Download Nitric Oxide and Regulation of Heart Rate in Patients With Postural

Original Article
Nitric Oxide and Regulation of Heart Rate in Patients With
Postural Tachycardia Syndrome and Healthy Subjects
Alfredo Gamboa, Luis E. Okamoto, Satish R. Raj, André Diedrich,
Cyndya A. Shibao, David Robertson, Italo Biaggioni
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Abstract—The objective is to study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural
tachycardia syndrome (POTS) patients. Reduced neuronal NO function, which could contribute to a hyperadrenergic
state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in
POTS. In protocol 1, 13 healthy volunteers (33±3 years) underwent autonomic blockade with trimethaphan and were
administered equipressor doses of Nω-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor) and phenylephrine
to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the
effects of L-NMMA in 9 POTS patients (31±3 years) and 14 healthy (32±2 years) volunteers, during autonomic blockade.
During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (27±2
versus 27±3 mm Hg). Phenylephrine produced only minimal heart rate changes, whereas L-NMMA produced a modest,
but significant, bradycardia (–0.8±0.4 versus –4.8±1.2 bpm; P=0.011). There were no differences between POTS and
healthy volunteers in the systolic blood pressure increase (22±2 and 28±5 mm Hg) or heart rate decrease (–6±2 and –4±1
bpm for POTS and controls, respectively) produced by L-NMMA. In the absence of baroreflex buffering, inhibition of
endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in
healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role
in POTS, it is through its interaction with the autonomic nervous system. (Hypertension. 2013;61:00-00.)
Key Words: autonomic blockade
■
autonomic nervous system ■ blood pressure
■ postural tachycardia syndrome
P
■
heart rate
■
nitric oxide
tonically inhibits sympathetic tone, a decrease in NO function in POTS could contribute to the hyperadrenergic state
seen in this disorder. Conversely, an increase in NO-induced
vasodilation could contribute to orthostatic intolerance, as
seen in patients with autonomic failure.9 It is also possible
that NO deficiency contributes to tachycardia. Both a direct
effect of NO on the sinoatrial node function and an indirect
effect through modulation of autonomic control of HR have
been reported.10 The mechanism of this putative effect of NO
on HR modulation is not yet fully understood,11 but all 3
known genomic isoforms of NO synthase (NOS) are reportedly present and functionally active in the heart,12 and NO
synthase is expressed in the sinoatrial node.13
We have developed an in vivo research model that allows
us to determine whether there is an intrinsic NO deficiency
in humans, independent of its interaction with the autonomic
nervous system.3 We used autonomic ganglionic blockade,
with the NN-nicotinic receptor antagonist trimethaphan, to
eliminate the restraining effect of the baroreflex, and thus allow
for the full expression of the effect of NOS inhibition. This
model also removes any potential interactions between NO
and the autonomic nervous system. Under these experimental
ostural tachycardia syndrome (POTS) is characterized
by an excessive increase in heart rate (HR; >30 bpm)
on assuming the upright posture, associated with symptoms
suggestive of cerebral hypoperfusion or sympathetic activation, but in the absence of orthostatic hypotension.1 POTS is
an important cause of disability in otherwise healthy young
adults, disproportionately affecting women of childbearing
age.2 The pathophysiology of POTS is not completely understood. Increased sympathetic activity appears to play a significant role, but the primary cause of this hyperadrenergic state
is not clear.
Nitric oxide (NO) is one of the most important metabolic
modulators of blood pressure and cardiovascular function.
Our previous studies suggest that NO tonically restrains
blood pressure by at least 30 mm Hg in healthy subjects.3
The mechanisms by which NO tonically decreases blood
pressure include a direct vasodilatory action4 and inhibition
of sympathetic nervous system tone.5,6 Given its importance
in cardiovascular regulation, the recent interest in the role of
NO in POTS is not surprising. Both excessive NO-mediated
dilation7 and decreased neuronal NO activity8 have been
reported in POTS. Given the evidence suggesting that NO
Received September 18, 2012; first decision November 20, 2012; revision accepted December 5, 2012.
From the Division of Clinical Pharmacology (A.G., L.E.O., S.R.R., A.D., C.A.S., D.R., I.B.), Departments of Medicine (A.G., L.E.O., S.R.R., A.D.,
C.A.S., D.R., I.B.), Pharmacology (S.R.R., D.R., I.B.), Biomedical Engineering (A.D.), and Neurology (D.R.), Vanderbilt University, Nashville, TN.
