Angiotensin Ii And Pots

[firewatcher]

Circ Arrhythm Electrophysiol. 2012 Jan 13. [Epub ahead of print]

Altered Systemic Hemodynamic & Baroreflex Response to Angiotensin II in Postural Tachycardia Syndrome.

Mustafa HI, Raj SR, Diedrich A, Black BK, Paranjape SY, Dupont WD, Williams GH, Biaggioni I, Robertson D.

Source

1 Vanderbilt University School of Medicine, Nashville, TN;

Abstract

BACKGROUND:

-Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that POTS patients had increases in plasma angiotensin II (Ang II) twice as high as normal subjects despite normal blood pressures. In this study we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.

METHODS AND RESULTS:

-Following a 3 day sodium controlled diet, we infused Ang II (3 ng/kg/min) for 1 hour in POTS patients (n=15) and healthy controls (n=13) in the supine position. All study subjects were females with normal blood pressure (BP). Ages were similar for POTS and control subjects (30±2 [mean±SEM] vs. 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure (MAP), renal plasma flow (RPF), plasma renin activity (PRA), aldosterone, urine sodium and baroreflex sensitivity in both groups. In response to Ang II infusion, POTS patients had a blunted increase compared with control subjects in MAP (10±1 mmHg vs. 14±1 mmHg; P=0.01), and diastolic BP (9±1 mmHg vs. 13±1 mmHg; P=0.01), but not systolic BP (13±2 mmHg vs. 15±2 mmHg; P=0.40). Renal plasma flow (RPF) decreased similarly with Ang II infusion in POTS patients and controls (-166±20 vs. -181±17 mL/min/1.73 kg/m2; P=0.58). Post-infusion, the decrease in PRA (-0.9±0.2 vs. - 0.6±0.2 ng/mL/h; P=0.43) and the increase in aldosterone (17±1 vs. 15±2 pg/ml; P=0.34) were similar in POTS and controls. The decrease in urine sodium excretion was similar in both POTS and controls (-49±12 vs. -60±16 mEq/g Cr; P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in POTS compared to healthy controls (10.1±1.2 vs. 16.8±1.5 ms/mmHg, P=0.003) and it was further reduced with Ang II infusion.

CONCLUSIONS:

-Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture, and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration Information-http://clinicaltrials.gov; NCT00962949. PMID: 22247480

[jangle]

Pacemakers in our future?

[juliegee]

Wow, Jennifer- more evidence of Stewart's "low-flow" population, but Vandy seems to throw all POTS patients into that pool???

Could someone translate this for me- what us a blunted vasopressor response? How about an impaired baroreflex function?

I'm guessing that this relates to renal function too- could have some helpful implications for you...

Julie

[sue1234]

Yes, someone dumb it down, please!

[ramakentesh]

So the vasopressor response - that is the vasoconstrictive response to orthostatis is blunted and ineffectual.

it is unclear whether the patients tested with angiotensin II administration were the subgroup found with elevated angiotensin II levels. In there previous study they suggested that elevated angiotensin II was downregulating angiotensin II vasoconstrictive receptors. they also suggested that elevated AGII might be effecting NE reuptake or transporter function.

Very interesting. I might pay for the whole article. Just dont tell my wife...

[Lemons2lemonade]

as per rama, baroreflex is describing the capability of your baroreceptors- receptors in your circulatory system that send the signals for pressure changes i.e. constrict,dilate--to reflex appropriately to maintain adequate blood pressure. Essentially, i am gathering from this that ours are not working properly. Jangle, i think i remember reading somewhere that pacemakers can make it worse--our problem isn't our heart, its everything else, the fast heart rate is probably keeping us conscious by accommodating for the lack of pressure as best it can. A better question is, "why aren't the receptors working" que autoimmune disease damaging them and/or "neuropathy". I also have my own theories that other hormones, viruses,or bacteria are "stealing" or blocking the receptor sites. Blocking receptors is something that a lot of poisons do such as botulism, snake venom, etc. However, these types of blockages are usually quick, systemic and fatal. Wonder if there is something like this out there that we are not yet aware of that just hangs out in our system. My question is, "what do the baroreceptors look like on a pots patient."

