Angiotensin: more than just blood pressure.

Pathologically low blood pressure can lead to shock & death.  Angiotensin II is there to prevent that, but it does much more.  A bit non-sequiter, perhaps.

This is what I call teamwork: low blood pressure detected by kidneys –> secretes renin.  Angiotensinogen (liver) is cleaved by renin to Angiotensin I.  Angiotensin Converting Enzyme (lungs [among other tissues]) cleaves angiotensin I into angiotensin II.

RAAS

Angiotensin II increases blood volume and restores blood pressure.  Good if you’ve lost a ton of blood fighting a wild beast; not good if you’re an overweight pen pusher on potato chips.  ACE inhibitors reduce angiotensin II, lowering blood pressure.  ACE is present in lungs probably because it deactivates bradykinin.  ACE inhibitors prevent this which might contribute to one of their side effects, a persistent dry cough which makes these drugs intolerable for many.  One alternative is angiotensin II receptor 1 blockers, or “ARBs.”


If anyone in pharma reads my blog (doubtful, unless they are monitoring for people to polonium-laced blow-dart), this will be their favorite post because I think ARBs are an interesting class of drugs.

If diet and weight loss are inadequate, telmisartan might be the next best thing to manage hypertension in diabetics:  Telmisartan for the reduction of cardiovascular morbidity and mortality (Verdecchia et al., 2011) –> effective at reducing mortality in patients with diabetes.

Efficacy of RAS blockers on cardiovascular and renal outcomes in NIDDM (Cae & Cooper 2012)  –> reduces morbidity and slows progression of renal disease (both hypertension and diabetes contribute to [irreversible] kidney damage, and frequently occur together, which makes this endpoint particularly relevant).  Hyperglycemia should be managed via diet, of course, and ARBs would need to be tested in people following something other than a Western diet (although said people may not even need treatment in the first place) (just thinking out loud here.  Or typing/whatever.)

But enough about blood pressure (<– boring); on to the more interesting stuff:

It started here: Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice (Duchemin et al., 2013)

Then: Candesartan prevents impairment of recall caused by repeated stress in rats (Braszko et al., 2012)

And: Anti-stress and anxiolytic effects of [candesartan] (Saavedra et al., 2005)

[Candesartan] prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding (Saavedra et al., 2006)

[Candesartan] ameliorates brain inflammation (Benicky et al., 2011)   brain inflammation induced by chronic exposure to artificial lights causes depression-like symptoms (in mice) (probably humans, too)

Finally, a human study: Candesartan and cognitive decline in older patients with hypertension (Saxby et al., 2008)

And then there’s this: Angiotensin receptor blockers for bipolar disorder (de Gois et al., 2013)


No mechanistic stuff because, well, I have no idea how it works.  On one hand, it might seem obvious that stress & anxiety can raise blood pressure, so something that lowers stress & anxiety could lower blood pressure.  Candesartan appears to do both (cause <–> effect?).  There are two unique properties of candesartan to note: 1) it gets into the brain; and 2) it leads to increased levels of angiotensin II (which presumably can’t do much because candesartan blocks the receptor for angiotensin II).  Perhaps angiotensin II targets a different receptor?  ARBs might blunt angiotensin II-induced CRH secretion, leading to anxiolysis, stress-tolerance, and pro-cognitive effects (that speculation was made possible by a thread on Avant Labs’ Forum and a few posts by Jane Plain on CRH [eg, here & here]).

Oh yeah, ARBs also prevent cafeteria diet-induced weight gain, insulin resistance, and ovulatory dysfunction [in rats] (Sagae et al., 2013).  And are sympatholytic like bromocriptine (Kishi & Hirooka 2013).

“The Angiotensin-melatonin axis” (Campos et al., 2013).

just sayin’

