Angiotensin II type 1 receptor blockade corrects cutaneous nitric oxide deficit in postural tachycardia syndrome

Abstract

Low-flow postural tachycardia syndrome (POTS) is associated with increased plasma angiotensin II (ANG II) and reduced neuronal nitric oxide (NO), which decreases NO-dependent vasodilation. We tested whether the ANG II type 1 receptor (AT₁R) antagonist losartan would improve NO-dependent vasodilation in POTS patients. Furthermore, if the action of ANG II is dependent on NO, then the NO synthase inhibitor nitro-l-arginine (NLA) would reverse this improvement. We used local heating of the skin of the left calf to 42°C and laser-Doppler flowmetry to assess NO-dependent conductance [percent maximum cutaneous vascular conductance (%CVC_max)] in 12 low-flow POTS patients aged 22.5 ± 0.8 yr and in 15 control subjects aged 22.0 ± 1.3 yr. After measuring the baseline local heating response at three separate sites, we perfused individual intradermal microdialysis catheters at those sites with 2 μg/l losartan, 10 mM NLA, or losartan + NLA. The predrug heat response was reduced in POTS, particularly the plateau phase reflecting NO-dependent vasodilation (50 ± 5 vs. 91 ± 7 %CVC_max; P < 0.001 vs. control). Losartan increased baseline flow in both POTS and control subjects (from 6 ± 1 to 21 ± 3 vs. from 10 ± 1 to 21 ± 2 %CVC_max; P < 0.05 compared with predrug). The baseline increase was blunted by NLA. Losartan increased the POTS heat response to equal the control subject response (79 ± 7 vs. 88 ± 6 %CVC_max; P = 0.48). NLA decreased both POTS and control subject heat responses to similar conductances (38 ± 4 vs. 38 ± 3 %CVC_max; P < 0.05 compared with predrug). The addition of NLA to losartan reduced POTS and control subject conductances compared with losartan alone (48 ± 3 vs. 53 ± 2 %CVC_max). The data suggest that the reduction in cutaneous NO-dependent vasodilation in low-flow POTS is corrected by AT₁R blockade.