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Science behind olmesartan (Benicar)

Patients on the Marshall Protocol (MP) take olmesartan (Benicar), a drug whose actions are well known, every six hours. A growing body of research supports the use of olmesartan as a part of a curative therapy for chronic disease. In general, olmesartan tends to be prescribed for its antihypertensive properties due to the fact that is an angiotensin receptor blocker.

For the purposes of the MP, olmesartan has two primary actions: it reduces inflammation by blocking the Nuclear Factor-kappaB cytokine pathway and it is an agonist of the Vitamin D Receptor (VDR). As a VDR agonist, olmesartan activates the innate immune response. Research supports the safety of the doses used by MP patients. Olmesartan has minimal interactions with other drugs and is one of the safest drugs on the market.

Safety of olmesartan

Main article: Olmesartan safety

Ample research supports the fact that olmesartan is one of the safest and has the most gentle side effects profiles of almost any drug on the market.

Potent anti-inflammatory

Olmesartan is classified as an Angiotensin II Receptor Blocking (ARB) drug. When olmesartan binds and blocks the Angiotensin Receptor, it prevents fibrotic tissue from forming and decreases levels of Nuclear Factor Kappa B, a protein that stimulates the release of inflammatory cytokines - proteins that generate pain and fatigue. These cytokines include interferon gamma and TNF-alpha. The drop in cytokines results in less inflammation and oxidative stress. As inflammation drops, the antibiotics can also perfuse the tissues more effectively.

Working at a higher level than the cytokines or chemokines, olmesartan stops TNF-alpha from being released from the macrophages. It also blocks the other cytokines released during an inflammatory reaction. It does not bind to just any TNF-alpha floating around so it doesn't interfere with the function of the immune system like the TNF-antagonists such as Remicade and Enbrel.

Olmesartan has both an affinity for the Vitamin D Receptor and a molecular structure which lends itself to easy activation of the receptor. The low level of interaction olmesartan has with the other nuclear receptors makes it even better than 1,25-D, the endogenous or native nuclear receptor for the VDR.

The olmesartan can make patients feel better, allowing them to more easily tolerate the increase in symptoms generated by bacterial die-off. In fact, if patients feel that their immunopathology is too strong, they can take extra olmesartan in order to help palliate the inflammatory response.

Though described below as an agent which stimulates the immune response, olmesartan may also reduce inflammation through activating the VDR:

The involvement of Vitamin D/VDR in anti-inflammation and anti-infection represents a newly identified and highly significant activity for VDR.

Jun Sun 1

Vitamin D Receptor agonist

The VDR has been praised as an attractive target for modulating inflammation in autoimmune disease.

Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced pro-tolerogenic activities…. These mechanisms of action can explain some of the immunoregulatory properties of VDR agonists in the treatment of Th1-mediated autoimmune diseases, but may also represent a physiologic element in the VDR-mediated regulation of innate and adaptive immune responses.

L. Adorini, from paper “Intervention in autoimmunity: the potential of vitamin D receptor agonists” 2

Olmesartan's action as VDR agonist makes it a critical component of the Marshall Protocol. This is evident in patients taking MP antibiotics who do not experience immunopathology until they take olmesartan. For this reason, olmesartan meets the definition of an antibacterial.

To us, olmesartan is not a “medication.” It is a method of turning-on your body’s Vitamin D Receptor. This is a key part of the immune system, and transcribes over 1,000 genes which affect body processes from calcium homeostasis to cancer metastasis.

Trevor Marshall, PhD

The ribosome blockades initiated by the Marshall Protocol antibiotics weaken the Th1 pathogens but are unable to actually kill the pathogens. For this reasons, patients on the MP take olmesartan, which activates the innate immune response. In this respect, olmesartan is distinct from other ARBs such as telmisartan, which has been shown to be a strong VDR antagonist.3 Molecular modeling has revealed that olmesartan binds and activates the Vitamin D Receptor among others. This action is validated by in silico data.4

Because the VDR itself is in constant motion and it is affected by the forces on the VDR from adjacent molecules, olmesartan has an ability to stay in that binding pocket for only a few hours before it is either ejected, or the VDR itself is pulled apart by outside forces.

