28 replies to this topic

[medievil]

AT1 antagonism looks interesting as an anti aging approuch, i recently came across those studies when looking into angiotensin.

Disruption of the Ang II type 1 receptor promotes longevity in mice.
Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G.

Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, Bergamo, Italy. abenigni@marionegri.it
Abstract
The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang II type 1 receptors (AT1 and AT2). Here, we show that targeted disruption of the Agtr1a gene that encodes AT1A results in marked prolongation of life span in mice. Agtr1a-/- mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect was inhibited by an AT1 antagonist. These results demonstrate that disruption of AT1 promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT1 pathway may be targeted to influence life span in mammals.

Angiotensin receptors as determinants of life span.
Cassis P, Conti S, Remuzzi G, Benigni A.

Mario Negri Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy.
Abstract
Angiotensin II (Ang II), the central product of renin-angiotensin system, has a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT(1)). Several experimental studies have demonstrated that Ang II acts through AT(1) as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT(1A)) in mice translates into marked prolongation of life span. The absence of AT(1A) protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT(1) receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT(1) pathway represents a feasible therapeutic strategy to prolong life span in humans.

EMBO Mol Med. 2010 Jul;2(7):247-57.
Angiotensin II revisited: new roles in inflammation, immunology and aging.
Benigni A, Cassis P, Remuzzi G.

Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Abstract
That the renin-angiotensin system (RAS) is involved in regulation of blood pressure, vasoconstriction, sodium intake and potassium excretion is well established. Studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease. Binding of Ang II to its receptors (in particular AT(1)) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents. Altogether these findings open the unanticipated perspective for exploring Ang II signalling in therapeutic interventions in inflammatory diseases and aging-related tissue injury. This review extends from the discovery of Ang II and its implications in renal and cardiovascular physiology to cover the roles of the system in inflammation, tissue injury, autoimmunity, oxidative stress and aging.

Nephrol Dial Transplant. 2010 Sep 2. [Epub ahead of print]
Angiotensin II blockade upregulates the expression of Klotho the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy.
Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, Ohashi N, Kobori H, Kuro-O M, Yang CW.

1Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, South Korea.
Abstract
BACKGROUND: The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin-angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury.

METHODS: Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription-polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG).

RESULTS: CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion.

CONCLUSIONS: Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.

More info about the klotho gene:
http://www.imminst.o...4&t=7759&hl=&s=

More information in general about Angiotensin II AT1 antagonists is in my thread on mind and muscle:
http://www.mindandmu...showtopic=43119

Edited by medievil, 19 September 2010 - 06:40 PM.

[leha]

Looks like RAS blockade does a bunch of other important things, as well:

Angiotensin II blockade: a strategy to slow aging by protecting mitochondria?

Abstract

Protein and lipid oxidation -mainly by mitochondrial reactive oxygen species (mtROS)- was proposed as a crucial determinant of life- and healthspan. Angiotensin-II enhances ROS production by activating NAD(P)H-oxidase and uncoupling endothelial-NOS. Angiotensin-II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS-bl) increases survival, and prevents age-associated changes. RAS-bl reduces mtROS, and enhances mitochondrial content and function. This suggests that angiotensin-II contributes to the aging process by prompting mitochondrial dysfunction. Since angiotensin-II is a pleiotropic peptide, the age-protecting effects of RAS-bl are expected to involve a variety of other mechanisms. Caloric restriction -an age-retarding intervention in humans and animals- and RAS-bl, display a number of converging effects, i.e., they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease and cancer; increase body temperature; reduce body weight, plasma glucose, insulin and insulin-like growth factor-I; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production, and increase UCP-2 and sirtuin expression. A number of these overlapping effects involve changes in mitochondrial function. In caloric restriction, PPARs seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition upregulates PPARs, therefore it is feasible that PPAR-modulation is pivotal for mitochondrial protection by RAS-bl during rodent aging. Other potential mechanisms that may underlie RAS-bl's mitochondrial benefits are TGF-beta downregulation and upregulation of Klotho and sirtuins. Concluding, the available data suggests that RAS-bl deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.

[tlm884]

AT1 antagonism looks interesting as an anti aging approuch, i recently came across those studies when looking into angiotensin.
[snip]

This looks like a good thing for those of us on AT1 antagonists such as Diovan and Cozaar. Haa, you gave me a good excuse to have hypertension now :P
Edit: trimmed quote.

Edited by niner, 20 September 2010 - 12:47 AM.

[medievil]

Personally really interested for their anti anxiety/stress activity.