Please refer to this study by ClinicalTrials.gov identifier: NCT00770484. http://clinicaltrials.gov/ct2/show/NCT00770484
Correspondence to Italo Biaggioni, 2222 Pierce Ave, Room 556 RRB, Vanderbilt University, Nashville, TN. E-mail [email protected]
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI:10.1161/HYPERTENSIONAHA.111.00203
1
2 Hypertension February 2013
conditions, the decrease in HR induced by systemic NOS
inhibition can be attributed to direct chronotropic effects of
NO. Similarly, any increase in blood pressure can be attributed
to inhibition of the tonic vasodilatory effects of NO.
In protocol #1, we tested the direct chronotropic effect of
NO, independent of neural modulation or systemic hemodynamic changes. We compared the effect on HR of equipressor doses of L-NMMA (NOS inhibitor) and phenylephrine
(α1-adrenergic agonist) in healthy subjects during autonomic blockade. In protocol #2, we compared the effect of
L-NMMA on HR and blood pressure during autonomic blockade in patients with POTS, and age- and sex-matched healthy
subjects. If POTS patients have excessive NO function, this
would be manifested as augmented bradycardia and pressor
response to L-NMMA.
Methods
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Subjects
POTS patients were enrolled from those referred to the Vanderbilt
University Autonomic Dysfunction Center. Patients met criteria for
POTS if they developed symptoms of orthostatic intolerance accompanied by a HR rise ≥30 bpm within the first 10 minutes of standing,
in the absence of orthostatic hypotension (a fall in blood pressure
>20/10 mm Hg).14 All patients had symptoms for at least 6 months
in the absence of an additional chronic debilitating disorder or prolonged bed rest, were aged at least 18 years, were free of medications
that could impair autonomic function, and were not taking fludrocortisone for at least 5 days before testing.
Healthy volunteers were recruited from the Vanderbilt
University Clinical Research Center volunteer database and
Research Match,15 a national register to recruit volunteers for
clinical trials. Subjects aged 18 to 60, both men and women, with
a body mass index between 20 and 40 kg/m2 were considered eligible for the study. Subjects were not current smokers, and were
otherwise healthy (no concomitant cardiovascular or other diseases). All subjects were asked to avoid pregnancy for the duration
of the study. Pregnancy was excluded in women subjects with a
pregnancy test. Women taking oral contraceptives were allowed to
continue using them.
Subjects abstained from caffeine for ≥72 hours before testing.
During the screening visit, all subjects underwent a clinical examination, ECG, and admission urinalysis and routine laboratory test.
The study was reviewed and approved by the Vanderbilt University
Institutional Review Board, and written informed consent was obtained from each subject before initiating the study. Before enrolling,
the study was registered in clinicaltrials.gov.
General Study Design
The studies were conducted in the morning with the subject fasting (≥8 hours after their last meal), while lying supine. Blood pressure was measured by the volume clamp method (Finapres 2300;
Ohmeda), and also with an automated oscillometric brachial cuff
(Vital-Guard 450C, Ivy Biomedical Systems). HR was determined
from continuous ECG monitoring. An intravenous line was inserted
in the nondominant arm in a large antecubital vein. Three infusion
ports were connected to this catheter, one for trimethaphan infusion, the second for infusion of phenylephrine, and the third for
L-NMMA. A saline lock was placed in the other arm to administer
phenylephrine.
After a 15-minute baseline recording, trimethaphan 4 mg/min
(Cambridge Pharmaceuticals) was infused, and this was continued
throughout the study to assure complete autonomic blockade.3,16
Effectiveness of autonomic blockade was verified by phenylephrine bolus injections. Briefly, after a new stable blood pressure was
achieved, phenylephrine bolus injections commenced starting at a
dose of 2.5 µg. The phenylephrine bolus was repeated every 3 to 5
minutes with an increasing dose until systolic blood pressure (SBP)
increased ≥20 mm Hg. The absence of reflex bradycardia in response
to the increase in blood pressure was taken as evidence of effective
autonomic blockade.