[Lemons2lemonade]

I know its only wiki, but it explains well, best part is the last paragraph. I think every potsy should know this info. Enjoy

http://en.wikipedia.org/wiki/Baroreceptor

[Lemons2lemonade]

"The arterial pressure of the adult human rarely deviates from normal by more than 10 to 15 percent during each day. To achieve such constancy, the body has a network of pressure control systems. Several are based on neural receptors that respond within seconds to help correct any abnormal pressure. The activities of these systems are followed within minutes by activation of hormonal controllers. Within hours or days, a kidney pressure control system is induced that increases body fluid volume when the pressure falls (or decreases the volume when the pressure rises). This kidney-fluid system is the dominant method of establishing long-term pressure control."

http://www.sciencemag.org/content/252/5014/1813.abstract

Blood pressure control--special role of the kidneys and body fluids AC Guyton

Science 28 June 1991:

Vol. 252 no. 5014 pp. 1813-1816

DOI: 10.1126/science.2063193

Oooh i stumbled upon a gold mine! Check out these other abstracts from this website:

• Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone J. Biol. Chem. 2 January 2012: 660-671
  
• Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension
  
• Both high and low maternal salt intake in pregnancy alter kidney development in the offspring Am. J. Physiol. Renal Physiol. 1 August 2011: F344-F354.
  
• 
  The WNK Kinase Network Regulating Sodium, Potassium, and Blood Pressure J. Am. Soc. Nephrol. 1 April 2011: 605-614.
  
• 
  The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure FASEB J. 1 July 2010: 2454-2463.
  

[ramakentesh]

From what I can tell basically the theory is that angiotensin II mediated vasoconstriction and baroreflex function is impaired in POTs causing a blunted vasoconstrictive response to standing, somehow effecting blood volume (although this isnt explained as the kidney response to the administrative of angiotensin II was normal in these patients) and the excessive sympathetic activity and norepinephrine response is a coping mechanism for this impaired constriction.

They established this my infusing random POTS patients (not ones found to have elevated ANG II before test) with ANG II and finding a blunted vasconstrictive response.

So in other words the mediator is under-responsive vascular ang II receptors. The pooling in this case is evident in the splanchnic (stomach) circulation thus they hypothesise that the resistance to angiotensin II is specific to the splanchnic circulation resulting in reduced thoratic blood flow, compensatory tachycardia and sympthetic activation and POTS.

In their previous study involving ang ii they suggested that it may resuilt in impaired norepinephrine transporter function or expression.

They as yet have not worked out why the ANG II receptors are faulty but suggest that it could be the result of elevated ANG II resulting in desensitization of these receptors.

Julian Stewart found impaired ACE activity was behind the elevated ANG II in some POTS patients.

Some thoughts I had were - could autoantibodies be clogging up ANG II receptors resulting in desensitization? Might sound far fetched but autoantibodies against these receptors have already been found in essential hypertension and M.Gravis.

Its also interesting that they did not check ANG II levels in teh POTs patients before testing and found that they were elevated.

[ramakentesh]

I am always attracted to autoantibody mediated etiologies because of the fluctuating course most of us experience. But Julian Stewart's ACE2 abnormalities is probablyt the most likely culprit.

[ramakentesh]

This may also be of interest:

http://informahealth...journalCode=clb

Venous plasma angiotensin II, measured at 4-hour intervals in healthy subjects, has a diurnal rhythm. The highest values are detected early in the morning and the lowest in the evening

And autoantibodies in this case activiating rather than blocking ANG II receptors:

http://www.nature.co...bs/nm.1856.html

there is a lot of other work on ANG II receptor antibodies.

[issie]

Would be nice if this were an explanation for us low-flow people. But the big question is - what to do about it.

Issie

[ramakentesh]

I dont really think this paper has looked at variations in flow. But I think that its interesting that they chose patients randomly and they all seemed to have elevated ANG II. Combined with low renin.