Olmesartan docks into several different cellular receptors to provide a variety of actions. Thus far, these actions appear to be beneficial.

The Vitamin D Receptor is relatively insensitive to changes in concentration of any given competing ligands (e.g. olmesartan). At some points in the curve, it takes a five-fold change in concentration to increase the amount of the drug docking at the VDR by only 10%.

Other ARBs also bind the same nuclear receptors as olmesartan but fail to activate them at the correct level.

Pharmacodynamics

Like other ligands, olmesartan binds to nuclear receptors above a certain concentration. For this reason MP patients do not use time-release tablets of olmesartan. The affinity for the VDR of olmesartan is low, which explains the need for a higher concentration. Although Benicar closes off the Angiotensin II Receptor (AT2R) at below 20mg/day, MP patients need a much higher dose to properly activate the VDR. Thus the displacement of ligands from the VDR is easier to control by dosage than its blockade of the AT2R.

The pharmacodynamic half life of Benicar is not the same as the pharmacokinetic half-life because there is a disassociation constant involved. That means olmesartan loses its affinity for the VDR more quickly than it decays from the bloodstream. So the effective useful lifetime is 6-8 hours rather than the approximately 13 hours of the plasma half-life.

Incidentally, this discrepancy between olmesartan's effect on the VDR and the A-II receptor is why Marshall Protocol patients are advised to avoid sustained-release versions of Benicar.

The unbound Vitamin D Receptor degrades quickly

Peleg and Nguyen observed that in the absence of an agonist such as 1,25-D, the VDR suffers from polyubiquitination and proteasome-mediated degradation in relatively short course – in the sub-4 hour region, and certainly in the sub-24hour region.5 This study offers some support for why sick patients need more frequent dosing than their healthy counterparts.

Recent published reports on the dynamics of VDR recruitment to promoters of target genes in cultured cells demonstrate that the time course for maximal recruitment of the 1,25D3–VDR complex to the promoter of the CYP24 gene in osteoblasts is 3 h, whereas the time course for maximal recruitment of the VDR to the promoter of this gene in IECs is only 30 min [Kim et al., 2005; Meyer et al., 2006].

S. Peleg and C. V. Nguyen 6

Infected cells have VDRs with a shorter life span

Some intracellular infections (notably Shigella), upregulate activity of the caspases, which are proteases that cleave the VDR.7 When the VDR is broken apart by the caspases, it is highly likely that any ligands bound to it (such as olmesartan) would stay bound to the fragments of the protein. Therefore, a VDR agonist would be effective over shorter periods of time in patients with infected cells.

Bacterial products down-regulate the expression of the VDR

Lipopolysaccharide (LPS), a part of the bacterial cell wall, reduces VDR protein levels 8

Pregnane X Receptor (PXR) agonist

Olmesartan docked in the PXR superimposed on a PXR agonist, SR12813. This emulation by Trevor Marshall, PhD suggests that olmesartan activates the PXR.

Many patients who have begun the MP find that their levels of 1,25-D drop dramatically in the first weeks. This can be explained by pointing to olmesartan's ability to activate both the VDR (discussed previously) and, quite possibly, the Pregnane X Nuclear Receptor (PXR).

Based on [an in silico] model published more recently I would today opine that Benicar is more likely a PXR agonist at this point, as it is active in the same PXR residues as the known agonist SR12813. The gene SR12813 is confirmed to transcribe is that for CYP3A4 [an enzyme which breaks down 1,25-D].

