Postural tachycardia syndrome (POTS), a chronic form of orthostatic intolerance, has signs and symptoms of lightheadedness, loss of vision, headache, fatigue, and neurocognitive deficits consistent with reductions in cerebrovascular perfusion. We hypothesized that young, normocapnic POTS patients exhibit abnormal cerebral autoregulation (CA) that results in decreased static and dynamic cerebral blood flow (CBF) autoregulation. All subjects had continuous recordings of mean arterial pressure (MAP) and CBF velocity (CBFV) using transcranial Doppler sonography in both the supine supine position and during a 70 degrees head-up tilt. During tilt, POTS patients (n = 9) demonstrated a higher heart rate than controls (n = 7) (109 +/- 6 vs. 80 +/- 2 beats/min, P < 0.05), whereas controls demonstrated a higher MAP than POTS (87 +/- 2 vs. 77 +/- 3 mmHg, P < 0.05). Also during tilt, mean CBFV decreased 19.5 +/- 2.6% in POTS patients versus 10.3 +/- 2.0% in controls (P < 0.05). We then used a transfer function analysis of MAP and CFBV in the frequency domain to quantify these changes. The low-frequency (LF; 0.04-0.15 Hz) component of CBFV variability increased during tilt in POTS patients (supine: 3 +/- 0.9 vs. tilt: 9 +/- 2, P < 0.02). In POTS patients, there was an increase in LF and high-frequency coherence between MAP and CBFV, an increase in LF gain, and a lack of significant change in phase. Static CA may be less effective in POTS patients compared with controls, since immediately after tilt CBFV decreased more in POTS patients and was highly oscillatory and autoregulation did not restore CBFV to baseline values until the subjects became supine. Dynamic CA may be less effective in POTS patients because MAP and CBFV during tilt became almost perfectly synchronous. We conclude that dynamic and static autoregulation of CBF are less effective in POTS patients compared with control subjects during orthostatic challenge.

Local cutaneous heating produces vasodilation that is largely nitric oxide (NO) dependent. We showed that angiotensin II (ANG II) attenuates this by an ANG II receptor, type 1 (AT1R)-dependent mechanism that is reversible with the antioxidant ascorbate, indicating oxidative stress. Reactive oxygen species (ROS) produced by ANG II employ NADPH and xanthine oxidase pathways. To determine whether these mechanisms pertain to skin, we measured cutaneous local heating with 10 μM ANG II, using apocynin to inhibit NADPH oxidase and allopurinol to inhibit xanthine oxidase. We also inhibited superoxide with tempol, and H(2)O(2) with ebselen. We heated the skin of the calf in 8 healthy volunteers (24.5-29.9 yr old) to 42°C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance. We remeasured while perfusing allopurinol, apocynin, ebselen, and tempol through individual microdialysis catheters. This was then repeated with ANG II combined with antioxidant drugs. tempol and apocynin alone had no effect on the heat response. Allopurinol enhanced the entire response (125% of heat alone), while ebselen suppressed the heat plateau (76% of heat alone). ANG II alone caused significant attenuation of the entire heat response (52%). When added to ANG II, Allopurinol partially reversed the ANG II attenuation. Heat with ebselen and ANG II were similar to heat and ANG II; ebselen only partially reversed the ANG II attenuation. Apocynin and tempol each partially reversed the attenuation caused by ANG II. This suggests that ROS, produced by ANG II via NADPH and xanthine oxidase pathways, modulates the response of skin to the application of heat, and thus contributes to the control of local cutaneous blood flow.

Vasovagal syncope may be due to a transient cerebral hypoperfusion that accompanies frequency entrainment between arterial pressure (AP) and cerebral blood flow velocity (CBFV). We hypothesized that cerebral autoregulation fails during fainting; a phase synchronization index (PhSI) between AP and CBFV was used as a nonlinear, nonstationary, time-dependent measurement of cerebral autoregulation. Twelve healthy control subjects and twelve subjects with a history of vasovagal syncope underwent 10-min tilt table testing with the continuous measurement of AP, CBFV, heart rate (HR), end-tidal CO2 (ETCO2), and respiratory frequency. Time intervals were defined to compare physiologically equivalent periods in fainters and control subjects. A PhSI value of 0 corresponds to an absence of phase synchronization and efficient cerebral autoregulation, whereas a PhSI value of 1 corresponds to complete phase synchronization and inefficient cerebral autoregulation. During supine baseline conditions, both control and syncope groups demonstrated similar oscillatory changes in phase, with mean PhSI values of 0.58+/-0.04 and 0.54+/-0.02, respectively. Throughout tilt, control subjects demonstrated similar PhSI values compared with supine conditions. Approximately 2 min before fainting, syncopal subjects demonstrated a sharp decrease in PhSI (0.23+/-0.06), representing efficient cerebral autoregulation. Immediately after this period, PhSI increased sharply, suggesting inefficient cerebral autoregulation, and remained elevated at the time of faint (0.92+/-0.02) and during the early recovery period (0.79+/-0.04) immediately after the return to the supine position. Our data demonstrate rapid, biphasic changes in cerebral autoregulation, which are temporally related to vasovagal syncope. Thus, a sudden period of highly efficient cerebral autoregulation precedes the virtual loss of autoregulation, which continued during and after the faint.

