The heating response is increased with Ang-II when losartan and NLA were present in healthy volunteers.  Thus, when AT1Rís 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

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.

 

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.
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.
 

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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