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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.
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PMID:Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. 1148 44

ACE-inhibitors and AT, receptor antagonists play an important role in the treatment of cardiovascular and renal diseases. The criteria of evidence-based medicine indicate that ACE-inhibitors (in appropriate combinations with other cardiovascular agents) continue to represent the treatment of first choice in chronic heart failure, post-myocardial infarction with compromised ventricular function, high cardiovascular risk, and diabetic (type 1) nephropathy. It is here that the AT1 antagonists should be used--in particular when ACE-inhibitors are not tolerated. The AT1 antagonists, Irbesartan and Losartan, are applied, at appropriately high doses, primarily in hypertensives with diabetic (type 2) nephropathy. With the current exception of chronic heart failure, no confirmed data are yet available on the value of combination treatment. The LIFE study has shown that an AT1 antagonist is superior to an established beta blocker in hypertensives with an increased risk (left-ventricular hypertrophy), in particular when diabetes mellitus is impending or already present.
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PMID:[ACE inhibitor or AT1 antagonist. Is there a differential therapy?]. 1213 23

During the past few years, several major intervention trials have been conducted in an attempt to determine the efficacy of specific antihypertensive agents in retarding progression of diabetic nephropathy. These studies have clearly demonstrated the importance of renin-angiotensin system blockade in attenuating progressive renal disease. The preferred initial therapy is an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin type I (AT1) receptor antagonist based on the recent 'landmark' proof-of-concept trials--the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL). However, these clinical trials also demonstrate that aggressive blood pressure targets are needed in patients with diabetes and hypertension. This frequently requires multiple-drug therapy with several different classes of antihypertensive agents. Data from several clinical trials, including RENAAL, suggest that calcium antagonists may be added to ACE inhibitor or AT1 receptor antagonist therapy as needed to achieve target blood pressure. Calcium antagonists could, therefore, constitute an important component of the antihypertensive regimen in the management of patients with diabetic nephropathy.
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PMID:Evolving therapeutic strategies for retarding progression of diabetic nephropathy--an update for 2002. 1222 27

Angiotensin II (Ang II) can enhance sympathetic neurotransmission by acting on (AT1) receptors that are located on sympathetic nerve terminals. We investigated presynaptic blockade by the selective AT1-receptor antagonist irbesartan in pithed spontaneously hypertensive rats and normotensive Wistar-Kyoto rats (WKY). We compared the presynaptic inhibitory dose with that required for the blockade of AT1-receptors on vascular smooth muscle in both strains. To investigate blockade of presynaptic AT1-receptors, we studied the effect of irbesartan on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow (0.25-8 Hz). To study the interaction between postsynaptic AT1-blockers and alpha-adrenoceptors, the effects of irbesartan on pressor responses to exogenous noradrenaline (NA) were established. Additionally, we studied the effect of irbesartan on dose-response curves for the vasoconstriction induced by exogenous Ang II. Pressor responses to electrical stimulation of thoracolumbar sympathetic neurones, to exogenous Ang II, as well as to (NA) were enhanced in spontaneously hypertensive rats (SHR) compared with WKY. The stimulation-induced rise in DBP could be dose-dependently reduced by irbesartan (0.3-10 mg/kg) in both SHR and WKY. The pIC50 values (doses which suppress the rise in DBP by 50% compared with control) were 5.60 +/- 0.09 and 5.72 +/- 0.08 for SHR and WKY, respectively (P > 0.05). In SHR, no effect of irbesartan (3 mg/kg) on pressor responses to exogenous NA was observed. In contrast, in WKY, irbesartan (3 mg/kg) caused a rightward shift of the dose-response curve to exogenous NA. Irbesartan (0.3-3 mg/kg) caused a depression of E(max) values and a rightward shift of the dose-response curves to exogenous Ang II in a similar fashion in both SHR and WKY. From these results we conclude that both in SHR and in WKY, Ang II exerts a facilitatory effect on sympathetic neurotransmission, which is mediated by prejunctional AT1-receptors in both strains. Irbesartan displays comparable sympatho-inhibitory potency in the normotensive and hypertensive pithed rat preparations. A facilitatory effect via postsynaptically located AT1-receptors on alpha-adrenoceptor-mediated responses exists in WKY, but not in SHR. In both strains the required dose to inhibit presynaptic effects is somewhat higher than the dose required to inhibit postsynaptic effects. No differences, therefore, seem to exist between the two strains regarding the affinity of irbesartan for pre- and postjunctional AT1-receptors, respectively.
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PMID:Sympatho-inhibitory actions of irbesartan in pithed spontaneously hypertensive and Wistar-Kyoto rats. 1258 34

