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)

Since renin catalyses the first and rate-limiting step of the renin-angiotensin system (RAS) cascade, interruption of the generation of angiotensin II (Ang II) by renin inhibitors at this highly specific initial step of the cascade has long been a therapeutic goal. The early development of renin inhibitors was hampered by problems with bioavailability and high costs of synthesis. However, more recently a potent non-peptidic inhibitor of renin, aliskiren, with acceptable oral bioavailability, has been synthesised. Aliskiren effectively reduces Ang II levels in normal volunteers and has been shown to lower blood pressure (BP) in patients with mild-to-moderate hypertension. Renin inhibitors would be expected to have similar, but not identical effects to those of the established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of Ang II production may be more effective with renin inhibition than with angiotensin-converting enzyme (ACE) inhibition. Furthermore, because renin has high specificity for only one substrate, angiotensinogen, side-effects would be expected to be less frequent. It is currently unclear whether blockade of Ang II type 1 (AT1) receptors, leaving other Ang II receptors (AT2, AT3 and AT4) unblocked, is preferable to the reduction in plasma and tissue Ang II levels achieved with either ACE or renin inhibition. Pharmacological suppression of the RAS, through ACE inhibition, or blockade of AT1, beta-adrenoceptor or mineralocorticoid receptors, has been proven to reduce morbidity and mortality in patients with hypertension, diabetes mellitus, atherosclerosis, heart failure and nephropathy. While, to date, aliskiren has only been shown to reduce BP, it appears likely that orally-active renin inhibitors could prove useful in the management of a wide range of cardiovascular pathologies.
 ...
PMID:Potential of renin inhibition in cardiovascular disease. 1269 47

The local renin-angiotensin system in cardiac tissue has been demonstrated to be involved in the pathophysiology of cardiac hypertrophy and heart failure. Angiotensin II type 1(AT1) receptor stimulation leads to vasoconstriction, cell growth, oxidation, aldosterone release, and fibrosis. Recent evidence suggests that angiotensin II type 2(AT2) receptor exerts cardioprotective effects by counteracting against AT1 receptor. However, the role of AT2 receptor signaling in cardiac hypertrophy and fibrosis still remain controversial. This review focused on the accumulating evidence for the cardiac renin-angiotensin system in heart failure.
 ...
PMID:[Renin-angiotensin system and heart failure]. 1275 98

The renin-angiotensin system is activated during myocardial ischemia, and angiotensin II is locally formed in ischemic hearts. At least four angiotensin II receptor subtypes have been identified, the AT1- and the AT2-receptor being the most prominent in the cardiovascular system. AT1-receptor blockade--like inhibition of the angiotensin-converting-enzyme (ACE)--limits infarct size, improves functional recovery following myocardial ischemia and attenuates ventricular remodeling, post-myocardial infarction and the resulting development of heart failure. The potential mechanisms responsible for the cardioprotection by AT1-receptor blockade remain to be elucidated in detail, but appear to involve AT2-receptor activation and--like ACE-inhibitors--bradykinin and prostaglandins. Combined treatment with ACE-inhibitors and AT1-receptor blockers has the potential to further reduce infarct size and improve ventricular remodeling over each monotherapy alone.
 ...
PMID:AT1-receptor blockade in experimental myocardial ischemia/reperfusion. 1294 May 36

Functional angiotensin II receptors have been documented in cardiac fibroblasts as well as an intracardiac aldosterone system that responds to short- and long-term physiological stimuli. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha1 (I) collagen, pro-alpha1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. In vivo, chronic infusion of angiotensin II increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats and in rat myocardium following myocardial infarction. 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. The cardiac fibrosis in this aldosterone model is prevented by spironolactone. During the continuous infusion of aldosterone in the rat, the appearance of fibrosis was delayed and started 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 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, reduced total mortality by 30%.
 ...
PMID:Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. 1457 Dec 85

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.
 ...
PMID:ACE-inhibition and angiotensin II receptor blockers in chronic heart failure: pathophysiological consideration of the unresolved battle. 1466 46

The renin-angiotensin system (RAS) plays an important role in regulating arterial pressure, blood volume, thirst, cardiac function, and cellular growth. Both a circulating and multiple tissue-localized systems have been identified, and are generally portrayed as a series of reactions that occur sequentially with a single outcome: angiotensinogen is cleaved by renin to form angiotensin I, which in turn is processed by angiotensin-converting enzyme (ACE) to angiotensin II, which then activates either the AT1 or the AT2 plasma membrane receptor. Evidence has emerged, however, showing that some RAS components play important roles outside of this canonical scheme. This article provides an overview of some recently identified extra-system functions. In addition to forming angiotensin II, ACE is a multifunctional enzyme equally important in the metabolism of vasodilator and antifibrotic peptides. As the membrane-bound form, ACE functions as a "receptor" that initiates intracellular signaling leading to gene expression. Both angiotensin I and II may lead to actions that are independent of, or even oppose, those of the RAS via their metabolism by the novel ACE-homologue ACE2. The two angiotensin II receptor types have ligand-independent roles that influence cellular signaling and growth, some of which may result from the ability to form hetero-dimers with other 7-transmembrane receptors. Finally, intracellular angiotensin II has been demonstrated to have actions on cell-communication, gene expression, and cellular growth, through both receptor-dependent and independent means. A greater understanding of these extra-system functions of the RAS components may aid in the development of novel treatments for hypertension, myocardial ischemia, and heart failure.
 ...
PMID:Working outside the system: an update on the unconventional behavior of the renin-angiotensin system components. 1583 68

