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

1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT1 receptor antagonist; losartan, in which a major active metabolite is a non-competitive angiotensin AT1 receptor antagonist; and enalapril, an angiotensin-converting enzyme inhibitor, using the salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP received orally ME3221 (3 and 10 mg/kg per day), losartan (10 mg/kg per day) and enalapril (10 mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age. 3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt-loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to > 90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N-acetyl-beta-D-glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion). 4. Competitive (ME3221) and non-competitive (losartan) angiotensin AT1 receptor antagonists showed comparable efficacy against the complications and mortality of the salt-loaded SHRSP; both were more potent than enalapril in the protective effect.
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PMID:Protective effects of ME3221 on hypertensive complications and lifespan in salt-loaded stroke-prone spontaneously hypertensive rats. 893 13

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

1. The type-1 angiotensin II (AngII) receptors, designated AT1, mediate most of the biological actions of the peptide hormone AngII. They are the most recent drug target for the treatment of hypertension and cardiac failure and basic research is now focusing on the mechanisms that regulate their expression. 2. In humans there is a single AT1 gene. It encodes a 47 kb pre-mRNA containing five exons, with the previously described AT1 open reading frame (ORF) on exon 5. Alternative splicing results in the production of mature mRNA that are translated at different efficiencies and encode two receptor isoforms. The inclusion of exon 2 markedly inhibits translation of the down-stream ORF, both in vitro and in vivo. Nonetheless, this exon is present in up to one-half of AT1 mRNA in all tissues studied. 3. Transcripts containing exon 3 spliced to exon 5 encode a receptor with an amino-terminal extension of 32 amino acids and represent up to one-third of total AT1 mRNA in each tissue examined. In vitro, these latter transcripts are translated to produce a longer receptor and, in transfected cells, they encode a functional AT1 receptor with ligand-binding and signalling properties similar to those of the short isoform. 4. Exon 4 is of minor significance as it is rarely spliced into AT1 mRNA. 5. These data indicate that, in addition to characterizing factors that modulate AT1 promoter activity and RNA stability, it is important to analyse the splicing patterns of this gene when studying the regulation of its expression.
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PMID:Human type-1 angiotensin II (AT1) receptor gene structure and function. 899 42

1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril. 2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent. 3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age. 4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-beta-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5. These results indicate that ME3221 has a stable anti-hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.
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PMID:Effect of chronic treatment with ME3221 on blood pressure and mortality in aged stroke-prone spontaneously hypertensive rats. 907 29

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.
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PMID:Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. 910 37

The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to produce a positive inotropic effect in some species, and differences in atrial and ventricular myocardium have been described. So far, the molecular events which govern angiotensin II-mediated changes in cardiac contractility are not completely understood. In order to study the dependency of the angiotensin II-induced positive inotropic effect on receptor density, we examined the effect of angiotensin II on cardiac function in atria, papillary muscles and isolated ventricular cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.
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PMID:Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats. 922 12

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

Current medical treatment of chronic heart failure makes use of a combination of diuretics, cardiac glycosides and ACE inhibitors. The latter have improved the chances of survival of patients with chronic cardiac insufficiency. The combination of hydralazine hydrochloride and isosorbide dinitrate also improves survival, but direct comparison of both regimens provided evidence for a less favourable effect than that of the ACE inhibitors. Inhibition of neuroendocrine activation has been demonstrated only for ACE inhibitors and cardiac glycosides. The use of beta blockers represents a new therapeutic strategy that over the long term improves cardiomyocyte function, cardiac output at rest, and physical performance. For this indication, however, beta blockers should be used with extreme caution and at very low initial doses. New approaches in the area of clinical research are, for example, calcium sensitizers, modulators of intracellular calcium and/or sodium homeostasis, imidazolin receptor antagonists with an action on the central nervous system and AT1 receptor antagonists.
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PMID:[Therapy of heart failure. II. Therapy of chronic heart failure]. 928 Jul 47

Nonpeptide angiotensin II type 1-receptor antagonists, AT1 receptor antagonists are newly developed and useful drugs for hypertension and congestive heart failure. In Japan, the efficacy and safety of losartan and candesartan cilexetil in patients with essential hypertension have been evaluated by the double-blind, parallel group-comparison study using enalapril as control drug. Both trials revealed that these drugs showed a hypotensive effect comparable to that of enalapril with a high safety since the adverse drug reaction of cough was recognized in very few patients. Furthermore, a recent randomised trial of losartan versus captopril in patients over 65 with heart failure, evaluation of losartan in the elderly study (ELITE), showed that losartan was associated with a lower mortality than that found with captopril. Further studies will clarify differences in protection of cardiovascular system with a long-term treatment between AT1, receptor antagonists and angiotensin-converting enzyme inhibitors.
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PMID:[Angiotensin receptor antagonist for therapy of patients with hypertension]. 928 26


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