Ann N Y Acad Sci. 2008 Dec;1148:360-6.
Peripherally administered angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo.
Pavel J, Benicky J, Murakami Y, Sanchez-Lemus E, Saavedra JM.

Section on Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Abstract
Angiotensin II AT(1) receptor blockers (ARBs) are commonly used in the clinical treatment of hypertension. Subcutaneous or oral administration of the ARB candesartan inhibits brain as well as peripheral AT(1) receptors, indicating transport across the blood-brain barrier. Pretreatment with candesartan profoundly modifies the response to stress. The ARB prevents the peripheral and central sympathetic activation characteristic of isolation stress and abolishes the activation of the hypothalamic-pituitary-adrenal axis during isolation. In addition, candesartan prevents the isolation-induced decrease in cortical corticotropin-releasing factor 1 and benzodiazepine receptors induced by isolation. When administered before cold-restraint stress, candesartan totally prevents the production of gastric ulcerations. This preventive effect of candesartan is the consequence of profound anti-inflammatory effects, reduction of sympathetic stimulation, and preservation of blood flow to the gastric mucosa. The ARB does not reduce the hypothalamic-pituitary-adrenal axis stimulation during cold restraint. Preservation of the effects of endogenous glucocorticoids is essential for protection of the gastric mucosa during cold restraint. Administration of the ARB to nonstressed rats decreases anxiety in the elevated plus-maze. Our results demonstrate that Angiotensin II, through AT(1) receptor stimulation, is a major stress hormone, and that ARBs, in addition to their antihypertensive effects, may be considered for the treatment of stress-related disorders.

Angiotensin II: multitasking in the brain.
Saavedra JM, Benicky J, Zhou J.

Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. Saavedrj@mail.nih.gov
Abstract
In addition to controlling systemic blood pressure, angiotensin II (Ang II) has several roles in the brain, including the regulation of cerebrovascular flow and the reaction to stress. In order to clarify the central effects of Ang II and its type 1 (AT1) receptors, we reviewed the literature reporting recent research on the effects of pretreatment with the AT1-receptor blocker, candesartan, on experimental ischemia, cerebrovascular remodeling, and inflammation in spontaneously hypertensive rats (SHRs), and the responses to stress induced by isolation and by cold-restraint. Angiotensin II regulates the brain circulation through stimulation of AT1-receptors located in the cerebrovascular endothelium and central pathways. SHRs express greater numbers of endothelial AT1-receptors and a central sympathetic overdrive, resulting in pathological cerebrovascular growth, inflammation, decreased cerebrovascular compliance, and enhanced vulnerability to brain ischemia. Sustained central AT1-receptor antagonism reverses these effects. Sustained reduction of AT1-receptor stimulation before stress prevents the hormonal and sympathoadrenal stress responses during isolation and prevents the gastric ulceration stress response to cold-restraint, indicating that increased AT1-receptor stimulation is essential to enhance the central sympathetic response and the formation and release of corticotropin-releasing factor (CRF) and arginine vasopressin that occur during stress. AT1-receptor blocking agents reverse the cortical alterations in CRF1 and benzodiazepine receptors characteristic of isolation stress, effects probably related to their anti-anxiety effect in rodents. Sustained reduction of Ang II tone by AT1-receptor antagonism could be considered as a preventive and therapeutic approach for brain ischemia and stress-related and mood disorders. Additional preclinical studies and controlled clinical trials are necessary to confirm the efficacy of this novel therapeutic approach.

Neuropsychopharmacology. 2006 Jun;31(6):1123-34.
A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding.
Saavedra JM, Armando I, Bregonzio C, Juorio A, Macova M, Pavel J, Sanchez-Lemus E.

Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. Saavedrj@mail.nih.gov
Abstract
Long-term pretreatment with an angiotensin II AT1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic-pituitary-adrenal responses to isolation stress. We determined whether AT1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT1 antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT1 receptor blockade prevented the isolation-induced increase in brain AT1 receptors and decrease in AT2 binding in the locus coeruleus. AT1 receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT1 receptor antagonist completely prevented the decrease in cortical CRF1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF1 receptors and the GABA(A) complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT1 receptor antagonists. We propose that AT1 receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.

Also the plethoria of abstracts showing potent neuroprotective effects.

[niner]

Is any of this showing up in post-marketing surveillance of ARBs that have been prescribed for hypertension, or in epidemiology among users? I took a low dose (40 mg) of Diovan for a few years before I learned how to eat right. If I took it today, my bp would crater. Anyone who needs one of these things is probably not the best candidate to show a super-longevity effect. Maybe we need a way to block ARS without killing bp.

