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

Autonomic Neuroscience: Basic and Clinical 145 (2009) 1–2

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Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

HIGHLIGHTS IN CLINICAL AUTONOMIC NEUROSCIENCES Prepared by: Satish R Raj MD MSCI Section Editors: Roy Freeman MD & Phillip Low MD

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

Stewart JM, Taneja I, Glover J, Medow MS (Valhalla, NY, USA) Am J Physiol Heart Circ Physiol 294: H466–H473, 2008. First published November 9, 2007; doi:10.1152/ajpheart.01139.2007. Article summary: 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. The authors 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. They measured skin blood flow after local heating of the skin of the left calf to 42 °C using laser Doppler 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, they perfused individual intradermal microdialysis catheters at those sites with losartan, NLA, or both. The predrug heat response was reduced in POTS, particularly the plateau phase reflecting NOdependent vasodilation (50 ± 5 vs. 91 ± 7%; P < 0.001 vs. control). Losartan increased baseline flow in both POTS and control subjects, such that it restored the peak “heat”-flow in POTS to the level of control subjects. The baseline increase was blunted by NLA. The data suggest that the reduction in cutaneous NOdependent vasodilation in low-flow POTS is corrected by AT1R blockade. Commentary: The study builds upon observations made by Stewart et al. since 2006. He and co-workers first reported that a subgroup of patients with POTS had an unexpectedly high level of angiotensin II in the plasma. Since that time, these investigators have performed a series of elegant studies using a heat-induced cutaneous vasodilation model to define further the functional significance of angiotensin II in this group of patients. First, they showed that patients with POTS had a diminished heat-induced cutaneous vasodilator response (measured using laser-Doppler) compared to healthy control subjects. The local application of a nitric oxide synthase inhibitor had no effect on heatinduced skin blood flow in patients with POTS, but did cause the skin blood flow in the control subjects to decrease to the level seen in the patients with POTS. In this way, Stewart et al. established a nitric oxide deficit in the regulation of skin blood flow in the patients with POTS. Using a similar skin blood flow model in this paper, Stewart et al. administered an angiotensin II type I receptor blocker (losartan) intradermally and showed the skin blood flow of patients with POTS could be “rescued” to the level seen in healthy control subjects. Further, the coadministration of losartan and a nitric oxide synthase inhibitor caused the skin blood flow of both the POTS patients and the control subjects to return to the diminished level seen initially only in POTS. Taken together, these data suggest an important role for angiotensin II and the angiotensin II type I receptor in the regulation of skin blood flow. Further, these data suggest that pii:S1566-0702(08)00197-5

there is dysregulation of the system in patients with POTS with excess of activity of angiotensin II that results in inhibition of nitric oxide synthase activity and diminished skin blood flow in these patients. These exciting data provide a plausible explanation for the striking dependent acrocyanosis noted in some patients with POTS. It is less clear if these findings of skin microvascular regulatory abnormalities are seen on a macrovascular scale, and if they play a role in the perturbed systemic hemodynamics seen in POTS. doi:10.1016/j.autneu.2008.10.018

Reduced stroke volume during exercise in postural tachycardia syndrome Masuki S, Eisenach JH, Schrage WG, Johnson CP, Dietz NM, Wilkins BW, Sandroni P, Low PA, Joyner MJ (Rochester, MN, USA) J Appl Physiol 103: 1128–1135, 2007. First published July 12, 2007; doi:10.1152/japplphysiol.00175.2007. Article summary: Postural tachycardia syndrome (POTS) is characterized by excessive tachycardia without hypotension during orthostasis and most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise in POTS patients (n=13) and healthy controls (n=10) these investigators performed graded cycle exercise at 25, 50, and 75 Watts (W) in both supine and upright positions while arterial pressure (arterial catheter), heart rate (HR; measured by ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac output, and total peripheral resistance at rest and during exercise were similar in patients and controls. However, supine stroke volume (SV) tended to be lower in the patients than controls at rest (99±5 vs.110±9 ml) and during 75-W exercise (97±5 vs.111±7 ml) (P =0.07), and HR was higher in the patients than controls at rest (76±3 vs. 62±4 bpm) and during 75-W exercise (127± 3 vs. 114± 5 bpm) (both P <0.01). Upright SV was significantly lower in the patients than controls at rest (57 ±3 vs. 81 ±6 ml) and during 75-W exercise (70±4 vs. 94±6 ml) (both P <0.01), and HR was much higher in the patients than controls at rest (103±3 vs. 81±4 bpm) and during 75-W exercise (164±3 vs. 131± 7 bpm) (both P <0.001). The change (upright–supine) in SV was inversely correlated with the change in HR for all participants at rest and during exercise [50 W] (R2 =0.60, P <0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance. Commentary: Patients with the postural tachycardia syndrome (POTS) are often debilitated by a constellation of symptoms that include excessive fatigue, lightheadedness/ presyncope, and profound exercise intolerance. The symptoms can lead to a marked limitation in quality of life, and sometimes limit patients' ability to perform activity activities of daily living. The reasons underlying the activity limitations are not well understood. Emerging work from Fu and Levine at the