NYHA functional class II-III) having end-diastolic left-ventricular volume > 160 ml, left ventricular ejection fraction < 35%, sinus rhythm, cardiothoracal index > 0.55 units. Patients with fibrillar tachyarrhythmia, high grade blocks, pacemaker migration, artificial pacemaker, myocardial infarction were not included in the trial. The patients were randomized into 3 groups 32 patients each. In addition to basic therapy patients of group 1 received long-acting nitrates, digoxin, aspirin and furosemide; group 2--enalapril in daily dose 10 mg; group 3--losartan in daily dose 25 mg. A course of treatment lasted 12 weeks. Endothelial function was assessed by high resolution echography, dopplerography performed before and after temporary occlusion of the shoulder artery and sublingual nitroglycerin. In patients with cardiac insufficiency, accelerated blood flow in the shoulder artery after its temporary occlusion promoted realization of the vasoconstrictory reaction. This was verified as endothelial dysfunction. In the course of the treatment all the patients achieved insignificant increase of the shoulder artery initial diameter. After sublingual intake of nitroglycerin vasodilation was also insignificant. 12-week enalapril and losartan prevented vasoconstriction in the shoulder artery in response to quicker circulation following arterial occlusion. However, higher maximal flow speed did not correspond to the increment in the artery diameter after the occlusion in any group. The flow-induced vasodilation was more pronounced in the enalapril group. Losartan group had a trend to an increase in the inner diameter of the shoulder artery. It is shown that enalapril and losartan in congestive cardiac insufficiency improves endothelium-dependent vasodilation caused by nitroglycerin. Enalapril demonstrated stronger ability than losartan to reverse endothelial dysfunction in patients with cardiac insufficiency resultant from ischemic heart disease.
 ...
PMID:[Prospects of endothelial dysfunction reversion in patients with congestive heart failure]. 1097 40

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.
 ...
PMID:Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure. 1102 48

The renin-angiotensin system plays a pivotal role in the regulation of fluid, electrolyte metabolism and blood pressure. Molecular cloning and pharmacological studies have defined two major classes of Angiotensin II (Ang II) receptors, designated AT1 and AT2. Recently, it has been well recognized that Ang II, beside its classical physiological actions, is a profibrogenic peptide and displays characteristics of a growth factor. The emerging picture suggests that angiotensin receptor subtypes exert opposing features in many aspects of their biological function, most importantly in cellular growth and proliferation. Accordingly, the proliferative and/or growth-promoting effects of Ang II are thought to be mediated by AT1 receptor, whereas the AT2 receptor subtype may have growth-inhibitory properties. The novel finding that Ang II is able to induce apoptosis by AT2 receptors in diverse cell types is of great scientific interest, as recent studies revealed a role for apoptosis as a deliberate form of cell death in the pathogenesis of various cardiovascular diseases such as heart failure and vascular remodeling. Furthermore apoptotic cell death might occur during the development of progressive glomerulosclerosis. It is tempting to speculate that autocrine-paracrine vasoactive substances such as Ang II might regulate these apoptotic processes during pathogenic conditions.
 ...
PMID:Apoptosis induction and inhibition of cellular proliferation by angiotensin II: possible implication and perspectives. 1103 44

Epidemiological evidence suggests that reducing blood pressure alone in hypertensive patients delays the onset of cardiovascular events without necessarily preventing the progression of chronic target-organ disease, such as end-stage renal failure and heart failure. Successful clinical management of hypertensive patients will therefore not be possible unless therapies are aimed both at the effective control of blood pressure and at the preservation of target-organ function. The new angiotensin II type I (AT1) receptor blocker candesartan cilexetil has been shown to be effective in reducing target-organ damage in animal models of hypertension, even at doses that do not produce significant reductions in blood pressure. Protective effects of candesartan cilexetil towards the heart and kidney have also been demonstrated in the clinical studies that have been conducted to date. Thus, candesartan cilexetil has been shown to induce regression of left ventricular hypertrophy within 8-12 weeks of treatment and to improve renal haemodynamics, both acutely and after 6 weeks of treatment in hypertensive patients. Furthermore, in hypertensive patients with co-existent non-insulin-dependent diabetes mellitus and microalbuminuria, 12 weeks of treatment with candesartan cilexetil, 8-16 mg, significantly reduced urinary albumin excretion. Clinical evidence is therefore accumulating that the antihypertensive efficacy and tolerability profile already established for candesartan cilexetil is combined with the renal and cardioprotective effects necessary for optimal management of hypertension.
 ...
PMID:Preserving target-organ function with candesartan cilexetil in patients with hypertension. 1105 35

Heart failure remains a major and increasing cause of mortality and morbidity, even when the best available treatments are used. One of its key causes is neuroendocrine activation via the sympathetic nervous system and the renin-angiotensin system (RAS). Neuroendocrine blockers of the sympathetic nervous system (beta-blockers) and of the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II type 1 [AT1] receptor blockers) therefore have an important potential therapeutic role in heart failure. The promising results from clinical trials with beta-blockers suggest that these drugs will become an established part of the future management of patients with mild to moderate symptomatic heart failure. Blockade of the RAS with ACE inhibitors has also been shown to be effective in reducing the risk of morbidity and mortality in patients with heart failure. Blockade of the AT1-receptor, with agents such as candesartan, produces more specific and, theoretically, more complete blockade of the major negative cardiovascular effects of angiotensin II than is possible using ACE inhibitors, whilst maintaining placebo-like tolerability. Furthermore, AT1-receptor blockade leads to increased stimulation of the angiotensin II type 2 (AT2) receptor, which, according to experimental data, may have favourable cardiovascular effects. Following encouraging results from two pilot studies, a major new international study programme - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been initiated to define the clinical benefits of candesartan cilexetil in a wide variety of patients with symptomatic heart failure. CHARM is the first study to accept all relevant heart failure patients who may benefit from RAS blockade, irrespective of their left ventricular function or tolerance of ACE inhibitors. The 6500 patients to be recruited will be divided among three integrated outcome studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who are tolerant or intolerant of ACE inhibitors. The third study arm will examine the benefits of candesartan cilexetil in a previously seldom studied group: those with symptomatic heart failure, but with preserved left-ventricular systolic function. Recruitment of patients into the study has started.
 ...
PMID:Exploring new treatment strategies in heart failure. 1105 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>