Trevor Marshall, PhD

As discussed further here, 1,25-D tends to be higher than normal in patients with chronic disease and high levels of 1,25-D interfere with the actions of other nuclear receptors – which themselves produce antimicrobial peptides. Therefore, a reduction in 1,25-D can contribute to a certain amount of symptom relief.

Olmesartan may also exert its palliative effects through binding other key receptors.

Other beneficial effects

Examples of some of the documented protective effects of ARBs include the ability to:

  • decrease the incidence and progression of Alzheimer's disease and dementia9
  • prevent migraines10
  • inhibit liver fibrosis and aid liver healing11
  • reduce insulin resistance in rats12
  • protect the mitochondria from age-associated damage from oxidation13
  • reduce liver fibrosis14
  • treatment of anxiety and stress-related disorders15
  • reduce oxidative damage16 and limit aging17

Cardiovascular disease

Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS).

R. Preston Mason18

Olmesartan and other ARBs have been used to block various bad effects of Angiotensin II, including heart failure. In this regard, olmesartan has been shown to:

  • protect the heart from damage from inflammation in myocarditis19
  • ameliorate acute experimental autoimmune myocarditis, in rats, suppressing cytotoxic myocardial injury 20
  • prevent acute left ventricular dysfunction21
  • lower C-reactive protein, one of the acute phase proteins that increase during systemic inflammation22
  • act as an antiarrhythmic23
  • block the production of Angiotensin II, thus improving mortality rates in heart failure patients24
  • reduces the volume of atherosclerotic plaques25 26

Olmesartan has also been shown to mildly reduce the risk of stroke in people at high risk for strokes (cerebrovascular events).27

Pharmacotherapy targeting the renin-angiotensin system [the mechanism of the ARBs] is one of the most effective means of reducing hypertension and cardiovascular morbidity.28 29

Nien-Chen Li et al.30

Kidney disease

A number of studies have found that olmesartan and other ARBs possess various ways of protecting the kidneys from the effects of inflammation and cytokine damage.

Historical note: early insights into the necessity of frequent ARB dosing

In August 2002, Trevor Marshall and Frances (Liz) Marshall published a NetPrint about valsartan (Diovan), in which they reported that the once daily dosing of the ARB caused psychedelic dreams and psychotic events in two sarcoidosis patients. On the theory that these symptoms were caused by changes in plasma concentration, the frequency of the dosing of ARB was increased, which ended up reducing symptoms of disease including psychedelic dreams. This early insight into ARBs anti-inflammatory effects led Marshall to conclude that for an ARB to provide symptomatic relief, it was necessary to use more frequent dosing than typical. Marshall would later go on to recommend frequent dosing of another ARB, olmesartan, as a part of the Marshall Protocol.

Related publications and presentations

Notes and comments

  • work in how low blood pressure is not caused by olmesartan
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Wow. This paper touches everything. VDR impact on DNA repair, Naltrexone actions, VDR downregulates RAS. Just wow…

..Trevor.. http://www.ncbi.nlm.nih.gov/pubmed/22763121 Opiates have been reported to induce T cell loss. We evaluated the role of vitamin D receptor (VDR) and the activation of the renin angiotensin system (RAS) in morphine-induced T cell loss. Morphine treated human T cells displayed down regulation of VDR and the activation of the RAS. On the other hand, a VDR agonist (VDA, EB1098) enhanced T cell VDR expression both under basal and morphine-stimulated states. Since T cells with silenced VDR displayed the activation of the RAS, whereas, activation of the VDR was associated with down regulation of the RAS, it appears that morphine-induced T cell RAS activation was dependent on the VDR status. Morphine enhanced ROS generation in a dose dependent manner. Naltrexone (an opiate receptor antagonist) inhibited morphine-induced ROS generation and thus, suggested the role of opiate receptors in T cell ROS generation. The activation of VDR as well as blockade of Ang II (by losartan, an AT1 receptor blocker) also inhibited morphine-induced T cell ROS generation. Morphine not only induced double strand breaks (DSBs) in T cells but also attenuated DNA repair response; whereas, activation of VDR not only inhibited morphine-induced DSBs but also enhanced DNA repair. Morphine promoted T cell apoptosis; however, this effect of morphine was inhibited by blockade of opiate receptors, activation of the VDR, and blockade of the RAS. These findings indicate that morphine-induced T cell apoptosis is mediated through ROS generation in response to morphine-induced down regulation of VDR and associated activation of the RAS.

