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)

Health economy is often addressed in terms of acquisition cost, i.e. the cost of the pill. For various reasons, mainly the stricter demands from drug regulatory agencies (increased development costs), novel agents must be expected to be more expensive than older drugs. However, if the costs of changing therapy and the costs induced by side effects and extra clinic visits are considered, the economic aspects become less of a consideration. If compliance is enhanced and better blood pressure control is achieved with the newer agents, then the therapeutic gains must be weighed against the economic aspects. Losartan, the first agent of the new class of angiotensin II receptor antagonists of the AT1 type, has been available for clinical use for more than 2 years. Losartan has proven antihypertensive effects and its safety profile in the initial controlled trials (approximately 2900 patients) and in general practice (more than 14,000 patients in Sweden) has been very good. Its effect on long-term morbidity and mortality has not yet been established but a large mortality endpoint trial is underway in hypertensive patients with cardiac hypertrophy (the LIFE trial). In heart failure, losartan has been shown to reduce 3-month mortality (the ELITE trial). Although it is too early to assess the full therapeutic benefit of losartan in relation to the total patient costs, its efficacy and low incidence of side effects has made it a useful new therapy for the treatment of hypertension.
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PMID:Medical and cost-economy aspects of modern antihypertensive therapy--with special reference to 2 years of clinical experience with losartan. 928 10

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a novel non-peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [125I][Sar1, Ile8]angiotensin II for angiotensin AT1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [125I][Sar1, Ile8]angiotensin II to the angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration-response curve for angiotensin II with a pA2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F2alpha or endothelin-1 even at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues, YM358 was approximately 3-10 times more potent than losartan in antagonizing angiotensin AT1 receptors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of angiotensin II in a dose-dependent manner. In conscious normotensive rats, YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced pressor response in a dose-dependent manner. YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that YM358 is a potent, AT1-selective and competitive nonpeptide angiotensin receptor antagonist. Moreover, YM358 is both orally active and long-lasting. This pharmacological profile suggests that YM358 would be suitable for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.
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PMID:Pharmacological profile of YM358, a novel nonpeptide angiotensin AT1 receptor antagonist. 936 70

The objective of this article is to give more information about the pharmacology of and recent clinical data on the angiotensin II receptors antagonists. The angiotensin II receptors antagonists, of which Losartan will be the first representative on the Belgian market, constitute a new therapeutic class in the treatment of hypertension and even heart failure. They are non peptic and orally active and their long mechanism of action allows one daily administration to improve therapeutic compliance. These agents block all known effects of the angiotensin II through binding to the AT1 receptors. Thanks to this unique mechanism of action they reduce blood pressure with a lower incidence of the adverse effects commonly associated with other antihypertensives. In controlled clinical trials, overall incidence of adverse experiences was comparable to placebo. Addition of thiazide-type diuretics provides additive efficacy.
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PMID:[The advent of a new class of antihypertensive agents: angiotensin II receptor antagonists]. 941 19

1. Dahl Iwai salt-sensitive (DS) rats have been reported as becoming hypertensive with left ventricular hypertrophy (LVH) and heart failure when on a high-salt diet. Their circulating renin-angiotensin system (RAS) has been reported to be suppressed. To evaluate the role of angiotensin II (AngII) type 1 and type 2 receptors (AT1 and AT2, respectively) in LVH, we compared cardiac AT1 and AT2 receptors in 10-week-old DS rats and Dahl Iwai salt-resistant (DR) rats. 2. Seven pairs of 6-week-old male DS and DR rats were fed either a low- or high-salt diet (0.3 or 8% NaCl, respectively) for 4 weeks. Left ventricular AngII receptors were measured by radioligand binding assays using [125I]-[Sar1,Ile8]-AngII in plasma membrane fractions from these four groups. The AT1 and AT2 receptors were distinguished using their specific antagonists CV 11974 and PD 123319, respectively. 3. The high-salt diet increased blood pressure and the left ventricle:bodyweight ratio in DS rats. However, neither Bmax for AT1 and AT2 receptors nor Kd for [125I]-[Sar1,Ile8]-AngII differed between the groups. These results are different from those of other reports of pressure-overload LVH, such as spontaneously hypertensive rats or renovascular hypertension rats, in which AT1 and AT2 receptors were reported to be up-regulated.
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PMID:Angiotensin II receptors in cardiac left ventricles of Dahl rats. 959 May 78

