Defects in cutaneous angiotensin-converting enzyme 2 and angiotensin-(1-7) production in postural tachycardia syndrome.
Postural tachycardia syndrome (POTS) is associated with increased plasma angiotensin II (Ang II). Ang II administered in the presence of NO synthase inhibition with nitro-L-arginine (NLA) and Ang II type 1 receptor blockade with losartan produces vasodilation during local heating in controls. We tested whether this angiotensin-mediated vasodilation occurs in POTS and whether it is related to angiotensin-converting enzyme 2 (ACE2) and Ang-(1-7). We used local cutaneous heating to 42 degrees C and laser Doppler Flowmetry to assess NO-dependent conductance at 4 calf sites in 12 low-flow POTS and in 12 control subjects 17.6 to 25.5 years of age. We perfused Ringer's solution through intradermal microdialysis catheters and performed local heating. We perfused one catheter with NLA (10 mmol/L)+losartan (2 microg/L) and repeated heating, and NLA+losartan+Ang II (10 micromol/L), repeating heating a third time. A second catheter received NLA+losartan+Ang II, heated, perfused NLA+losartan+Ang II+DX600 (1 mmol/L; a selective ACE2 inhibitor), and reheated. A third catheter received NLA+losartan+Ang II, heated, perfused NLA+losartan+Ang II+Ang-(1-7) (100 micromol/L), and reheated. The fourth catheter received Ang-(1-7) then reheated a second time only. Angiotensin-mediated vasodilation was present in control but not POTS. Ang-mediated dilation was eliminated by DX600, indicating an ACE2-related effect. Ang-mediated vasodilation was restored in POTS by Ang-(1-7). When administered alone during locally mediated heating, Ang-(1-7) improved the NO-dependent local heating response. ACE2 effects are blunted in low-flow POTS and restored by the ACE2 product Ang-(1-7). Data imply impaired catabolism of Ang II through the ACE2 pathway. Vasoconstriction in POTS may result from a reduction in Ang-(1-7) and an increase in Ang II.
Stewart
Julian M
JM
The Center for Pediatric Hypotension, Suite 1600 S, 19 Bradhurst Ave, New York Medical College, Hawthorne, NY 10532, USA. stewart@nymc.edu
Ocon
Anthony J
AJ
Clarke
Debbie
D
Taneja
Indu
I
Medow
Marvin S
MS
D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000502:physiology*; D000085962:Angiotensin-Converting Enzyme 2; D005260:Female; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D054972:Postural Orthostatic Tachycardia Syndrome / Q000503:physiopathology*; D012867:Skin / Q000378:metabolism*; D014664:Vasodilation
D010446:Peptide Fragments; D019335:Nitroarginine; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D019808:Losartan