Olmesartan medoxomil in elderly patients with essential or isolated systolic hypertension : efficacy and safety data from clinical trials. Heagerty AM, Mallion JM Olmesartan medoxomil in elderly patients with essential or isolated systolic hypertension : efficacy and safety data from clinical trials. Drugs Aging. 2009;26:61-76.

See above:

The pharmacodynamic half life of Benicar is not the same as the pharmacokinetic half-life because there is a disassociation constant involved. That means olmesartan loses its affinity for the VDR more quickly than it decays from the bloodstream. So the effective useful lifetime is 6-8 hours rather than the approximately 13 hours of the plasma half-life.

I think this could use some more elaboration to be more understandable and unambiguous. For instance: is this to say that low doses of olmesartan in the bloodstream is different from larger doses, i.e. that the as olmesartan goes down to, say, 50 % of it's peak level after a 40 mg dose, the ability to bind the VDR has fallen by much more than 50 %? And is this a general disassociation mechanism, or is it specific for olmesartan and VDR?

Removed because it is too speculative:

In other circumstances, the reduction in inflammation that olmesartan promotes allows better tissue perfusion of the antibiotics and, as a consequence, greater immunopathology. Without an olmesartan blockade it is difficult to get enough antibiotic into the tissues to kill off all the recalcitrant pathogens. Also, the production of antimicrobial peptides due to VDR-activation by olmesartan (see below) may also increase bacterial killing and outweigh the antiinflammatory effects of olmesartan.

J Eur Acad Dermatol Venereol. 2010 Aug;24(8):977-8. Epub 2009 Dec 15. Porphyria cutanea tarda induced by olmesartan.31

Mas-Vidal A, Coto-Segura P, García-Varona A, Santos-Juanes J. PMID: 20015057

Olmesartan medoxomil ameliorates sciatic nerve regeneration in diabetic rats. Nakamura H, Domon Y, Inoue T, Arakawa N, Yokoyama T.

Biological Research Laboratories II, R&D Division Daiichi-Sankyo Co. Ltd., Tokyo, Japan. nakamura.hiroaki.xn@daiichisankyo.co.jp

To evaluate the effect of angiotensin II type1 receptor blocker on nerve regeneration delay in diabetic rats, nerve regeneration was monitored by a pinch test on the crushed sciatic nerves of streptozotocin-induced diabetic rats. Nerve regeneration was significantly delayed in diabetic rats and was partly ameliorated by treatment with olmesartan medoxomil (3 mg/kg/day, orally). In the ipsilateral dorsal root ganglia, the mRNA level of insulin-like growth factor-1 and ciliary neurotrophic factor (CNTF) was downregulated, whereas the mRNA level of neurotrophin-3 and CNTF receptor was upregulated. Olmesartan medoxomil significantly enhanced the CNTF expression. These results showed that angiotensin II type1 receptor blocker treatment is effective on nerve regeneration delay in diabetic animals and may provide an effective therapy for clinical diabetic neuropathy.

PMID: 19786922 [PubMed - in process]

Angiotensin-II behaves as an endogenous pro-inflammatory molecule.32

Since ACE is present in many tissues, this suggests that angiotensin-II may play a significant role in atherosclerosis, congestive cardiac failure, stroke, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, psoriasis, atopic and non-atopic dermatitis, eczema, several acute and chronic inflammatory diseases, and cancer, conditions in which inflammation is an aetiopathogenic factor. Thus, ACE inhibitors and/or angiotensin-II receptor blockers could be of benefit in these conditions.

