Angiotensin II type 1 receptor blockade corrects cutaneous nitric oxide deficit in postural tachycardia syndrome.
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 (AT(1)R) 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 degrees 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 microg/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 AT(1)R blockade.
Stewart
Julian M
JM
The Center for Pediatric Hypotension, New York Medical College, 19 Bradhurst Avenue, Hawthorne, NY 10532, USA. stewart@nymc.edu
Taneja
Indu
I
Glover
June
J
Medow
Marvin S
MS
D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D007024:Hypotension, Orthostatic / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D007866:Leg; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D017551:Microdialysis; D009569:Nitric Oxide / Q000172:deficiency / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage; D011187:Posture; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D012107:Research Design; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D013577:Syndrome; D013610:Tachycardia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019808:Losartan