Review: Molecular-specific effects of angiotensin II antagonists: clinical relevance to treating hypertension?

Reid, John L.

doi:10.3317/jraas.2005.002

Cited by 16 publications

(8 citation statements)

References 92 publications

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“…It is also becoming apparent that some ARBs may possess additional effects that appear to be not only independent of AT 1 receptor blockade, but also of PPAR γ activation [154]. Such effects include TXA 2 (thromboxane A 2 ) receptor blockade, decreased platelet aggregation and reduction of serum uric acid levels [154].…”

Section: Pleitropic Neuroprotective Effects Of Arbsmentioning

confidence: 99%

“…Such effects include TXA 2 (thromboxane A 2 ) receptor blockade, decreased platelet aggregation and reduction of serum uric acid levels [154]. However, there is no definitive evidence for these molecule-specific effects giving rise to a therapeutic advantage for the treatment of cardiovascular disease [154]. Consequently, whether selective ARBs have advantage for the treatment of brain disorders is at the present time still an open question.…”

Section: Pleitropic Neuroprotective Effects Of Arbsmentioning

confidence: 99%

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Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

2012

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The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT1 receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT1 receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer’s disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer’s disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury.

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Section: Pleitropic Neuroprotective Effects Of Arbsmentioning

confidence: 99%

Section: Pleitropic Neuroprotective Effects Of Arbsmentioning

confidence: 99%

Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

2012

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“…Thus, the AT 1 R-antagonist induction of ␤-arrestin 1 cleavage could be a signal in itself, but the functional consequences are unknown at this time. Both of these AT 1 R blockers are used in cardioprotection, antihypertensive, and anti-diabetes therapies, but their molecular mechanism is largely unknown (35,36). Our finding of losartan-induced ␤-arrestin proteolysis provides a novel insight into the molecular mechanism of losartan action through the AT 1 R that could be physiologically important.…”

Section: Discussionmentioning

confidence: 86%

Site-specific Cleavage of G Protein-coupled Receptor-engaged β-Arrestin

Lee

Bhatt

Shukla

et al. 2008

Journal of Biological Chemistry

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The discovery of ␤-arrestin-related ϳ46-kDa polypeptide in transfected cells and mouse hearts led us to examine angiotensin II type 1 receptor (AT 1 R)-dependent proteolytic cleavage of ␤-arrestin(s). Receptor-ligand induced proteolysis of ␤-arrestin(s) is novel, especially in the endocrine system, since proteolytic and/or splice variants of nonvisual arrestins are unknown. We used a strategy to retrieve AT 1 R-engaged isoforms of ␤-arrestin 1 to confirm direct interaction of fragments with this G protein-coupled receptor and determine cleavage sites. Here we show that the angiotensin II-AT 1 R complex is associated with full-length and ϳ46-kDa ␤-arrestin forms. Mass spectrometric analysis of the AT 1 R-associated short form suggested a scissile site located within the Arg 363 -Arg 393 region in the bovine ␤-arrestin 1. Edman degradation analysis of a ␤-arrestin 1 C-terminal fragment fused to enhanced green fluorescent protein confirmed the major cleavage to be after Phe 388 and a minor cleavage after Asn 375 . Rather unexpectedly, the inverse agonist EXP3174-bound AT 1 R generated different fragmentation of bovine ␤-arrestin 1, at Pro 276 . The angiotensin II-induced cleavage is independent of inositol 1,4,5-trisphosphateand Ca 2؉ -mediated signaling pathways. The proteolysis of ␤-arrestin 2 occurs, but the pattern is more complex. Our findings suggest that ␤-arrestin cleavage upon AT 1 R stimulation is a part of the unraveling ␤-arrestin-mediated G protein-coupled receptor signaling diversity.

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“…Losartan add-on therapy resulted in a significant decrease in serum uric acid levels, although the baseline level of uric acid was within the normal range in the study patients [53]. Losartan possesses an uricosuric effect both after single and multiple doses, increasing urinary excretion of uric acid dose-dependently [54]. Losartan could inhibit ATP-dependent uric acid secretion [55]; it reduces the URAT1-mediated uptake of uric acid [56].…”

Section: Pharmacodynamicsmentioning

confidence: 88%

Irbesartan and Hydrochlorothiazide Association in the Treatment of Hypertension

Derosa¹,

Ferrari²,

Cicero³

2009

CVP

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Blood pressure (BP) is one of the most important and common vascular risk factors but it is often poorly controlled. Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides beneficial effects in hypertensives. The association of low-dosed diuretics in combination with RAAS blocking agents allows maximum benefit from potassium depletion and control of compensatory increase in renin secretion, so increasing the efficacy and safety of RAAS blockers. Irbesartan is a potent and selective angiotensin II subtype 1 receptor antagonist indicated for use in patients with hypertension, including those with type 2 diabetes mellitus and nephropathy. Once-daily irbesartan administration provides 24h control of BP. In patients with mild-to-moderate hypertension, irbesartan was as effective as enalapril, atenolol and amlodipine, and more effective than losartan and valsartan in terms of absolute reduction in BP and response rate. Irbesartan also induced regression of left ventricular hypertrophy. Moreover, irbesartan 300 mg/day exerts a significant renoprotective effect in hypertensive type 2 diabetic patients. The relative risk of doubling of serum creatinine was significantly lower with irbesartan than amlodipine or placebo. Irbesartan was also effective in non-diabetic nephropatic patients. Moreover, irbesartan has peroxisome proliferator-activated receptor agonistic effects in in vitro studies, and it also demonstrated beneficial effects on inflammatory markers of atherosclerosis and endothelial function. The overall incidence of adverse events is similar to that of placebo. A fixed dose of hydrochlorothiazide (HCTZ) and irbesartan shows additive antihypertensive effect in a dose dependent manner up to HCTZ 25 mg and irbesartan 300 mg with high tolerability in diverse patient groups. Combination effects on end organ protection must be evaluated by broad spectrum studies. Ongoing trials about irbesartan and its combination with diuretics may provide necessary data to interpret the value of this association among others.

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Review: Molecular-specific effects of angiotensin II antagonists: clinical relevance to treating hypertension?

Cited by 16 publications

References 92 publications

Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

Site-specific Cleavage of G Protein-coupled Receptor-engaged β-Arrestin

Irbesartan and Hydrochlorothiazide Association in the Treatment of Hypertension

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