Russ, I can explain to you how Olmesartan works, at least to the current limits of knowledge. How you negotiate with your Doctor about the dosage he is willing to prescribe is quite another thing. As you point out, choosing the best compromise is often difficult. Additionally, our knowledge has increased tremendously this past year.

At low doses, Olmesartan blocks the Angiotensin-II Type 1 receptor. Bane can send you a paper showing how that inhibits NuclearFactor-kappaB expression of cytokines, and reduces the inflammation and symptoms of Th1 disease, or you can [url=http://clinmed.netprints.org/cgi/content/full/2003010001]wadethrough my old 2002 paper[/url], which discusses it (at the “Angiotensin Hypothesis” section).

At intermediate doses, Olmesartan incrementally displaces other ligands from the VDR, and activates the innate immune system, reversing many of the disease processes resulting from the microbes (the intraphagocytic metagenomic microbiota).

At more frequent dosing intervals, Olmesartan also starts to affect other receptors, including the CB1 receptor, for which it is an agonist. The overall effect of these is additional palliation. With Olmesartan Medoxomil there is little advantage increasing the frequency of dosing beyond every 3 hours, as the drug is absorbed slowly by the body. Indeed, it takes 1-2 hours for the Olmesartan from an Olmesartan Medoxomil tablet to build to a decent level in the bloodstream on an empty stomach, and an average 4.5 hours on a full stomach (FDA data).

Thus the interval we suggest as providing optimal palliation is every 3-4 hours. That is what we suggest in the Stage 5 document. We have tightened the general protocol recommendations over the past several years to a maximum dosing interval no longer than 6 hours. The historical 8 hour interval leaves the patient suffering much more than they need to (from ImmunoPathology).

Because Olmesartan Medoxomil is [url=http://www.ncbi.nlm.nih.gov/pubmed/20177059]typicallymetabolized by rare enzymes[/url] in the GI tract the process of absorption is slow. A small dose of sublingual Olmesartan Medoxomil gets the drug to the bloodstream quickly (15-30 minutes), where it is metabolised by different enzymes than in the gut. Sublingual administration is different from oral (swallowing) administration - oral administration must be continued as it leads to more certain system-wide actions than sublingual, which primarily helps the Brain.

Your physician receives his on-going in-sevice training from the Drug Company salespeople who call on him every week. If your Physician is constraining your dosage of Olmesartan it is not because of uncertainties in the science, and it is certainly not because large doses, or frequent dosing, (which are two different things) are harmful. Olmesartan is one of the safest drugs in the Pharmacopoeia, and the FDA has set no unsafe level, no maximum dosage. IF Doc is uncertain about prescribing you adequate Olmesartan it is because the manufacturer's salespeople have not been helping him understand the drug's actions. Indeed, they don't have a clue how it works. Nor do many of the researchers using it :)

I hope that helps :) ..Trevor..

On Mon, Jan 10, 2011 at 11:18 PM, Trevor Marshall wrote:

During the web seminar last Saturday I told members that, if they could not handle the IP from Olmesartan+Antibiotics, I am convinced they would continue to recover on Olmesartan alone – as long as they keep their 25-D in the therapeutic range and do not take drugs and supplements which interfere with the immune activity of the Olmesartan. I have come under some criticism for making this statement without having what some see as “adequate data.” So here is my reasoning.

First, it is clear that some of our members have been pushing their IP very hard indeed in the belief that this would speed their healing. I do not believe acceleration to be likely. I observe that everybody can handle a little bit of immunopathology without experiencing any noticeable symptoms. Reasonably healthy people, for example, do not get IP even when taking full doses of Olmesartan+mino+clindy. There seems to be a threshold between no noticeable IP, and IP, and it is this threshold I believe we should try to target. The cytokine storm from too much IP is likely to cause damage – how much? – probably not too much, but IMO this is an unwarranted risk.

