Blood Pressure

 

High blood pressure or hypertension afflicts one in four adults in the developed world. Hypertension is diagnosed when sustained blood pressure reaches or exceeds 140 mm HG systolic pressure (maximum arterial pressure) over 90 mm Hg diastolic pressure (minimum arterial pressure). Hypertension is a major risk factor for heart disease and stroke and should never be ignored.

Approximately 95% of hypertension is classified as primary hypertension meaning there is no known medical cause. The remaining cases of hypertension, also known as secondary hypertension, are due to dysfunction in various organs or glands.

Blood pressure varies throughout the day with readings typically higher in the afternoon and lower at night. Blood pressure also varies due to stress, physical activity, sleep or the lack thereof, digestion, drugs and alcohol and diet.

Blood pressure is dependent on physical characteristics like blood volume, the level of resistance to its movement within blood vessels and the viscosity of blood. All things being equal, the higher the volume of blood, the greater the resistance to its movement and the thicker it is, the higher blood pressure is apt to be.

Blood pressure regulation relies on the renin-angiotensin-aldosterone system. Talking about blood pressure without referring to this system is impossible, so I’m going to briefly cover it now. I’ll try to make this as simple as possible.

 

Courtesy: Wikipedia

 

OK, we’re going to begin with the kidney(s) seen in the lower left-hand corner of this graphic. Renin is an enzyme produced in the juxtaglomerular apparatus of the kidneys and is typically the start of the process that ultimately increases blood pressure.

Renin is released in response to low fluid pressure in the kidneys or reduced sodium content in blood. High blood pressure normally works to suppress renin release along with high-salt diets. However, in those with hypertension this negative feedback system is unable to keep blood pressure at optimal levels.

Renin is also increased by abnormally low concentrations of plasma potassium. When potassium levels are high, its release is decreased.

Renin acts on angiotensinogen produced in the liver resulting in its conversion to angiotensin I. Angiotensin I has no biological activity. By the way, elevated cortisol levels increase angiotensinogen production in the liver which increases the conversion rate of renin to angiotensin I.

Angiotensin I is converted by angiotensin-converting enzyme (ACE) to its biologically active form of angiotensin II. ACE is mostly located in the cell membranes of the lung. The use of ACE inhibitors to control blood pressure works at this step in the process.

Another enzyme called amino peptidase A also acts on angiotensin II to produce angiotensin III. (not shown). Both angiotensin II and III have equal effects on aldosterone secretion by the adrenal glands.

Angiotensin II and III receptors in the adrenals increase the secretion of a hormone called aldosterone. Aldosterone in turn acts on the kidneys to conserve sodium, secrete potassium, increase water retention and elevate blood pressure.

While not part of the renin-angiotensin-aldosterone system, cortisol can also stimulate aldosterone release. When elevated, cortisol overwhelms what is known as the cortisol-cortisone shunt that typically prevents cortisol from stimulating aldosterone secretion.

Angiotensin II also acts to increase the activity of the sympathetic nervous system. It acts on angiotensin II receptors in vascular smooth muscle cells to constrict them, causing blood pressure to rise and blood flow to the kidneys to decrease.

Angiotensin II causes the release of the stress hormones norepinephrine and epinephrine (adrenaline) from the adrenals. (not shown). Finally, it acts on the pituitary gland to increase the release of vasopressin (ADH). This hormone promotes the retention of water and also constricts blood vessels.

Because this process is initiated by renin, renin serves as the rate-limiting step in this chain of events.

And that, my dear reader, is the CliffsNotes version of the renin-angiotensin-aldosterone system. That wasn’t so painful now was it?

Now it’s clear that high blood pressure can be caused by the defective functioning of different organs and glands in this system leading to secondary hypertension. For example, increased release of aldosterone caused by a benign tumor in the adrenals (one cause of primary aldosteronism) can cause high blood pressure apart from renin release.

Other common disease states that can account for elevated blood pressure include Cushing’s syndrome, Cushing’s disease, hyper- or hypothyroidism and acromegaly, a disorder of excessive growth-hormone release. A competent physician would screen for these other disorders before arriving at a diagnoses of primary hypertension.

OK, it’s now time to segue into the role of gut flora and smell receptors.

Smell receptors?!?!?

Ray, what the hell do smell receptors have to do with blood pressure?

Patience my little doves, patience.

Smell receptors, here on out called olfactory receptors, exist in the nasal epithelium where they detect odors, both good and bad. Seven of these receptors have been identified.

However, these olfactory receptors don’t just exist in the nose. They exist in a variety of other tissues including the kidneys. Yes, technically speaking, your kidneys can smell.

Olfactory receptors have been shown to play important roles in the rate kidneys form urine (glomerular filtration rate), and the rate renin is released. Six members of the olfactory receptor family have been discovered in kidney tissue.