[tlm884]

Is any of this showing up in post-marketing surveillance of ARBs that have been prescribed for hypertension, or in epidemiology among users? I took a low dose (40 mg) of Diovan for a few years before I learned how to eat right. If I took it today, my bp would crater. Anyone who needs one of these things is probably not the best candidate to show a super-longevity effect. Maybe we need a way to block ARS without killing bp.

Its possible that something further down the cascade is responsible for the antiaging effect without causing a decrease in BP. I guess someone needs to look further into it.

[simon007]

AT1 antagonism looks interesting as an anti aging approuch, i recently came across those studies when looking into angiotensin.
[snip]

This looks like a good thing for those of us on AT1 antagonists such as Diovan and Cozaar. Haa, you gave me a good excuse to have hypertension now :P
Edit: trimmed quote.

In this post http://www.fightagin...hemical-tin.php Reason suggests that both ACE inhibitors and ARB's have a similar effect. I use an ACE inhibitor for my elevated bloodpressure :-)

[medievil]

Is any of this showing up in post-marketing surveillance of ARBs that have been prescribed for hypertension, or in epidemiology among users? I took a low dose (40 mg) of Diovan for a few years before I learned how to eat right. If I took it today, my bp would crater. Anyone who needs one of these things is probably not the best candidate to show a super-longevity effect. Maybe we need a way to block ARS without killing bp.

Would it tough?

Someone on mind and muscle that tried a AT1 blocker reported a paradoxal increase in blood pressure at first:

Blocking this receptor with candesartan has paradoxically increased my BP to the common 120/70.

Whole post:
This stuff is fantastic. After feeling completely whacked out for a few days, I seemed to have adjusted to candesartan. I'm taking 4mg before bed and 4mg in the morning.

• My anxiety, which is usually a constant buzz in the background, is almost completely gone.
• When I hit the sack at night and relax, it's pure bliss. Is this what normal feels like?
• My sleep requirement has dropped from 10 hours to 8 hours, and I awake so much more clear headed.
• Average resting pulse has dropped from 80bpm to 70bpm.

Interestingly, I just got my 23andme results back which show multiple polymorphisms in AGTR1. These should increase my risk for hypertension, however, I've always had low, nearly hypotensive, blood pressure. Blocking this receptor with candesartan has paradoxically increased my BP to the common 120/70.


Seems that they "modulate" blood pressure rather then just lowering it, and not make your blood pressure go too low if its allready on the low side but thats just based on one anecdotal report.

Edited by medievil, 20 September 2010 - 10:56 AM.

[medievil]

ARB blockers being superior to ACE inhibitors:

Expert Rev Neurother. 2009 Sep;9(9):1413-31.
Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors.
Fournier A, Oprisiu-Fournier R, Serot JM, Godefroy O, Achard JM, Faure S, Mazouz H, Temmar M, Albu A, Bordet R, Hanon O, Gueyffier F, Wang J, Black S, Sato N.

Internal Medicine Department, University Hospital, Amiens, France. fournier.albert@chu-amiens.fr
Abstract
Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer's disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. beta-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating beta-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Abeta(42) into less toxic Abeta(40). Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Abeta(42) brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on beta-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.

J Hypertens. 2008 Oct;26(10):2008-15.
Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors.
Faure S, Bureau A, Oudart N, Javellaud J, Fournier A, Achard JM.

Division of Nephrology, University of Limoges, Limoges, France.
Abstract
OBJECTIVES: The contribution of the AT2 and AT4 angiotensin receptors to the protective role of the AT1 receptor blocker candesartan in acute ischemic stroke was investigated.

METHODS: Embolic stroke was induced by injection of calibrated microspheres (50 microm) in the right internal carotid in Sprague-Dawley rats.

RESULTS: Inhibition of production of endogenous angiotensins by pretreatment for 24 h with lisinopril significantly increased mortality and infarct volume, whereas candesartan for 24 h reduced blood pressure to the same extent but had no deleterious effect. A more sustained pretreatment with candesartan for 5 days significantly decreased mortality, neurological deficit and infarct size. The AT2 receptor antagonist PD123319 and the AT4 receptor antagonist divalinal abolished the protective effect of 5 days' AT1 blockade. Combined blockade of AT2 and AT4 in candesartan pretreated rats resulted in an increased mortality, neurological deficit and infarct volume of similar magnitude to lisinopril pretreatment. Coadministration of lisinopril 24 h before surgery completely blunted the protective effect of candesartan pretreatment. Administration of exogenous angiotensin IV (1 nmol) reversed the deleterious effect of lisinopril pretreatment.