Heart failure is associated with attenuation of parasympathetic nervous function and enhanced renin-angiotensin activity. We tested whether there was a dysfunction in the efferent cholinergic neurotransmission in the heart of rats with chronic myocardial infarction (MI) and the potential role of angiotensin II (Ang II) receptors in such changes. Rats with MI and sham-operation were anesthetized, and heart rate (HR) reduction in response to vagal nerve stimulation was measured before and after losartan administration (10 mg/kg, i.v.) in the presence or absence of physostigmine to inhibit acetylcholinesterase. Infarcted rats had an average infarct size (IS) of 38% of the left ventricle (LV), depressed LV dP/dtmax, elevated LVEDP, and cardiac hypertrophy. Nerve stimulation (1-16 Hz) reduced HR in a frequency-dependent manner. The bradycardiac responses were significantly attenuated in infarcted versus control rats (p < 0.01), indicating an impaired efferent vagal tone. In contrast, the bradycardic response to exogenous acetylcholine was similar in both groups, implying an unchanged muscarinic receptor responsiveness in hearts with MI. HR response to nerve stimulation was potentiated by losartan in infarcted rats by 21 +/- 4 versus 4 +/- 2 beats/min (p < 0.01) but was unaffected in control rats. This effect of losartan was inversely related to the extent of attenuation of vagally mediated HR reduction. IS was correlated with both the extent of attenuation in vagally mediated bradycardia and the effect of losartan. In conclusion, the efferent vagal control of HR is attenuated in rats with MI and heart failure. This attenuation may be partly due to a presynaptic inhibition of acetylcholine release through the tonic activation, by Ang II, of neuronal AT1 receptors.
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PMID:Depression of efferent parasympathetic control of heart rate in rats with myocardial infarction: effect of losartan. 964 80

The pharmacokinetics of a selective AT1-subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady-state was 34 L, and terminal plasma half-life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple-dose oral administration for 7 to 8 days. Terminal plasma half-life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.
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PMID:Pharmacokinetics of intravenous and oral losartan in patients with heart failure. 965 May 42

Blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is now recognized as an effective approach for the treatment of hypertension and congestive heart failure. In addition, ACE inhibitors are very effective for the prevention of chronic renal failure. Today, it is possible to antagonize the effects of angiotensin II more specifically using AT1 receptor antagonists. Several non-peptide, orally active angiotensin II receptor antagonists have recently been developed clinically. These new molecules are as effective as ACE inhibitors, calcium antagonists and beta-blockers at reducing blood pressure in hypertensive patients. Furthermore, they appear to have similar systemic and renal hemodynamic properties in patients with congestive heart failure and renal diseases. Now, several large clinical trials such as the LIFE, the RENAAL and the ELITE II studies are under way to investigate the long-term benefits of one of these compounds in hypertension, heart failure and type II diabetic nephropathy.
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PMID:[Angiotensin II AT1 receptor antagonists: clinical development and future perspectives]. 977 27

