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)

The discovery of orally active nonpeptide angiotensin II (A II)-receptor antagonists has initiated a growing understanding of the physiologic and pathophysiologic roles of A II. Losartan is the first of the new class of antagonists that block all the well-known effects of A II, including vasoconstriction, aldosterone release, renin release (negative feedback), and the stimulation of thirst. A II-receptor subtypes have been described, with losartan antagonism defining the AT1 subtype and with PD123319 antagonism defining the AT2 subtype. The AT1 receptor is G-protein-coupled, involving PLC, PLA2, PLD, or adenylate cyclase and the release of intracellular calcium. The receptor-response coupling of the AT2 site remains elusive but may involve protein tyrosine phosphatase and subserve an antiproliferative role. Losartan as the prototype of an AT1-selective antagonist: i) inhibits A II binding, ii) antagonizes effects of A II in vivo and in vitro, and iii) lowers blood pressure in models of A II-dependent hypertension A II stimulates growth in vitro (DNA and protein synthesis) and in vivo (cardiac and vascular hypertrophy), and these effects are blocked by losartan. Losartan, like angiotensin-converting enzyme inhibitors, has significant renal, cardiac, and cerebral protective effects in models of renal failure, cardiac failure, and stroke, confirming the pathologic role of A II in these models. The pioneering studies in experimental animals are being confirmed by a growing number of other AT1-selective blockers and provide the basis of use of losartan for hypertension and its clinical trial in other disease states.
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PMID:The diversified pharmacology of angiotensin II-receptor blockade. 891 41

Angiotensin receptors have been described in the human heart and are suspected to play a central role in remodeling after myocardial infarction and in cardiac hypertrophy. Two subtypes, AT1 and AT2, have so far been described in humans, with AT2 being the dominant subtype in human atria. We have now determined subtype numbers and distribution by binding in ventricular myocardium from patients with end-stage heart failure. We found about 50-80% of subtype AT2 in the right and left ventricles from patients with end-stage heart failure due to coronary artery disease and cardiomyopathy, indicating that AT2 is the dominant angiotensin receptor subtype in the whole human heart. To determine the cellular localization of angiotensin receptors in human myocardium in addition to the known localization on myocytes, smooth muscle cells and endothelial cells, we investigated cardiac fibroblasts. They express an angiotensin receptor with yet incompletely understood binding characteristics which is coupled to proliferation and DNA synthesis. As AT2 is the dominant angiotensin receptor subtype in human heart, we cloned the complete mRNA sequence by a rapid amplification of cDNA ends (RACE) procedure and thereafter the promoter sequence from a human genomic library. Once the sequence of the mRNA and thus exon 1 was obtained by the RACE-PCR, a probe was constructed for the most 5' region of exon 1 and used for screening of a human genomic DNA bank. After cutting of the positive clones with EcoR1 and Not1, a 4000 bp fragment hybridized with the probe and was further sequenced. A functional AT2 promoter, with > 90% homology with the mouse promoter and 35% homology with the human AT1 promoter containing numerous cis-acting sequences for basal (TFIID) and inducible (AP-1, PEA-3, CBF) transcription factors in the first 1000 bp was identified.
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PMID:Subtype 2 and atypical angiotensin receptors in the human heart. 895 48

As a net effect of ACE-inhibitors and AT1-receptor antagonists on the renin-angiotensin system (RAS) cardioprotection due to vasodilative (reduction of blood pressure, afterload reduction), antiproliferative (reduced cell growth, reduction of "vascular" and/or "ventricular remodeling", reduced formation of extracellular matrix), as well as antiadrenergic actions and due to the stimulating effect on natriuresis, reduction of blood pressure, preload reduction can be expected. These aims of therapy have mostly been confirmed for the action of ACE-inhibitors by experimental and clinical studies but except for the treatment of arterial hypertension and few preliminary reports concerning the treatment of cardiac dysfunction, no comparable data are available for AT1-receptor antagonists. To date, an antithrombotic and profibrinolytic action could only be demonstrated for ACE-inhibitors. This effect has been discussed to be responsible for the improvement of long-term prognosis in patients with coronary artery disease. Despite the similar spectrum of action there exist important differences between ACE-inhibitors and AT1-receptor antagonists that might underline the need of an individual use of these drugs: the dual action of ACE-inhibitors on the RAS and the kinin system bears many benefits but has been also shown to be accompanied by side-effects, mainly chronic dry cough, in a relatively high percentage of patients thus leading to discontinuation of therapy in 8-14%. This respective side-effect can be prevented by the use of AT1-receptor antagonists. It has been discussed whether the incomplete action of ACE-inhibitors on AT1-receptor-mediated effects is at least in part responsible for the efficacy of this drug which is relatively high (75-80%) as compared to other substances. Due to their direct action, AT1-receptor-blockers might also be of high effectiveness for the treatment of severe heart failure. A combination of the ACE-inhibitor-mediated activation of the kinin-system with the more specific blockade of AT1-receptors by AT1-receptor antagonists might be of benefit and is currently under investigation. Finally, it has been discussed that the increased AT II concentration in case of AT1-receptor-blockade activates AT2-receptor-mediated mechanisms thus leading to an additive vasoprotective effect.
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PMID:[Pathophysiological mechanisms of the renin-angiotensin system and its pharmacologic modification by ACE inhibitors or angiotensin II (type 1) receptor blockers in cardiovascular diseases]. 923 95

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

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

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

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

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


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