CONCLUSION: Protection against acute cerebral ischemia induced by AT1 blockade for 5 days is blood pressure independent and mediated by both AT2 and AT4 angiotensin receptors.

By blocking only AT1 we can increase activation of AT2 and AT4 at the same time wich shows neuroprotective effects in various conditions.

Edited by medievil, 20 September 2010 - 10:59 AM.

[tlm884]

By blocking only AT1 we can increase activation of AT2 and AT4 at the same time wich shows neuroprotective effects in various conditions.

If blocking AT1 results in increased activation of AT2 at a sufficient concentration it looks like an organism could benefit from a plethora of affecrts.

"Effects mediated by the AT₂ receptor are suggested to include inhibition of cell growth, fetal tissue development, modulation of extracellular matrix, neuronal regeneration, apoptosis, cellular differentiation, and maybe vasodilation and left ventricular hypertrophy^[5]" http://en.wikipedia....tensin_receptor

I know I know, Wikipedia is far from reliable.

[medievil]

The more i'm looking AT1 blockade the more i'm getting convised that this is something of major benefit for a variety of things, i will be trying telmisertan soon.

[FunkOdyssey]

What do you guys think of this:

Myocardial infarction controversy

Whether angiotensin receptor blockers may or may not increase the risk of myocardial infarction (heart attack) was announced in BMJ[4] and was debated in 2006 in the medical journal of the American Heart Association.[5][6] To date[when?], there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.

In the VALUE trial, the angiotensin II receptor blocker valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine.[7]

The CHARM-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.[8]

Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.[9][10][11]

[medievil]

Telmisertan may be the best option then, kimber posted this on mind and muscle:

What's interesting is, drugs like candesartan and losartan are frequently shown to have anxiolytic effects. These two ARBs also increase ACE activity and plasma angiotensin II. Telmisartan, despite being even more lipophilic, does not increase ACE activity or angiotensin II.

Havent seen a source for that yet tough.

He also stated that this one may lack the anxiolytic effect, wich is the mean reason i want to try those, but will have to experiment.

Edited by medievil, 20 September 2010 - 07:58 PM.

[FunkOdyssey]

Telmisertan may be the best option then, kimber posted this on mind and muscle:

What's interesting is, drugs like candesartan and losartan are frequently shown to have anxiolytic effects. These two ARBs also increase ACE activity and plasma angiotensin II. Telmisartan, despite being even more lipophilic, does not increase ACE activity or angiotensin II.

Havent seen a source for that yet tough.

He also stated that this one may lack the anxiolytic effect, wich is the mean reason i want to try those, but will have to experiment.

alldaychemist has it among many other sources.

[medievil]

Well, i'l be trying it soon.

[smithx]

Researchers from Case Western Reserve University School of Medicine in Cleveland examined data from previous trials of ARBs. They also looked at new cancer data in five trials involving 61,590 patients, common types of cancers (lung, prostate, breast) in another five trials of 68,402 patients, and cancer deaths in eight trials involving 93,515 patients.

Most of the patients in these trials (85.7%) had received the ARB telmisartan.

The researchers report that, overall, those who had taken ARBs had a significantly increased likelihood of new cancer diagnosis compared with patients in comparison groups (7.2% as opposed to 6%).

Among the solid-organ cancers examined, only the risk of lung cancer was significantly increased in patients taking ARBs compared with the comparison groups (0.9% as opposed to 0.7%).

http://www.webmd.com...s-linked-cancer

[brunotto]

Telmisartan is immunosupressive (that can explain the cancer issue)... inhibits cytokine-induced nuclear factor-kappaB activation independently of the peroxisome proliferator-activated receptor-gamma

http://www.ncbi.nlm....pubmed/19590508

[medievil]

Telmisartan looks definatly interesting for this use but i would avoid using candesartan as in patients where it actively lowers blood pressure it doesnt even lower the risk of myocardial infarction, this is attributed to negative effects induced by increased angiotensin II levels wich in turn activate AT2 wich has a negative effect. The question is wheter we can encounter increased negative effects in patients where there wasnt a too high blood pressure in the first place?

[brunotto]

Is there someone besides Medievil who uses Telmisartan for life extension purposes ?
Ways of taking it (not having hypertension) ?

[brunotto]

Nice effect of telmisartan on prostate (given the incidence of prostate cancer this is not to undervalue)

Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.


Source

Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. sattak@med.nagoya-cu.ac.jp.