We recently described that a treatment with the angiotensin AT1 receptor antagonist irbesartan inhibits atherosclerotic lesion development, macrophage accumulation, and monocyte chemoattractant protein-1 (MCP-1) as well as the chemokine KC expression in apolipoprotein E-deficient (apoE-deficient) mice. The present study addresses whether these and other chemokines are expressed not only during the initiation but also during the development of atherosclerotic lesions and whether irbesartan can inhibit the expression of these chemokines during lesion progression. The time course of lesion development was assessed in apoE-deficient mice aged 1 to 9 months and the relative expression of chemokines was quantified by RT-PCR. Significant lesion formation already appeared in 3-month-old apoE-deficient mice, and progressed further to the age of 9 months. The expression of MCP-1 and KC (the mouse homologue of Groalpha), was induced at 1 month in apoE-deficient as compared with wild type (C57/Bl6) mice, and was observed before any detectable histologic changes. MCP-1 and KC expression remained high during lesion progression. The expression of macrophage inflammatory protein-2 (MIP-2, the mouse Grobeta/gamma homologue) and macrophage inflammatory protein-1alpha (MIP-1alpha) was increased in lesions from 4-month-old mice onward, whereas Regulated upon Activation of Normal T-cells Expressed and Secreted (RANTES) was significantly induced in 6- to 9-month-old mice only. Irbesartan (50 mg/kg/d) administered from the age of 3 months onward significantly reduced the progression of the lesions as well as the expression of the chemokines. A short-term treatment with irbesartan significantly inhibited the expression of MCP-1 and KC, suggesting that activation of the renin-angiotensin system is involved in up-regulation of these chemokines and that this effect represents a potential mechanism by which irbesartan inhibits plaque development and progression.
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PMID:Lesion progression in apoE-deficient mice: implication of chemokines and effect of the AT1 angiotensin II receptor antagonist irbesartan. 1471 5

Irbesartan is a long-acting angiotensin II antagonist acting specifically at the level of the Type 1-receptor subtype (AT1-receptor). This compound lowers blood pressure dose-dependently in hypertensive patients and has a placebo-like tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available. Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure. Irbesartan may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of angiotensin II. Irbesartan given alone or in combination with a diuretic therefore represents a rational approach to treat hypertensive patients.
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PMID:AT1-receptor antagonism in hypertension: what has been learned with irbesartan? 1503 Feb 94

Irbesartan (Aprovel) belongs into the new group drugs for the cardiovascular system which exert an antagonistic effect at the level of angiotensin II, but experimental pilot studies as well as clinical studies draw also attention to the possible therapeutic potential of AT1 receptor blockers in the treatment of chronic heart failure. Irbesartan has a marked antihypertensive effect as is apparent from a recent clinical study in 139 patients with mild and moderate hypertension--implemented in the Czech Republic. Twelve-week treatment with Irbesartan led to a marked drop of the systolic and diastolic blood pressure (159.2 +/- 14 vs. 137 +/- 13 mmHg/99.2 +/- 7 vs. 85.3 +/- 7 mmHg, p < 0.01). A very favourable therapeutic effect was recorded in this investigation also in 24-hour monitoring of the blood pressure. The use of irbesartan in patients with arterial hypertension has according to other studies also a favourable effect on organ complications of hypertension and diabetes (regression of left ventricular hypertrophy, reduction of albuminuria). Irbesartan may prove due to its favourable effect a suitable alternative in conditions associated with intolerance of ACE-inhibitors in patients with moderate and severe forms of arterial hypertension, in chronic heart failure and in diabetic nephropathy.
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PMID:[Irbesartan in the treatment of arterial hypertension]. 1564 39