The natriuretic peptide (NP) system is one of the most important systems regulating blood pressure and body-fluid homeostasis. The biological activities of the system are determined by the NPs and the receptors, which are comprised of three subtypes: NP-AR and NP-BR related to biological activities and NP-CR related to the clearance of NP. We focused our studies on the receptor subtypes. In hypertensive rats (SHR-SP/Izm, DOCA/salt), NP-AR was upregulated and NP-CR was downregulated. The ACE inhibitor derapril, but not the Ca2+ blocker manidipine, normalized the upregulated NP-AR, but the effect was completely abolished by the bradykinin beta 2-receptor antagonist, suggesting that bradykinin regulates the vascular NP-AR. The AT1 antagonist TCV-116, but not manidipine, reversed the downregulated NP-CR. Ang II decreased NP-CR in cultured aortic smooth muscle cells. These results suggest that upregulation of NP-AR and downregulation of NP-CR with the increased plasma NPs counteract hypertension by enhancing the action of NP. A beta-blocker (carvedilol) potentiated the hypotensive action of NPs by increasing plasma NPs and enhancing the vascular response to NPs via downregulation of the vascular and lung NP-CR. The newly found mode of actions could be related to its anti-heart failure effect. In genetically hyperglycemic Wistar fatty rats, vascular NP-BR and NP-AR were upregulated. Since plasma ANP and vascular CNP were significantly increased, the local CNP/NP-BR system as well as the systemic ANP/NP-AR system may play an important role in counteracting vascular remodeling in diabetes mellitus. All these observations provide in vivo evidence for the pathophysiological significance of the receptor subtype of the NPs.
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PMID:[Pathophysiological significance of the natriuretic peptide system: receptor subtype as another key factor]. 979 68

The expression pattern of angiotensin (Ang) II type 2 receptor (AT2-R) in the remodeling process of human left ventricles (LVs) remains poorly defined. We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II. In autopsy samples from the nonfailing heart group, the ratio of AT1-R and AT2-R was 59% and 41%, respectively. The expression of AT2-R was markedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold) levels compared with AMI or OMI. AT1-R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas in OMI and DCM hearts, AT1-R expression was significantly downregulated. AT1-R-mediated response in inositol phosphate production was significantly attenuated in LV homogenate from failing hearts compared with nonfailing hearts. AT2-R sites were highly localized in the interstitial region in either nonfailing or failing heart, whereas AT1-R was evenly distributed over myocardium at lower densities. Mitogen-activated protein kinase (MAPK) activation by Ang II was significantly decreased in fibroblast compartment from the failing hearts, and pretreatment with AT2-R antagonist caused an additional significant increase in Ang II-induced MAPK activity (36%). Cardiac hypertrophy suggested by atrial and brain natriuretic peptide levels was comparably increased in OMI and DCM, whereas accumulation of matrix proteins such as collagen type 1 and fibronectin was much more prominent in DCM than in OMI. These findings demonstrate that (1) AT2-R expression is upregulated in failing hearts, and fibroblasts present in the interstitial regions are the major cell type responsible for its expression, (2) AT2-R present in the fibroblasts exerts an inhibitory effect on Ang II-induced mitogen signals, and (3) AT1-R in atrial and LV tissues was downregulated during chronic heart failure, and AT1-R-mediated functional biochemical responsiveness was decreased in the failing hearts. Thus, the expression level of AT2-R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expression and function of AT1-R and AT2-R are differentially regulated in failing human hearts.
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PMID:Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. 981 51

The cardiac renin angiotensin system (RAS) is the target for number of therapeutic interventions which proved successful in heart failure. Angiotensin converting enzyme (ACE) inhibitors belong to the most efficient strategies available and angiotensin receptor (ATR) antagonists may be comparably effective. The direct myocardial effects of both classes of substances depend on the cardiac ANG II receptors. Both subtypes, AT1 and AT2, are expressed in the human heart. AT1 is localized on myocytes, non-myocytes, vascular smooth muscle and endothelial cells, nerve endings, and conduction tissues. AT2 has so far been found in fibrous tissue and endothelial cells. AT1 mediates myocyte hypertrophy, fibroblast proliferation, collagen synthesis, smooth muscle cell growth, endothelial adhesion molecule expression, and catecholamine synthesis. AT1 is downregulated in cardiac failure as well as in the hypertrophied transplanted heart, indicating that a 50% loss of AT1 does not impede cardiac hypertrophy. In heart failure therapy, AT1 antagonists differ from ACE inhibitors by their inhibition of the degradation of bradykinin. Bradykinin has a number intrinsic effect including vasodilation, proinflammatory actions, and modulation of fibrous tissue synthesis. In addition to bradykinin, the functional role of AT2 seems crucial for the therapeutic differences of AT1 antagonists versus ACE inhibitors.
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PMID:Myocardial angiotensin receptors in human hearts. 983 60


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