Introduction to the patient and the most frequent orthostatic complaintThe most frequent orthostatic complaint in young people is lightheadedness or dizziness on rapid standing, sometimes from a seated position, most often from a supine position after hours of recumbency(1,2). The most common complainant is an adolescent in the middle of a growth spurt. Often the patient is already tall or is growing rapidly. Similar complaints are seen among young people of both sexes, particularly in patients of slender build and reduced blood volume (3). The complaints relate to normal physiology shared by people of all ages and have been identified by students of orthostasis in the past (1,2,4-6). Typically, there is transient pallor, perhaps some loss of postural tone, blurred vision or even loss of vision (black out, white out, spots), and less commonly, loss of consciousness. Symptoms instantly disappear with recumbency and are reduced or even abolished by standing up more slowly or in stages (7). Symptoms and signs peak soon after standing, in synchrony with a transient and substantial decrease in blood pressure which has its nadir at approximately 8-15 seconds after standing as shown in Figure 1. Heart rate increases as BP falls. These findings can be demonstrated using beat-to-beat finger arterial photoplethysmography (Finapres, Finometer, TNO Amsterdam) (2,8,9) or other means for beat-to-beat assessment. The BP decrements are usually not apparent by auscultatory or oscillometric blood pressure measurement, having a far too rapid and fleeting time course to be detected by these methods (10).Thus, the clinician needs to rely on clinical history and perhaps observation of the patient. The history is that of rapid-onset, short-lived dizziness and other symptoms on rapidly standing upright. If the patient can remain upright or can be held upright, all symptoms abate and disappear within 60 seconds and usually within less than 30 seconds (11). After recovery, the patient is usually entirely well and is free of subsequent fainting and of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors declare no conflicts of interest. . These studies should be cautiously interpreted because they excluded subjects with known OI. However, they do demonstrate that IOH need not cause more pernicious forms of OI. This short-lived hypotension is different from simple faint, in which maintaining the patient in the upright position makes the faint persistent and the patient often becomes much worse, clinically (12). NIH Public AccessCan it occur on a tilt table? We often observe the phenomenon as t...

Abstract-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°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)ϩlo-sartan (2 g/L) and repeated heating, and NLAϩlosartanϩAng II (10 mol/L), repeating heating a third time. A second catheter received NLAϩlosartanϩAng II, heated, perfused NLAϩlosartanϩAng IIϩDX600 (1 mmol/L; a selective ACE2 inhibitor), and reheated. A third catheter received NLAϩlosartanϩAng II, heated, perfused NLAϩlosartanϩAng IIϩAng-(1-7) (100 mol/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.

Background-Limitation of the blood supply to skeletal muscle in chronic heart failure may contribute to the symptoms of fatigue and diminished exercise capacity. The pathophysiology underlying this abnormality is not known. The purpose of this study was to assess the effect of endothelium dependent and independent vasodilator agents on blood flow in the leg of patients with heart failure. Methods and results-Blood flow in the leg was measured in patients with heart failure (n = 20) and compared with that in patients with ischaemic heart disease and normal left ventricular function (n = 16) and patients with chest pain and normal coronary arteries (n = 8). External iliac artery blood flow was measured using intravascular Doppler ultrasound and quantitative angiography. Flow was recorded at rest and in response to bolus doses of the endothelium independent vasodilator, papaverine. Endothelium dependent responses were measured by infusion of acetylcholine and substance P. Mean (SEM) baseline blood flow was reduced at rest (2-9 (0-4) v 4 5 (0.3) mVs, P < 0 001) and vascular resistance was raised (37.4 (3.6) v 27'1 (3.0) units, P < 0.05) in patients with heart failure compared with that in controls. The peak blood flow response to papaverine (8 mg), acetylcholine (10-7-10-5 moIl), and substance P (5 pmollmin) was reduced in heart failure, with greater impairment of the response to acetylcholine than substance P. There was a correlation between baseline blood flow in the heart failure group and diuretic dose (r = -0-62, P = 0 003), New York Heart Association classification (r = -0 65, P = 0.002), and left ventricular ejection fraction (r = 0-80, P = 0.0004). Conclusions-There is reduced blood flow and raised vascular resistance at rest in the legs of patients with heart failure. The degree of impaired blood flow in the leg correlates with the severity of heart failure. There is impairment of the response to both endothelium dependent and independent vasodilators. Abnormal function of the vascular myocyte in heart failure may explain these results as would structural abnormalities of the resistance vessels. (Heart 1996;75:469-476)

IL, Ocon AJ, Taneja I, Terilli C, Medow MS. Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation. Am J Physiol Heart Circ Physiol 300: H1492-H1500, 2011. First published February 11, 2011 doi:10.1152/ajpheart.01217.2010.-Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18 -26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V E), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V E increased from 8.8 Ϯ 1.3 l/min in room air to 14.6 Ϯ 0.8 l/min during hypoxia and to 20.1 Ϯ 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V E doubled during SNP. CO increased from 4.9 Ϯ .3 l/min in room air to 6.1 Ϯ .6 l/min during hypoxia and 6.4 Ϯ .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V E versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia.baroreceptors; ventilation; blood pressure In intact animals (dogs) hyperpnea follows occlusion of the common carotid arteries; it is wholly reflex in origin because the effect is the same even though all branches of the carotids have been previously tied excepting only the lingual arteries, and because section of the sinus nerves completely abolishes the reaction.Carl F. Schmidt (45) DETECTION OF ARTERIAL BLOOD PRESSURE (AP) by the arterial baroreceptors causes changes in heart rate (HR), sympathetic vasoconstriction, adrenal function, and renal sympathetic activity (2, 5). Evidence primarily derived from animal experiments suggests that the carotid sinus baroreflex also affects respiratory function (7,26,45,48). Rapidly increasing blood pressure causes decreased ventilation, whereas decreasing blood pressure causes increased ventilation. While these ventilatory effects were at one time attributed to increased or decreased perfusion of the arterial chemoreceptors (26, 32), s...

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.