Of these six, one in particular, olfactory receptor 78 (Olfr78) in mice and its human equivalent, olfactory receptor 51 E2 (OR51E2), are specifically attuned to “sniff out” and respond to short-chain fatty acids.

As you recall, short-chain fatty acids (SCFAs) are produced as a byproduct of soluble fiber fermentation by gut flora in the colon. These SCFAs are butyrate, acetate and propionate.

Of these three SCFAs, acetate and propionate have demonstrated abilities to lower blood pressure. For example, the presence of acetate in hemodialysis solution can cause very low blood pressure. (1)

Other studies have pointed to the positive effect of fiber intake on blood pressure control implicating SCFAs as the causative agents. (2) SCFAs have also been shown to widen or dilate blood vessels in rodents and humans. (3) (4) However, until now how these short-chain fatty acids affected blood pressure was a mystery.

In a recently published paper, researchers using a mouse model were able to localize Olfr78 in the major branches of kidney arteries as well as the juxtaglomerular apparatus, site of renin release. (5) Apart from the nose and kidneys, olfactory receptor 78 was also detected in the heart, diaphragm, skeletal muscle, brain, testes, skin, large intestine, bladder, lung, liver, pancreas, spleen and fat tissue of these rodents.

This receptor and its human equivalent are responsive to just two short-chain fatty acids: propionate and acetate. These researchers were able to show that the administration of propionate could cause either an increase or decrease in blood pressure depending on which receptors were operative.

When Olfr78 was activated, propionate consistently raised blood pressure. Yet, as I’ve mentioned, both propionate and acetate, have been shown to lower blood pressure. So how did these researchers explain these findings?

By also focusing their attention on two non-olfactory receptors called G protein-coupled receptor 41 (Gpr41) and G protein-coupled receptor 43 (Gpr43). Both receptors are widely expressed in tissues throughout the body, including the kidneys and major arteries.

When these receptors are activated by propionate and acetate, they inhibit renin release and the downstream initiation of the renin-angiotensin-aldosterone system. This was confirmed in mice lacking Gpr41 receptors where the administration of propionate failed to reduce blood pressure.

Therefore, activating olfactory receptor 78 or its human equivalent, olfactory receptor 51 E2, with short-chain fatty acids increases renin release. Conversely, activating Gpr41 (and perhaps Gpr43) by these same fatty acids lowers blood pressure.

Lucky for mice and us, the G protein-coupled receptors respond to propionate and acetate at lower plasma concentrations than do either Olfr78 or OR52E2. This means that under normal physiological conditions, the blood pressure lowering effects of these two short-chain fatty acid metabolites of bifidobacteria predominate.

So to answer the question that serves as the title of this post, yes it appears that beneficial gut flora influences blood pressure for the better. This makes sense as we know that gut dysbiosis and resulting endotoxemia are associated with ill health.

In my humble opinion, many if not most cases of primary hypertension are but another manifestation of gut dysbiosis.

Recall that endotoxemia always results in elevated cortisol release by activating the hypothalamic-pituitary-adrenal axis. The chronically elevated cortisol levels that are a characteristic feature of both Cushing’s syndrome and Cushing’s disease cause chronic hypertension in 75% to 80% of those afflicted with these disorders.

Cortisol can increase blood pressure by increasing the production of angiotensinogen, a precursor to angiotensin I, II and III and by directly acting on the adrenals to increase aldosterone production. There are two other ways cortisol increases blood pressure.

First, cortisol enhances sensitivity to blood vessel constrictors like adrenaline and angiotensin II. Secondly, cortisol increases cardiac output.

So putting it all together, gut dysbiosis leads to:

  • reduced production of butyrate, a short-chain fatty acid essential for maintaining intestinal epithelial cell health and gut barrier function
  • increased gut permeability
  • increased translocation of lipopolysaccharides to systemic circulation
  • increased inflammatory immune responses via cytokine and prostaglandin PGE2 release
  • activation of the hypothalamic-pituitary-adrenal axis
  • increased production of cortisol that further increases intestinal permeability
  • increased production of angiotensinogen in the liver and conversion of renin to angiotensin
  • increased aldosterone production
  • increased sensitivity to endogenous substances that constrict blood vessels
  • increased cardiac output
  • decreased production of the short-chain fatty acids acetate and propionate that would normally serve to counter increases in renin and blood pressure.

I’ve said it before and I’ll no doubt say it again, you’re only as healthy as your gut flora!

 

References:

Gardner, D.G. and Shoback, D. (2011). Greenspan’s Basic and Clinical Endocrinology, Ninth Edition (LANGE Clinical Medicine). New York: McGraw Hill.

 

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