Abstract

BACKGROUND:

With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression.
METHODS:

Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells.
RESULTS:

We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control.
CONCLUSION:

These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Prostate © 2012 Wiley Periodicals, Inc.

http://www.ncbi.nlm....pubmed/22430461

[brunotto]

<sub>Telmisartan exerts renoprotective actions via peroxisome proliferator-activated receptor-γ/hepatocyte growth factor pathway independent of angiotensin II type 1 receptor blockade.


Source

Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.

Abstract

Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-γ (PPARγ), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPARγ activation in the renal protective actions of telmisartan using Ang II type 1 receptor-deficient mice. Renal injury was induced in Ang II type 1 receptor-deficient mice by producing unilateral ureteral obstruction, which exhibited severe renal interstitial fibrosis and inflammation. In these mice, telmisartan prevented hydronephrosis induced by unilateral ureteral obstruction more strongly than did losartan. Importantly, the prevention of renal atrophy and fibrosis by telmisartan was significantly attenuated by GW9662, a PPARγ antagonist. Interestingly, the downstream effector of PPARγ activation by telmisartan is hepatocyte growth factor (HGF), a well-known antifibrotic factor, because renal HGF expression was significantly increased by telmisartan, and a neutralizing antibody against HGF diminished the renal protective action of telmisartan. These beneficial changes by telmisartan were associated with a decrease in the expression of transforming growth factor-β1 and other proinflammatory and profibrotic cytokine genes through PPARγ/HGF activation. Our findings provide evidence of organ protective actions of telmisartan through the PPARγ/HGF pathway, independent of Ang II type 1 receptor blockade. Further development of the next generation of Ang II type 1 receptor blockers with added organ protective actions, such as PPARγ activation, might provide new beneficial drugs to treat renal and cardiovascular diseases.</sub>

http://www.ncbi.nlm....pubmed/22252391

[brunotto]

Protective for prostate cancer but not for all cancers... so it's best suited for males.

Risk of cancer associated with the use of angiotensin II-receptor blockers.


Source

School of Pharmacy, Wingate University, 515 North Main Street, Wingate, NC 28174, USA. jolin@wingate.edu

Abstract

PURPOSE:

The proposed mechanism by which angiotensin II and angiotensin II-receptor blockers (ARBs) may influence the risk of cancer and the literature describing a possible causal relationship between ARB use and specific types of cancers are reviewed.
SUMMARY:

A number of cell-signaling pathways have been identified to establish a relationship between angiotensin II and cancer. Preclinical data support agonism of the angiotensin type-1 receptor by angiotensin II and unopposed stimulation of the angiotensin type-2 receptor as possible causes of proliferative and angiogenic processes. Results from a large meta-analysis suggested that ARB use is associated with a modest increase in risk of new cancer incidence. The publication of that meta-analysis led to subsequent large population analyses. A comprehensive literature review was conducted to identify studies evaluating the relationships among angiotensin II, ARBs, cancer, and malignancy. Preclinical studies evaluating the effects of angiotensin II and ARBs on proliferation and angiogenesis were selected to review how the renin-angiotensin system is involved in cellular proliferation and growth. Human studies evaluating the role of ARBs in specific types of cancer were also analyzed. The literature review found limited patient-specific data in humans to support the association. The Food and Drug Administration has concluded that there is no evidence of an increased risk of cancer with ARBs.
CONCLUSION:

At this time there is insufficient evidence to conclude that ARBs increase the risk of cancer. Blockade of the angiotensin system through both AT(1) and AT(2) receptors may have a protective effect against malignancy.

[brunotto]

Strongly strongly anthi-atherogenic...

Telmisartan prevents VCAM-1 induction and monocytic cell adhesion to endothelium exposed to non-uniform shear stress and TNF-α

BACKGROUND:

Atherosclerotic plaques develop at arterial regions subjected to non-uniform shear stress, and are initiated by increased leukocyte-endothelial interactions. Here we applied the in vitro model of arterial bifurcations to investigate whether telmisartan, an anti-inflammatory angiotensin II receptor blocker with PPAR-gamma activating ability, prevents monocyte recruitment by endothelium.
METHODS:

Human umbilical vein endothelial cells (ECs) were exposed to 18 h non-uniform shear stress in bifurcating flow-through slides, followed by 2 h stimulation with 2.5 ng/mL TNF-alpha. During flow, cells were treated with telmisartan. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Adherent THP-1 monocytes were quantified by light microscopy. Endothelial protein expression was determined by immunofluorescence.
RESULTS:

Non-uniform shear stress in combination with TNF-alpha dramatically induced monocytic cell recruitment by endothelial cells. In cells treated with telmisartan (0.5-2.5 μmol/L) during exposure to non-uniform shear stress, dose-dependent inhibition of monocytic cell adhesion was observed, with about 45% reduction at 1 μmol/L. This effect was mediated by a significant reduction of endothelial VCAM-1 expression. On the contrary, the induction of E-selectin by TNF-alpha in ECs exposed to non-uniform shear stress was not affected by telmisartan. The inhibitory effect of telmisartan on monocytic cell recruitment and VCAM-1 induction was prevented in the presence of the PPAR-gamma antagonist GW9662.
CONCLUSIONS:

Treatment with telmisartan decreases the TNF-α-induced recruitment of monocytic cells and endothelial expression of VCAM-1 in regions of non-uniform shear stress in vitro. This mechanism can contribute to the beneficial pleiotropic effects of telmisartan in atherosclerosis-prone arterial regions.

http://www.ncbi.nlm....pubmed/21876235

Edited by brunotto, 13 April 2012 - 11:50 AM.

[brunotto]

Telmisartan exerts antiatherosclerotic effects by activating peroxisome proliferator-activated receptor-γ in macrophages

OBJECTIVE:

Telmisartan, an angiotensin type I receptor blocker (ARB), protects against the progression of atherosclerosis. Here, we investigated the molecular basis of the antiatherosclerotic effects of telmisartan in macrophages and apolipoprotein E-deficient mice.
METHODS AND RESULTS:

In macrophages, telmisartan increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and PPAR ligand-binding activity. In contrast, 3 other ARBs, losartan, valsartan, and olmesartan, did not affect PPARγ activity. Interestingly, high doses of telmisartan activated PPARα in macrophages. Telmisartan induced the mRNA expression of CD36 and ATP-binding cassette transporters A1 and G1 (ABCA1/G1), and these effects were abrogated by PPARγ small interfering RNA. Telmisartan, but not other ARBs, inhibited lipopolysaccharide-induced mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α, and these effects were abrogated by PPARγ small interfering RNA. Moreover, telmisartan suppressed oxidized low-density lipoprotein-induced macrophage proliferation through PPARγ activation. In apolipoprotein E(-/-) mice, telmisartan increased the mRNA expression of ABCA1 and ABCG1, decreased atherosclerotic lesion size, decreased the number of proliferative macrophages in the lesion, and suppressed MCP-1 and tumor necrosis factor-α mRNA expression in the aorta.
CONCLUSION:

Telmisartan induced ABCA1/ABCG1 expression and suppressed MCP-1 expression and macrophage proliferation by activating PPARγ. These effects may induce antiatherogenic effects in hypertensive patients

http://www.ncbi.nlm....pubmed/21474824

Edited by brunotto, 13 April 2012 - 12:00 PM.

[brunotto]

Telmisartan Enhances Mitochondrial Biogenesis and Protects From Endothelial Cell Damage Through Peroxisome Proliferator-Activated Receptor-Independent Pathways


Background Mitochondrial dysfunction in endothelial cells (EC) might be involved in atherogenesis. Telmisartan (TELMI), which has peroxisome proliferator-activated receptor (PPAR)- activating properties, has been shown to reduce cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function in human coronary artery endothelial cells (HCAEC).

Methods and Results Pretreatment of HCAEC with 10µM TELMI preserved the mitochondrial function from H₂O₂ exposure (1.0mM, 60min) evaluated by mitochondrial nicotinamide adenine dinucleotide (NADH) levels (NADH: 1.3±0.2 fold greater than vehicle, n=6, p<0.01), and also reduced apoptotic annexin V positive EC induced by H₂O₂ (100µM, 30min) (% apoptosis EC: vehicle 38.3±3.1%, TELMI 26.0±2.3, n=6, p<0.01). TELMI increased EC mitochondrial number as assessed by fluorescence intensity of MitoTracker Green (vehicle 17.5±0.7, TELMI 21.3±2.1, n=6, p<0.01) and enhanced EC mitochondrial function as assessed by colorimetric NADH assay, in a time and concentration dependent manner (0–48 hours, 0.1–10µM, up to 1.9±0.1 fold, n=7, p<0.01), but other sartans did not have the similar effects. In senescent HCAEC at the 16^th passage, TELMI inhibited the appearance of giant EC (vehicle 44.3±5.2/field; TELMI 0.8±1.0, n=6, p<0.01). TELMI treatment significantly enhanced EC tube formation (tube length: 4.1±0.4 fold greater than vehicle, n=5, p<0.01), and we observed significant increases in mRNA expression levels of eNOS, VEGFA, mitochondrial transcription factor A, and Sirt1 in HCAEC after 48 hours TELMI treatment (1.3±0.2, 2.0±0.5, 1.2±0.04, 1.3±0.2 fold, respectively, all p<0.05). To determine the possible involvement of PPAR pathway, we knocked down PPAR with siRNA and inhibited PPAR-mediated signaling by selective PPAR blockers; GW9662 and T0070907. These two strategies did not affect the increased mitochondrial NADH levels induced by TELMI. Consistently, GW1929, a selective PPAR agonist, did not alter mitochondrial function in HCAEC.

