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We tested whether the AT1R antagonist losartan improves NO-dependent local
heating in LFP and whether this improvement was r
eve
rsed by the nitric oxide
synthase inhibitor nitro-L-arginine (NLA)
.
12 LFP patients were compared to 15 control subjects. Ages ranged
from 22.0±1.3 years. We perfused 3 microdialysis catheters with
Ringer solution followed by losartan in 1 catheter, NLA in the second
catheter, and
NLA+losartan in a third catheter.
Results are depicted in the Figure. Losartan increased the POTS heat
response to control levels. NLA decreased both POTS and control subject
heat responses to similar conductances. The addition of NLA to losartan
reduced POTS and control subject conductances compared to losartan alone.
The data suggest that the reduction in cutaneous nitric oxide dependent vasodilation in LFP is corrected by AT1R blockade.
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The
Figure shows the local heat
response expressed as %CVCmax before and after administration of losartan,
NLA and losartan + NLA. POTS
patients are shown in gray and control subjects in black. POTS heating
response is reduced pre-drug compared to control subjects (top left
panel). Losartan causes an increase in conductance in POTS (top right
panel). NLA greatly reduces the heating response in POTS and control
subjects (bottom left panel). Adding NLA to losartan results in blunting
in losartan induced vasodilation (bottom right panel).
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Exogenous angiotensin-II
duplicates cutaneous POTS findings in control subjects
| Further studies
indicated that intradermal Ang-II administration attenuates local
cutaneous vasodilator heating in dose-dependent fashion similar to results
observed in LFP patients. Panel D indicates that
during NOS and AT1R blockade Ang-II increases %CVC suggesting that a
substance related to Ang-II is responsible. Importantly, the attenuated
heat response was improved by the administration of ascorbate and
clearly by losartan. The vasoconstrictive response to Ang-II is largely
due to increased ROS formation especially H2O2,
and NO scavenging through the binding of Ang-II to NADPH and xanthine
oxidases producing peroxynitrite 93-95.
The antioxidant sodium ascorbate restores local vasodilation which
confirms the importance of oxidants in mediating blunting of the local
heat response. |
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The
figure shows the averaged local heating as %CVCmax before and after
administration of losartan, NLA and losartan + NLA averaged over all
subjects. Two experiments are represented: one (black lines healthy
subjects received Ringer’s solution, in the other (gray lines) healthy
subjects were premedicated with cutaneous Ang-II. The heating response is
reduced by Ang-II perfusion in panel A). Losartan counteracted Ang-II in
this regard (panel B). NLA reduced the heating response in subjects (C)
regardless of Ang-II premedication. Ang-II and Ringer heat responses
become similar. Adding NLA to losartan blunts the heat response but the
addition of angiotensin to NLA and losartan (panel D) produces an increase
in heat dependent flow compared to losartan and NLA alone. |
Also, No
relation with plasma angiotensinogen, ACE, Renin or Angiotensinogen
Polymorphisms were found
Plasma angiotensinogen was studied as a cause of increased Ang-II production in
Low Flow POTS. Plasma levels are said to reflect tissue levels. Results
failed to reveal any difference from control. Unusual polymorphisms in
angiotensinogen, ACE, or renin were also not found.
Next
The
Metabolism of Ang-II by angiotensin converting enzyme-II (ACE-II) is defective
in Low Flow POTS causing a reduction of the vasodilator Ang-(1-7).
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Ang-II reduced available NO and AT1R Blockade reverses reduced NO