Some of our members cannot handle the extra IP from adding antibiotics at all. Yet they are often discouraged from stopping antibiotics in order to control their IP. For example, the August CIR newsletter specifically stated:

[testimonial?] “Better on lower dose of Benicar and increased Mino - Susieq”

IMO our members deserve the best guidance we can provide on whether any particular therapy is going to lead to recovery in the long-term. Members can't afford to spin their wheels for several years only to find out they have been using a sub-optimal approach.

Since we have started to gather experience with Pure Olmesartan it is pretty obvious that it has a more profound effect than Olmesartan Medoxomil tablets. Further, this additional 'kick' doesn't seem to be dose-related, as lowering the dose does not help to control IP in the way that it does with the tablets. Several of my research colleagues have dropped back to using tablets, as the pure formulation produces just too much IP. So what is happening here?

First, when we were testing the Pure Olmesartan using Impact Analytical's Nuclear Magnetic Resonance facility, I also got them to test both Sankyo and Cipla tablets. Neither tablet appeared to contain exactly what we expected. Indeed, the Cipla tablet seem to have a marginally different chemical formulation, an extra CH2 group which wasn't in the formula published by the FDA. Sankyo's tablets were frankly too impure to get accurate data from.

I have decided to get both tablets tested again, with a more accurate HETCOR analysis – just to make sure we understand all the variables in the clinical pattern we are seeing. However, my assessment at this time is that the Pure Olmesartan has a 'bigger kick' because it contains the 'right stuff' with very few impurities block the 'pure stuff' from some of the receptors it targets.

So when I opine that members can recover on Olmesartan alone, I am drawing on data with the Pure Olmesartan as well as from data with both major varieties of Olmesartan tablets. Going forward, after FDA approval of Pure Olmesartan, I see us able to target the pure stuff at people who are not very ill, especially those who have been many years on the MP and just need to 'clean up' the remaining microbiota. The Medoxomil tablets, or perhaps a slightly different pure molecular formula, can be used when IP from the pure stuff is just too great.

We know from the Road Back, and from other antibiotic-only therapies, that antibiotics alone do not induce long-term healing after people have become clinically ill with a Th1 condition. We also now have a better idea of the molecular mechanisms by which antibiotics affect the human body. Antibiotics are useful at the moment for increasing the overall level of IP, and for pulsing that IP in a 48 hr cycle. Once Pure Olmesartan becomes widely available, I do not see antibiotics as fulfilling any major ongoing role. I think they will be used intermittently, not as a fundamental core of therapy.

It is much easier to get Mainstream Medicine to accept a single-element therapy than one involving multiple drugs. Further, many deprecate the use of antibiotics, especially long-term antibiotics. We are making our job harder by continuing to suggest a rigid, formulaic, antibiotic-based-protocol.

Thus, it is my opinion that the best suggestion I can give is that Th1 disease can be treated with Olmesartan alone, and members can still expect to recover, albeit gradually :)

Sincerely

Trevor

The exact interaction between Olmesartan and VDR in-vivo is still not fully defined. It may well up-regulate both pathways. There is also olmesartan activity in the proteases which degrade VDR, and there may be other mechanisms as well :)

Trevor

Effect of olmesartan on oxidative stress in hypertensive patients. Mechanistic support to clinical trials derived evidence. Calò LA, Maso LD, Caielli P, Pagnin E, Fusaro M, Davis PA, Pessina AC. Source

Department of Clinical and Experimental Medicine,University of Padova, Italy.