Conclusion TELMI upregulates mitochondrial function in human EC through PPAR independent signaling mechanisms. TELMI could exhibit anti-atherogenic effects through improving mitochondrial dysfunction in EC.

http://circ.ahajourn...Abstracts/S1039

[MarcD]

I'm taking Valsartan (160mg) for at least a year. Should I switch to Telmisartan?

[tunt01]

I'm taking Valsartan (160mg) for at least a year. Should I switch to Telmisartan?

Yes. I personally think 10-50%+ of the US population should be on some form of a Telmisartan (with dosing as low as 4-5mg/day).

[tunt01]

RE:  Telmisartan / ARB Lung Cancer risk from the other thread.

u

 

 

 

Dispute Flares Inside FDA Over Safety of Popular Blood-Pressure Drugs

 

By 

THOMAS M. BURTON

May 30, 2013 10:35 p.m. ET

The top-selling class of blood-pressure drugs is under attack from an unusual source: a senior regulator at the Food and Drug Administration.

Bucking his bosses, Thomas A. Marciniak is seeking stronger warnings about the drugs known as angiotensin receptor blockers, or ARBs, according to internal documents reviewed by The Wall Street Journal.

The drugs, which are taken by millions of people and generated $7.6 billion in U.S. sales in 2012, may be linked to higher cancer rates, Dr. Marciniak argues, a view shared by some outside doctors. Top FDA officials say evidence doesn't support a link.

The debate over ARBs highlights the question of whether the U.S. drug-safety agency devotes enough effort to examining the safety of long-marketed blockbusters as it focuses on new drugs. In a rare rebellion by an FDA reviewer, Dr. Marciniak has clashed with his bosses over his desire to spend time on ARB safety, instead of just on new-drug applications.

Ellis Unger, chief of the drug-evaluation division that includes Dr. Marciniak, called the complaints a "diversion," and said in an interview, "We have no reason to tell the public anything new."

ARBs on the market in the U.S. include Novartis AG's Diovan, Daiichi Sankyo Co.'s Benicar, Merck & Co.'s Cozaar, Boehringer Ingelheim GmbH's Micardis; Avapro, fromSanofi SA and Bristol-Myers Squibb Co.; and AstraZeneca PLC's Atacand. Patients take these medicines daily to avoid heart attack, stroke and heart failure.

ENLARGE

 

In a 2010 study published in Lancet Oncology, Ilke Sipahi and colleagues at University Hospitals in Cleveland looked at five studies involving 68,402 patients and found that people taking ARBs had an 11% greater risk of new cancer overall and a 25% greater risk of new lung cancer, compared with patients who didn't get the drugs.

But within a year, the FDA gave the all-clear signal, saying its own analysis found "no increase in risk" from taking ARBs. Europe's drug regulator also dismissed the cancer concerns.

Dr. Marciniak wasn't persuaded. In its analysis, the FDA combined different studies to look at more patients, multiplying its statistical power to find possible side effects from the drugs, a technique called meta-analysis. If the original studies have flaws, however, meta-analyses can simply compound the problem, researchers say.

That is what happened to the FDA, says Dr. Marciniak, who warned others in the agency that taking results tabulated by companies was likely to produce unreliable results: "Garbage in, garbage out," he wrote.

Among other things, Dr. Marciniak said in an internal analysis viewed by the Journal that the FDA meta-analysis didn't count cases of "lung carcinomas" as lung cancers, which they are.

While such vocal dissent by FDA reviewers is rare, internal disputes about drugs or medical devices have occasionally arisen. In 2008, nine employees in the FDA's device division wrote to members of Congress saying the division's leaders were ignoring safety issues when approving devices.

After the FDA's 2011 verdict dismissing cancer concerns about ARBs, Dr. Marciniak decided to go through the raw data of the drug studies, patient by patient. By this March, he had concluded that lung-cancer risk increased by about 24% in ARB patients, compared with patients taking a placebo or other drugs, a figure that he said was statistically significant. He found that in 10 of the 11 studies he examined, there were more lung cancer cases in the ARB-treated patients than in the control group.

He sent a memo to senior FDA officials, saying: "The FDA needs to inform patients and physicians about the ARB lung-cancer risks. The FDA must act now."

