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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blockade of the renin-angiotensin-aldosterone system (RAAS) has been shown to be useful, or even mandatory, in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and nephropathy with albuminuria, due to diabetes or not. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors and/or recently a direct inhibitor of renin such as aliskiren. Various studies have demonstrated the advantage of optimising RAAS blockade in order to benefit of the best cardiorenal protection. The present article describes the various modalities to optimize the RAAS blockade, either by using a maximal dosage of a monotherapy, or by choosing a double inhibition of RAAS. New prospects for the RAAS blockade will be also briefly considered.
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PMID:[How I treat... by optimizing the blockade of the renin-angiotensin-aldosterone system]. 1857 70

The blockade of the renin-angiotensin-aldosterone system (RAAS) is helpful in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and diabetic nephropathy. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors, an aldosterone receptor antagonist and/or a direct inhibitor of renin such as aliskiren. Various studies have demonstrated that a dual or even triple RAAS inhibition may offer a better cardiorenal protection, in refractory congestive heart failure and in nephropathy with proteinuria. However, in the ONTARGET study, the dual inhibition with ramipril plus telmisartan did not provide any additional benefit compared to ramipril alone in high-risk cardiovascular patients, but showed a worse tolerance profile.
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PMID:[What is the purpose of dual or triple inhibition of the renin-angiotensin-aldosterone system?]. 1881 62

Angiotensin II (Ang II) not only mediates the effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Ang 1I activates pathways of MAPK, NADPH and ROS, non-receptor tyrosine kinases and receptor tyrosine kinases via AT1 receptor to produce various effects involved in regulation of endothelial functions, endothelial dysfunction and vascular inflammation response.
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PMID:[Progress in signal transduction pathways mediating effects of angiotensin II in endothelial cells]. 1881 91

Aliskiren (Rasilez) is the first oral renin inhibitor. Its present indication is essential hypertension, as monotherapy or in combination with other antihypertensive agents (diuretic, calcium antagonist, ...). It may also be associated with an angiotensin converting enzyme inhibitor (or an AT1 angiotensin receptor antagonist) in order to benefit of a dual blockade of the renin-angiotensin-aldosterone system. The usual daily dose is 150 mg, to be increased up to 300 mg if necessary. New clinical trials are ongoing to validate this novel therapeutic approach in other indications such as congestive heart failure and diabetic nephropathy.
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PMID:[Aliskiren (Rasilez), direct renin inhibitor]. 1905 13

Angiotensin AT1 receptor antagonists, drugs affecting the renin-angiotensin system, are commonly used in the treatment of hypertension and congestive heart failure. It is also known that the renin-angiotensin system exists in the brain and therefore it may be involved in the regulation of seizure susceptibility. The aim of the current study was to evaluate the effects of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)-biphenil-4-yl)methyl]imidazole) and telmisartan (49-[(1,49-dimethyl-29-propyl[2,69-bi-1H-benzimidazo]-19-yl)methyl]-[1,19-biphenyl]-2-carboxylic acid), the angiotensin AT1 receptor antagonists which are widely used in clinical practice, on the protective action of conventional antiepileptic drugs (carbamazepine, phenytoin, valproate and phenobarbital) against maximal electroshock-induced seizures in mice. Losartan (10, 20 and 50 mg/kgi.p.) and telmisartan (5, 10 and 30 mg/kgi.p.) did not influence the threshold for electroconvulsions. However, both drugs potentiated the anticonvulsant activity of valproate. Losartan (50 mg/kgi.p.) decreased its ED50 value from 249.8 to 194.6 mg/kg while telmisartan (30 mg/kgi.p.) lowered the ED50 value for valproate from 249.8 to 190.6 mg/kg. The antiseizure action of the remaining antiepileptics was not affected by losartan or telmisartan. The observed interactions between tested angiotensin AT1 receptor antagonists and valproate were pharmacodynamic in nature as either losartan or telmisartan did not alter total brain concentrations of valproate. This finding can be important for epileptic patients receiving valproate and also angiotensin AT1 receptor antagonists due to other medical causes.
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PMID:Angiotensin AT1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock. 2046 98

Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.
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PMID:Targeting cardiac mast cells: pharmacological modulation of the local renin-angiotensin system. 2210 45

A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT1 receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT1 receptor. However, recent in vitro studies have demonstrated that AT1 receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT1 receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II-independent activation of AT1 receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT1 receptor.
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PMID:ARB and cardioprotection. 2253 56

In patients with CHF (chronic heart failure) sympathetic activity increases as cardiac performance decreases and filling pressures increase. We hypothesized that in patients with mild-to-moderate CHF, higher than conventional doses of an AT1-receptor [AngII (angiotensin II) type 1 receptor] antagonist would achieve greater central AT1-receptor blockade, resulting in diminished MSNA (muscle sympathetic nerve activity) and augmented MSNA variability, two indices of central effects on sympathetic outflow. In total, 13 patients with ischaemic cardiomyopathy [NYHA (New York Heart Association) class II-III] were weaned off all pharmacological RAS (renin-angiotensin system) modifiers, and then randomized to receive a low (50 mg/day) or high (200 mg/day) dose of losartan. Central haemodynamics, MSNA and its variability, plasma catecholamines, AngI (angiotensin I) and AngII and aldosterone were assessed both before and 3 months after randomization. Neither dose altered BP (blood pressure), PCWP (pulmonary capillary wedge pressure) or CI (cardiac index) significantly. Compared with 50 mg daily, losartan 200 mg/day decreased MSNA significantly (P<0.05), by approximately 15 bursts/min, and increased MSNA variability within the 0.27-0.33 Hz high-frequency range by 0.11 units(2)/Hz (P=0.06). PNE [plasma noradrenaline (norepinephrine)] fell in parallel with changes in MSNA (r=0.62; P<0.05). These findings support the hypothesis that higher than conventional doses of lipophilic ARBs (AT1-receptor blockers) can modulate the intensity and variability of central sympathetic outflow in patients with CHF. The efficacy and safety of this conceptual change in the therapeutic approach to heart failure merits prospective testing in clinical trials.
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PMID:Do high doses of AT(1)-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure? 2316 25

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Although patients with advanced CHF or CKD often have increased angiotensin II (Ang II) levels and cachexia and Ang II causes skeletal muscle wasting in rodents, the potential effects of Ang II on muscle regeneration are unknown. Muscle regeneration is highly dependent on the ability of a pool of muscle stem cells (satellite cells) to proliferate and to repair damaged myofibers or form new myofibers. Here we show that Ang II reduced skeletal muscle regeneration via inhibition of satellite cell (SC) proliferation. Ang II reduced the number of regenerating myofibers and decreased expression of SC proliferation/differentiation markers (MyoD, myogenin, and active-Notch) after cardiotoxin-induced muscle injury in vivo and in SCs cultured in vitro. Ang II depleted the basal pool of SCs, as detected in Myf5(nLacZ/+) mice and by FACS sorting, and this effect was inhibited by Ang II AT1 receptor (AT1R) blockade and in AT1aR-null mice. AT1R was highly expressed in SCs, and Notch activation abrogated the AT1R-mediated antiproliferative effect of Ang II in cultured SCs. In mice that developed CHF postmyocardial infarction, there was skeletal muscle wasting and reduced SC numbers that were inhibited by AT1R blockade. Ang II inhibition of skeletal muscle regeneration via AT1 receptor-dependent suppression of SC Notch and MyoD signaling and proliferation is likely to play an important role in mechanisms leading to cachexia in chronic disease states such as CHF and CKD.
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PMID:Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration. 2383 88

Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.
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PMID:A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker. 2455 91


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