Blockade of the renin-angiotensin system (RAS) is now recognised as an effective approach for the treatment of hypertension and congestive heart failure (CHF). Today, it is possible to antagonise the effects of angiotensin II more specifically by blocking its receptors using non-peptide receptor antagonists. These compounds, which at first were used to identify the various subtypes of angiotensin II receptors, are now available clinically. Some of them have recently been launched on the market and several others are preregistered for the treatment of hypertension. These new molecules are as effective as angiotensin converting enzyme (ACE) inhibitors at lowering blood pressure in hypertensive patients, and appear to have similar systemic and renal haemodynamic properties in patients with CHF and renal diseases. Large-scale clinical trials such as the LIFE, the ELITE and the RENAAL studies are now underway to investigate the long-term benefits of one of these agents in hypertension, heart failure and Type II diabetic nephropathy. The major clinical advantage of AT1 receptor antagonists is that, in contrast to ACE inhibitors, they do not induce cough. With the more widespread use of AT1 receptor antagonists, two unresolved questions remains unanswered: what is the role of AT2 receptors? Are the unblocked effects of angiotensin II on AT2 receptor sites of any clinical relevance to the safety profile or efficacy of AT1 receptor antagonists? Another interesting question is whether the combination of an ACE inhibitor with an AT1 receptor antagonist is advantageous. Studies attempting to answer these questions are underway and will certainly enable researchers to define more precisely the role and the advantages of these new specific non-peptide AT1 receptor antagonists in the treatment of hypertension and heart failure.
 ...
PMID:Angiotensin II receptor antagonists - antihypertensive agents. 1598 15

This study assessed the behaviour of angiotensin II (Ang II) receptors in an experimental hypothyroidism model in male Wistar rats. Animals were subjected to thyroidectomy and resting for 14 days. The alteration of cardiac mass was evaluated by total heart weight (HW), right ventricle weight (RVW), left ventricle weight (LVW), ratio of HW, RVW and LVW to body weight (BW) and atrial natriuretic factor (ANF) expression. Cardiac and plasma Ang II levels and serum T3 and T4 were determined. The mRNA and protein levels of Ang II receptors were investigated by RT-PCR and Western blotting, respectively. Functional analyses were performed using binding assays. T3 and T4 levels and the haemodynamic parameters confirmed the hypothyroid state. HW/BW, RVW/BW and LVW/BW ratios and the ANF expression were lower than those of control animals. No change was observed in cardiac or plasma Ang II levels. Both AT1/AT2 mRNA and protein levels were increased in the heart of hypothyroid animals due to a significant increase of these receptors in the RV. Experiments performed in cardiomyocytes showed a direct effect promoted by low thyroid hormone levels upon AT1 and AT2 receptors, discarding possible influence of haemodynamic parameters. Functional assays showed that both receptors are able to bind Ang II. Herein, we have identified, for the first time, a close and direct relation of elevated Ang II receptor levels in hypothyroidism. Whether the increase in these receptors in hypothyroidism is an alternative mechanism to compensate the atrophic state of heart or whether it may represent a potential means to the progression of heart failure remains unknown.
 ...
PMID:Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism. 1797 84

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.
 ...
PMID:An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. 1769 38

Angiotensin II receptor blockers (ARBs) are widely used in patients with hypertension, heart failure, diabetic nephropathy, and other conditions. Over-stimulation of AT2 receptor as a result of AT1 blockade may contribute to the beneficial effects of ARBs through vasodilation and inhibition of cardiac and vascular hypertrophy and fibrosis. Some experimental studies, however, suggested that AT, receptor overstimulation, in addition to beneficial effects, might trigger inhibition of angiogenesis and apoptosis. In a review, some authors suggested that ARBs may increase the risk of myocardial infarction. This position triggered a hot scientific debate and further analyses of existing data. We completed a meta-analysis of randomized clinical trials comparing ARBs with either placebo or active drugs different from ARBs. ARBs were not associated with an excess risk of myocardial infarction (odds ratio 1.03 in a random-effect model and 1.02 in a fixed-effect model). Cardiovascular mortality did not differ between ARBs and drugs different from ARBs (odds ratio 1.00 in a random-effect model and 0.99 in a fixed-effect model) and it was slightly lesser with ARBs than with placebo (odds ratio 0.91; 95% confidence interval 0.83-0.99; p = 0.042) in a prespecified subgroup analysis. Other meta-analyses confirmed these data. In conclusion, evidence from randomized trials does not support the hypothesis that AT2 receptor over-stimulation produces harmful clinical effects. Current indications and contraindications to the use of ARBs in patients with hypertension, heart failure, and diabetic nephropathy should be maintained and probably extended to the entire class of these drugs.
 ...
PMID:[Antihypertensive therapy and cardiovascular prevention. The role of angiotensin II receptor blockers]. 1769


<< Previous 1 2 3 4 5 6 Next >>