Despite the introduction of new antihypertensive agents such as angiotensin-converting enzyme inhibitors and calcium channel antagonists, the blood pressure of fewer than 30% of hypertensive patients is controlled with current therapies; compliance and continuation with medication are poor. The renin-angiotensin system is important in the pathophysiology of hypertension, end-organ damage and congestive cardiac failure. Irbesartan is an angiotensin II receptor antagonist that provides dose-dependent, specific, insurmountable blockade of the AT1 receptor both in vivo and in vitro. It is rapidly absorbed after oral administration, has a bioavailability of 60-80% with no food effect, does not require metabolism to a bioactive compound, and is excreted by both biliary and renal routes so that dosage adjustments are unnecessary in patients with renal or hepatic disease. Irbesartan produces dose-dependent blood pressure reductions, with 24 h activity confirmed by ambulatory blood pressure monitoring. Irbesartan is effective in the elderly and non-elderly, men and women and in cases of mild and severe hypertension. The recommended starting dosage is 150 mg once daily (o.d.), which can be increased to 300 mg. Its antihypertensive effect is accentuated by diuretic co-administration. In controlled clinical trials, irbesartan was at least as effective as atenolol, hydrochlorothiazide, amlodipine and enalapril. In a double-blind study, irbesartan 300 mg was more effective than losartan 100 mg, and in a dose-titration study, irbesartan 150-300 mg produced significantly greater blood pressure reductions than losartan 50-100 mg. In pooled data from nine placebo-controlled studies, adverse event and discontinuation rates for irbesartan were similar to those for placebo, and there was no relationship between dose and adverse effects. Preliminary clinical data suggest positive haemodynamic effects in heart failure and renoprotective effects in diabetic nephropathy.
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PMID:Pharmacology of irbesartan. 1599 21

Losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)-biphenil-4-yl)methyl]imidazole, and Irbesartan, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, are two angiotensin AT1 receptor antagonists largely used in human health care as antihypertensive agents. Their ability to cross the blood-brain barrier and to influence the central renin-angiotensin system are widely investigated, but how this brain system responds to the subchronic and chronic block of the angiotensin AT1 receptor is still unknown. Normotensive rats were intragastrically implanted for 7- and 30-day administration, with a dose of 3 and 30 mg/kg body weight. Treatments were shown to influence, in a dose-, time- and brain-area-dependent manner, angiotensinogen mRNA levels in scanned areas. This study showed a general up-regulation of angiotensinogen mRNA expression after 7 days and a widespread down-regulation or basal level of expression after a 30-day administration of two angiotensin AT1 receptor antagonists.
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PMID:Effects of losartan and irbesartan administration on brain angiotensinogen mRNA levels. 1632 81

Despite the well-documented effect of irbesartan, an angiotensin AT1 receptor antagonist, on diabetic nephropathy, its effect on mortality related to multiple metabolic risk factors is unknown. To address this question, obese fa/fa Zucker rats were submitted to a 13-month treatment by irbesartan (30 mg/kg/day p.o.). Vehicle-treated obese fa/fa Zucker rats exhibited an important mortality (72%), which was markedly reduced by irbesartan (22%, P<0.05). Mortality in control lean fa/+ rats attained 12%. Irbesartan diminished the elevation in urinary protein excretion, plasma creatinine and urea nitrogen levels, and reduced the extent of glomerular and tubulo-interstitial lesions together with a reduction of urinary monocyte chemoattractant protein-1 excretion in fa/fa Zucker rats. Irbesartan treatment prevented the rise in plasma total cholesterol, triglycerides and glucose levels, and partially corrected low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio in fa/fa Zucker rats. Therefore, prolonged irbesartan treatment preserves renal function and metabolic profile, and substantially increases survival in obese fa/fa Zucker rats.
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PMID:Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats. 1651 82


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