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The heating response is increased with Ang-II when
losartan and NLA were present in healthy volunteers. Thus, when AT1R’s
are blocked, Ang-II causes NO-independent vasodilation in controls. This does
not occur in LFP . This vasodilation is unaffected by AT2R blockade with
PD123,319, but suppressed by the ACE2 inhibitor DX600 indicating that
vasodilation may result from the actions of ACE2 which metabolizes Ang-II to the
vasodilator Ang-(1-7). LFP vasodilation is unaffected. Ang-(1-7)
restores most of the heating response in the presence or absence of AT1R
blockade and NOS inhibition providing evidence for ACE2 deficiency in LFP.
Angiotensin Cascade
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| The Figure shows the
heating response, %CVCmax, before (left panel) and after administration
of NLA + losartan (middle panel) and NLA + losartan + Ang-II (right
panel) averaged for control subjects (in black) and POTS (in gray). The
middle panel demonstrates a significant reduction in contro lresponse by
NLA + losartan but only a small effect in POTS. The addition of Ang-II
(right panel) increases the heating response in control subjects but not
in POTS. |
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| The figure compares
heating responses expressed as %CVCmax after the administration of NLA +
losartan +Ang-II (left panel) and after DX600 has been added to yield NLA
+ losartan + Ang-II + DX600 (right panel) in the perfusate. The addition
of DX600 causes a reduction of the local heating response in control
subjects but not LFP. |
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| The figure compares heating
responses expressed as %CVCmax after the administration of NLA + losartan
+Ang-II (left panel) and after Ang-(1-7) has been added to yield NLA +
losartan + Ang-II + Ang-(1-7) (right panel). The addition of Ang-(1-7)
produces an increase of the local heating response in POTS patients such
that the heat response in POTS becomes comparable to control. |
 |
| The figure compares the
heating response expressed as %CVCmax before (left panel) and after (right
panel) the administration of Ang-(1-7). The left panel shows the reduced
NO-dependent heat response in POTS patients compared to control subjects.
The right panel demonstrates that the addition of Ang-(1-7) markedly
improves the local heating response in POTS. |
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Implications
Cutaneous bioavailable NO is reduced in LFP and nNOS is involved. Plasma
Ang-II is increased and dissociated from plasma renin activity and serum
aldosterone. AT1R blockade and antioxidant treatment reverse Ang-II
mediated reduction of NO in LFP and during exogenous Ang-II excess.
Reduced ACE2 may be involved in Ang-II excess and decreases the
vasodilator Ang-(1-7). Handgrip and tilt studies are consistent with
increased sympathetic activity and attenuation of sympathetic sensitivity
to baroreflex and exercise pressor inputs. Additional pilot
information will support the benefit of antioxidants as well as AT1R
blockade. Data support a sympathoexcited state promoted by increased
angiotensin-II and decreased NO of nNOS origin.
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ACE-II is Deficient causing Ang-II Excess and reduced vasodilator Ang-(1-7) in Low Flow POTS