calories proper

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  • Jack Kruse

    Angiotensin is electronically induced by electron addition or subtraction causing changes in its ionization to alter protein confirmation Bill. This is why it can act in multiple fashions based upon the surrounding redox potential and water hydration shell that surrounds it. Angiotensin 2 can play the role of a hormone, a neurotransmitter, a cytokine, and a growth factor. Angiotensin 2 can make blood clot or prevent blood from clotting. ACE can cause systemic hypertension or can cause a local plaque to form in a specific blood vessel location. Working together, ACE and angiogenesis 2 can cause vasodilation or vasoconstriction, depending on which angiotensin receptors are present on the target cell surface. Likewise, ACE and angiotensin 2 can exert a pro-inflammatory or anti-inflammatory effect in the immune system, depending on which angiotensin receptors are present and activated or deactivated by the redox potential in the target immune cells or the bone marrow/thymus. The dual roles are reminiscent and parallel the roles of oxidative stress and free radical generation – they can open the door of heaven or hell based upon the local cellular milleu. ACE and angiotensin 2 increases oxidative stress in the vascular system and can therefore accelerate aging and hardening of the arteries via one receptor type on the target cell, but can do the opposite with another receptor type. ACE and angiotensin 2 can increase oxidative stress in other tissues and drive cancer formation via one receptor type, but in other cells, the pair can trigger an anti-oxidant response. CO, NO, H2S, Prostacyclin (PGI2), and Endocanabanoids are biological antagonists of Angiotensin II. H2S is now the known molecular mechanism that underpins endovascular vaso relaxation. Angiotensin 2 also induces ROS and this is why it can generate oncogenesis when electrons are missing and protons are abundant. Angiotensin II induces the transcription of several protein components of NADH oxidase and NADPH oxidase. NOX produces a lot of superoxide and are bound just below the plasma membrane of the following types of cells:

    endothelial cells,
    vascular smooth muscle cells,
    adventitial fibroblasts
    Good stuff.

  • Wenchypoo

    I just take potassium orotate and l-theanine for my hypertension. No need to get Big Pharma involved.

  • http://www.caloriesproper.com/ William Lagakos

    Influence of losartan intake on the circadian rhythm of melatonin secretion in humans.

    http://www.ncbi.nlm.nih.gov/pubmed/24716408

    …no effect after 7 days @ 50mg/d

    • bea

      After going lc. Paleo my BP became very low. It was around 80/60 last Dr. visit. Dr. did not say anything. Other symptoms are insomnia, fatigue.
      I discovered I was not consuming enough sodium. If I don’t get at least 2,000 mg a day it tanks. Just happened to me again. I slacked off and I couldn’t sleep, cramps, low BP. Powered down the salt and symptoms gone that night. I now measure my salt out into a little dish in the morning and make sure I put it in my food and drink. Doctors seem to ignore when patients present with low BP.

      • http://www.caloriesproper.com/ William Lagakos

        I don’t think this is uncommon, especially in the LC community. Glad to hear you solved it!

    • Jack Kruse
      • http://www.caloriesproper.com/ William Lagakos

        Thanks for the link, Jack.

        Paolo Sassone-Corsi is OG – he’s been studying circadian biology in rodents since the early 90′s.

  • valerie

    brain inflammation induced by chronic exposure to artificial lights causes depression-like symptoms (in mice) (probably humans, too)

    Any chance you can develop on that?

    Otherwise, I have taken ARBs (losartan or olmesartan) for years, and I haven’t become leaner/calmer/happier. I agree that ARBs are good drugs for hypertension, especially compared to diabetes-inducing beta-blocker or cancer-giving CCBs. It works well to reduce my blood pressure, I just have to keep an eye on my electrolytes (I easily get hyponatremic, and ARBs encourage that).

    • http://www.caloriesproper.com/ William Lagakos

      Hi Valerie, sure. Chronic exposure to artificial light induces the expression pro-inflammatory cytokines in mouse & hamster brain, and this was associated with depressive-like symptoms in the latter (see: http://bit.ly/1qmjuP4 & http://bit.ly/1jI9pXy).

      As mentioned previously (http://caloriesproper.com/?p=4559), I’m not entirely sure rodent “depressive-like symptoms” completely parallel human clinical depression, but it’s an interesting finding.

      Also, it’s possible that those [beneficial] side effects of ARBs may only come into play when challenged with a stressor… at least that’s what the rodent studies seem to imply.

      • valerie

        Thanks.

        With the right keyowrds (“light at night”) I found some data on humans too.

        For depression:
        http://www.ncbi.nlm.nih.gov/pubmed/23856285

        For blood pressure:
        http://www.ncbi.nlm.nih.gov/pubmed/24673296

        My own blood pressure seems to trend low when I go to bed earlier (regardless of how long I sleep). I am not entirely sure of the link, though, since there were confounding factors the few times I observed it. I wanted to test it more rigorously, but, well, going to bed early is not easy! I blame the Internet. Low carb seems to make it worse. I tried f.lux and blue blockers, but no luck so far.

  • http://www.caloriesproper.com/ William Lagakos

    The Role of the Circadian Clock in Animal Models of Mood Disorders.

    http://bit.ly/1fUW3aQ