Intrinsic blood pressure (in the absence of autonomic influences)
was recorded, and then SBP was clamped at ≈110 mm Hg by titrating
phenylephrine infusions starting at a rate of 0.05 µg/kg per min. This
allowed us to study all subjects at similar clamped adrenergic tone
and a comparable starting blood pressure. Once blood pressure was
stable and no more adjustments in phenylephrine dose were needed, a
new baseline period was recorded for 15 minutes. Systemic inhibition
of NOS with L-NMMA (Bachem, Switzerland) was then started and
continued throughout the study. The doses of L-NMMA range from
125 to 250 µg/kg per min. Each dose was maintained for 15 minutes.
Blood pressure was measured every 2 minutes for the first 8 minutes
and every 1 minute for the last 7 minutes, when a stable recording
was achieved. The last 5 measurements after stable recording were
used for the analysis.
Protocol 1: NO Effects on HR Regulation During
Autonomic Blockade in Healthy Controls
Thirteen healthy controls were studied in this protocol (33±3 years;
body mass index=25±1 kg/m2, 8 women). All procedures were identical, as described for the general protocol.
After autonomic blockade with trimethaphan was achieved, we targeted for an increased systolic blood pressure of ≈25 mm Hg, either
with L-NMMA 250 µg/kg per min for systemic NOS inhibition or
with boluses of phenylephrine (2.5–50 µg) for direct α-adrenergic
activation.
Protocol 2: NO Effects on HR and Blood Pressure
Regulation in POTS Patients
A parallel group design was used to compare the effects of NOS inhibition between healthy subjects and POTS patients. Thirteen healthy
controls (all women) and 9 POTS patients (all women) were included
in this study. Instrumentation and pharmacological testing were identical to those described for the general protocol.
The dose of L-NMMA ranged from 125 to 250 µg/kg per min
depending on the individual increase on systolic blood pressure.
For safety reasons, we did not increase the dose of L-NMMA if a
SBP of ≈150 mm Hg was already achieved. The main comparison
was the change in systolic blood pressure at the dose of 250 µg/kg
per min.
Data Acquisition
The surface ECG lead II was amplified, and no additional filters were
applied. ECG and blood pressure were digitized with 14-bit resolution and 500-Hz sample frequency, and recorded using the WINDAQ
data-acquisition system (DATAQ). Data were analyzed offline using
a customized program for data analysis written in PV-Wave (VNI), by
one of the authors (A.D.).
HR Variability and Blood Pressure Variability
A QRS detection algorithm, modified from Pan and Tompkins,17 was
used to generate beat-to-beat values. The nonequidistant event time
series of RR intervals and blood pressure values were interpolated,
low-pass filtered (cutoff: 2 Hz), and resampled at 4 Hz. Data segments of 300 seconds, recorded during stable resting conditions, were
used for spectral analysis. Linear trends were removed, and power
spectral density was estimated with the fast Fourier transform-based
Welch algorithm, using segments of 256 data points with 50% overlapping and Hanning window.18 The Hanning window was applied
to previous estimation of the power spectral density. The power in
the frequency ranges for very low frequencies (0.003 to <0.04 Hz),
low frequencies (0.04 to <0.15 Hz), and high frequencies (0.15 to
<0.40 Hz) were calculated for each interval, according to Task Force
recommendations.19
Gamboa et al Nitric Oxide in Postural Tachycardia Syndrome 3
Results
Statistical Analysis
Data are presented as mean±SEM. Comparison of outcomes by interventions in the same subjects were performed by Wilcoxon signedrank test, and comparisons of demographics and outcomes by groups
were performed using Mann–Whitney U test.
For protocol 1, the null hypothesis was that, given the same increase in systolic blood pressure, there would be no difference in HR
responses to either phenylephrine or L-NMMA during autonomic
blockade. The primary end point for protocol 1 was the decrease in
HR produced during autonomic blockade and NOS inhibition.
For protocol 2, the null hypothesis was that there would be no difference in outcomes in the response to systemic infusion of L-NMMA
between POTS patients and healthy subjects. The primary outcome for
protocol #2 was the change in HR produced by NOS inhibition during autonomic blockade in POTS patients and healthy subjects. The
change in SBP during the same period was a secondary end point.
All of the tests were 2-tailed, and a probability value of <0.05 was
considered significant. Analyses were performed with the SPSS statistical software (SPSS version 19.0, SPSS Inc).