Abstract

Abstract The role of oxidative stress in the pathophysiology of hypertension and target organ damage is widely recognized. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of the angiotensin II type 1 receptor blocker olmesartan on the mononuclear cell (PBMC) protein expression of major elements in the oxidative stress and vascular remodeling-related pathways, p22(phox) and HO-1, along with the phosphorylation state of ERK1/2 and plasma oxidized low-density lipoproteins (oxLDL). Twenty untreated essential hypertensive patients (range blood pressure: 142-156/94-98 mmHg) were treated with olmesartan medoxomil (20 mg/day for 6 months) and blood samples collected at baseline, 3 and 6 months for PBMC p22(phox) and HO-1 protein expression, phosphorylation state of ERK1/2 (western blot) and oxLDL level (ELISA) evaluations. Olmesartan normalized blood pressure since the third month (149 ± 4.7/94.88 ± 1.9 mmHg vs 137.89 ± 2.08/88.44 ± 2.0 at 3 months and vs 135.44 ± 2.18/85.78 ± 1.2 at 6 months, analysis of variance: p < 0.001). p22(phox) protein level declined at 3 months (7.10 ± 2.61 vs 9.32 ± 2.43 densitometric units (d.u.; p < 0.001), further declining at 6 months (4.55 ± 1.26 d.u., p < 0.001). HO-1 levels increased at 3 months (10.87 ± 1.92 vs 7.70 ± 0.71 d.u., p = 0.001) and remained elevated (11.11 ± 1.89 d.u., p = 0.001), without further increase at 6 months. Phosphorylated ERK1/2 declined at 3 months (3.94 ± 1.44 vs 5.62 ± 1.11 d.u., p = 0.001), further declining at 6 months (1.94 ± 0.87, p < 0.001). oxLDL significantly declined at 3 and 6 months. These results demonstrate that olmesartan inhibits oxidative stress. Given the involvement of oxidative stress and its signaling in atherogenesis, and the available evidence of olmesartan's vasoprotective, anti-inflammatory and antiatherosclerotic effects derived from clinical trials in humans, the results of our study provide a mechanistic rationale for the omelsartan's antioxidant and anti-inflammatory potential translation, in the long term, toward the antiatherosclerotic and antiremodeling effects reported on the clinical ground.

PMID: 21504378

This was an older post that was up for a couple of hours back in Feb 2010 but was inadvertendtly taken down. I never posted it again but think it is germane to this discussion. The use of ARBs is associated with a significant increase in the number of circulating endothelial progenitor cells (vascular stem cells). Of the ARBs, Olmesartan seems to be most effective in boosting circulating EPC's. More recent papers have explored the use of these cells in regressing atherosclerosis. As the health of the cardiovascular system is one of the biggest determinants of mamallian lifespan, I believe this concept has therepeutic relevance.

“olmesartan (n=9) significantly increased EPCs from 231+/-24 to 465+/-71 per high-power field (P<0.05)”

When I first read these papers, I was concerned that the increase in EPC's may be due to their inability to implant into the vascular architecture as ARB's reduce various adhesion molecules, but I came across a recent paper that explored this and it turns out that these are in fact competent EPC's. The downside is that these cells are associated with angiogenesis and the proliferation of existing tumors. This may be one of the reasons for the association of increased cancers while on ARB's. The MP cohort of course has a rather stark absence of cancer so there may be some CV renewal benefit without the associated increase in solid tumors. I believe the VDR transrepresses VEGF so it may offset the angiogenesis associated with this cell type.

———————————-

Interesting that you made this observation. This has been kicking around in my head for several months now after reading multiple papers related to this topic. Some ATI receptor blockers (including olmesartan) dramatically boost the quantity of circulating endothelial progenitor cells (vascular stem cells).

This first one is my favorite!