Dr. Unger, the FDA division chief, said in the interview that he didn't agree. He said Dr. Marciniak's use of raw data from patients could include as cancers some patient-reported ailments that doctors might not agree are cancers, making the FDA's own research more credible.

Daiichi-Sankyo, Merck, Sanofi and Bristol-Myers said they haven't seen Dr. Marciniak's data and couldn't comment. Novartis said it did an "initial analysis" of studies of its Diovan and found "no increased risk." Other drug makers didn't respond to requests for comment.

Some of the drugs are known generically as valsartan, olmesartan, losartan, telmisartan, irbesartan and candesartan.

Dr. Marciniak's analysis didn't include data from trials on some ARB drugs, including Benicar, but he concluded "that the increased incidence of lung cancers with ARB use is likely a class effect of ARBs" and that it would be "inappropriate" to classify specific ARBs as safe due to a "lack of adequate studies."

Opinion is divided among outside doctors familiar with the ARB studies. "I have no doubt that ARBs increase cancer risk," Dr. Sipahi, an author of the 2010 study, told The Wall Street Journal.

Cleveland Clinic cardiologist Steven Nissen, a frequent critic of the FDA, said the FDA "has a huge advantage over academic researchers, of having access to patient-level data" that it hasn't fully examined. "Until I see such a rigorous analysis, I remain concerned about the ARB cancer problems," he said.

Eric J. Topol, a cardiologist and chief academic officer at Scripps Health in La Jolla, Calif., said, "My impression is there isn't a relationship between ARBs and cancer, but there could be one with a low frequency. It's not something easily detectable."

Dr. Marciniak specialized in cancer during his residency at the Mayo Clinic and spent a decade at the National Cancer Institute before coming to the FDA.

The debate he has sparked over ARBs has been accompanied by a dispute with his boss over how Dr. Marciniak spent his time.

Writing to Dr. Marciniak last August, Dr. Unger discouraged a safety investigation of the ARB drugs. "This would represent a lot of man-hours, so I have to assume that there is a paucity of work in the [cardio-renal] division at this point," he wrote, "or that you will be doing this mostly after-hours."

Dr. Marciniak responded on Aug. 31. "You are faced with a serious, unanswered question of whether drugs taken by millions of Americans increase cancer rates, and you're concerned about 62 to 93 man-days for my entire plan?" he asked. He went ahead with his inquiry.

In another email exchange, Dr. Unger wrote that even if Dr. Marciniak "found an increased cancer risk of [30%], I doubt there would be much enthusiasm for basing a regulatory decision (labeling or otherwise) on that."

Dr. Marciniak shot back, "Astonishingly, you would ignore a 30% increase in cancer rates for any drug, much less drugs for which there are many alternatives?"

Dr. Unger said in the interview he meant that if the 30% cancer increase weren't convincingly proven, the FDA wouldn't act.

Write to Thomas M. Burton at tom.burton@wsj.com

 

[Skyguy2005]

http://www.ncbi.nlm....pubmed/16776966

 

"

[Extract of Ginkgo biloba and quercetin inhibit angiotensin-II induced hypertrophy in cultured neonatal rat cardiomyocytes].

[Article in Chinese]

Wu Y¹, Gu YM.

Author information

Abstract

OBJECTIVE:

To investigate the effect and related mechanisms of extract of ginkgo biloba (EGb) and quercetin (Que) on angiotensin II (AngII) induced hypertrophy in the primary cultured neonatal rat cardiomyocytes.

METHODS:

Primary cultured neonatal rat cardiomyocytes were treated with placebo (control), AngII (10(-6) mol/L), AngII + EGb (40 microg/ml), AngII + Que (4 microg/ml), AngII + captopril (10(-5) mol/L) and AngII + DPI [diphenylene iodonium chloride, NADPH inhibitor (10 micromol/L)] respectively. Total protein content of cardiomyocytes, cardiomyocytes size, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured. The expression of phospho-Extracellular-signal regulated kinase 1/2, phospho-c-Jun N-terminal kinase and phospho-P38 were detected by Western blot.

RESULTS:

The total protein content and cell size of cardiomyocytes increased significantly in AngII treated cells and these effects could be blocked by EGb and Que. EGb and Que also enhanced the SOD activity and reduced the production of MDA. AngII significantly activated ERK1/2, JNK and P38 expressions and only JNK activation could be inhibited by Que and DPI.

CONCLUSION:

EGb and Que can inhibit AngII-induced cardiomyocyte hypertrophy through a ROS-dependent pathway. Que could also block the JNK activation induced by AngII.

"