Angiotensin receptors as determinants of life span - 1/2010

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.

http://www.ncbi.nlm.nih.gov/pubmed/19763608?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=23

Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil

http://www.ncbi.nlm.nih.gov/pubmed/19436655?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=6

Endothelial dysfunction is the common link between cardiovascular disease risk factors and the earliest event in the cascade of incidents that results in target organ damage. Angiotensin II, the terminal pressor effector arm of the renin-angiotensin-aldosterone system, increases blood pressure (BP) by vasoconstriction and sodium and fluid retention, and has a pro-oxidative action that induces endothelial dysfunction and contributes to vascular remodeling. Angiotensin receptor blockers (ARBs) reduce BP and morbidity and mortality in patients with hypertension, ventricular hypertrophy, diabetes mellitus, and renal disease. Olmesartan medoxomil is a long-acting, well-tolerated, effective ARB that prevents or reverses endothelial dysfunction in animal models of atherosclerosis, hypertension, diabetes, nephropathy, and retinopathy. Olmesartan medoxomil, a prodrug of olmesartan approved for the treatment of hypertension, has been shown to ameliorate endothelial dysfunction in patients with hypertension or diabetes. In randomized studies, the drug reduces vascular inflammation and the volume of large atherosclerotic plaques, increases the number of regenerative endothelial progenitor cells in the peripheral circulation, improves endothelium-dependent relaxation, and restores the normal resistance vessel morphology. Importantly, the impact of olmesartan medoxomil on endothelial dysfunction is thought to be independent of BP lowering.

http://www.ncbi.nlm.nih.gov/pubmed/19193378?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=9

Telmisartan induces proliferation of human endothelial progenitor cells via PPARgamma-dependent PI3K/Akt pathway

OBJECTIVE: Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs. METHODS AND RESULTS: Human peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into methylcellulose medium with or without telmisartan. In the presence of telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and lectin and CD31, CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARgamma. In addition, we observed that specific inhibitors of phosphoinositide-3 kinase (PI3K) abolished telmisartan-stimulated increase of monocytic EPC-like cells and telmisartan induced phosphorylation of Akt. Furthermore, mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth inductive effects of telmisartan might be regulated by the PI3K/Akt and p21 signaling pathway. CONCLUSIONS: These findings suggest that telmisartan might contribute to endothelial integrity and vasculogenesis in ischemic regions by increasing numbers of EPCs.

The role of the renin-angiotensin-aldosterone system in cardiovascular progenitor cell function

Intervention in the RAAS (renin-angiotensin-aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type 1 receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1-7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factorsignalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1-7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. (Note: AT1-7 may be upregulated by VDR). Furthermore, aldosterone, bradykinin and Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type 1 receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.

Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists

The number of circulating endothelial progenitor cells (EPCs) correlates with endothelial dysfunction and cardiovascular risk in humans. We explored whether angiotensin II receptor antagonist therapy affects the number of regenerative EPCs in patients with type 2 diabetes. In a prospective double-blind parallel group study, we randomly treated 18 type 2 diabetics with olmesartan (40 mg) or placebo for 12 weeks. We analyzed circulating CD34+ hematopoietic progenitor cells (flow cytometry) and EPCs (in vitro assay) before and after therapy. We verified the results in a second open trial treating 20 type 2 diabetics with 300 mg of irbesartan for 12 weeks. The number of EPCs was significantly lower in diabetic patients as compared with 38 age-matched healthy subjects (210+/-10 versus 258+/-18 per high-power field; P<0.05), whereas there was no significant difference with respect to hematopoietic progenitor cells. Treatment with olmesartan (n=9) significantly increased EPCs from 231+/-24 to 465+/-71 per high-power field (P<0.05), but not hematopoietic progenitor cells. In contrast, placebo treatment (n=9) did not affect EPCs and hematopoietic progenitor cells. With irbesartan therapy, EPC number increased significantly from 196+/-15 to 300+/-23 per high-power field (P<0.05) already after 4 weeks of treatment. At the end of 12-week therapy, patients had 310+/-23 EPCs per high-power field (P<0.05 versus baseline). Angiotensin II receptor antagonists increase the number of regenerative EPCs in patients with type 2 diabetes mellitus. This action may be of therapeutic relevance contributing to their beneficial cardiovascular effects.

  • include the research on olmesartan's beneficial effects in the respective articles about diseases/symptoms

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