We studied a total of 28 subjects. Thirteen healthy volunteers
(5 men) were included in protocol 1. Nine POTS patients and
14 healthy, sex- and age-matched volunteers were included in
protocol 2. All 8 healthy women that participated in protocol 1
also participated in protocol 2. Demographics, baseline characteristics, and response to orthostatic stress test are described
in Table 1. We included normative data for catecholamines
from our laboratory to serve as a reference to compare orthostatic changes in POTS patients.
The orthostatic stress test produced significant changes
in HR and diastolic blood pressure in all 3 groups (P<0.05
when compared with supine; Table 1). The increase in HR
was more dramatic among POTS patients (15±2, 17±2, and
52±4 bpm, for healthy controls in protocol 1, controls in protocol 2, and POTS patients, respectively; Table 1, P<0.001
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Table 1. Baseline Characteristics of All Participants
Protocol 1
Clinical Characteristics
Age, y
Controls
(n=13)
33±3
Protocol 2
Controls
(n=14)
POTS
(n=9)
P Value
32±2.4
31±3.1
0.487
23±1.1
0.413
BMI, kg/m
25±1.2
24±1.0
Sex (women/total)
8/13
14/14
9/9
LFRRI, ms2
1097±298
1527±446
534±170
HFRRI, ms
1256±446
1469±423
427±173
0.186
LFRRI/HFRRI, ms2
1.51±0.33
1.42±0.31
1.74±0.36
0.284
LFSBP, mm Hg2
9.64±2.62
6.89±1.85
4.92±0.93
0.950
SBP, mm Hg
110±3.51
107±2.96
107±5.3
0.360
DBP, mm Hg
64±2.17
65±2.22
69±2.79
0.486
HR, bpm
65±2.3
68±2.47
71±1.93
0.681
113±3.44
109±3.29
115±6.58
0.508
2
2
0.166
Orthostatic stress test
Supine
Standing
SBP, mm Hg
DBP, mm Hg
73±2.55*
74±2.50*
74±2.77*
0.801
HR, bpm
80±3.27*
86±3.13*
123±5.08*
<0.001
3±2.13
2±2.4
8±3.9
0.155
∆ SBP
∆ DBP
9±1.22
9±1.4
6±2.1
0.165
∆ HR
15±2.11
17±1.9
52±4.4
<0.001
Supine
186±13
256±83
0.512
Upright
397±18*
666±104*
0.003
∆NE (standing-supine)
211±19.8
411±109
0.005
Supine
15±2.4
27±6.3
0.036
Upright
39±9.0*
96±29.5*
0.001
∆Epi (standing-supine)
24±8.5
69±30.9
0.023
Plasma norepinephrine (ρg/mL)†
Plasma epinephrine (ρg/mL)†
BMI indicates body mass index; HF, high frequency, HR, heart rate; LF, low frequency; POTS, postural tachycardia syndrome; RRI, R-R heart rate interval; and SBP,
systolic blood pressure.
Values are presented as mean±SEM.
*P<0.05 when compared with supine.
†Controls values from the Autonomic Dysfunction Database at Vanderbilt University presented as a reference.
4 Hypertension February 2013
RRI, ms
p=0.0005
Table 2. Hemodynamic Changes in Response to Both
Autonomic Blockade and NOS Inhibition
p=0.861
40
Protocol 2: Response to Autonomic Blockade and NOS Inhibition
150
30
100
20
50
10
0
-50
L-NMMA
Phe
L-NMMA
Phe
SBP, (mm Hg)
RR, (ms)
200
50
SBP, mm Hg
0
Figure 1. Tonic positive chronotropic effect of nitric oxide (NO)
in healthy volunteers. Intravenous doses of L-NMMA (circles) and
phenylephrine (Phe, squares) were titrated to produce similar
increases in systolic blood pressure (right y axis, closed dots) in the
presence of autonomic blockade with trimethaphan. Under these
conditions, L-NMMA, but not phenylephrine, decreased heart rate,
shown as an increase in RR interval (left y axis, open dots).
Variables
Baseline
Trimethaphan
P Value
102±2.94
95±3.30
0.115
99±3.49
86±4.66*
0.024
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∆ Trimethaphan
–2.5±2.06
–9.6±3.44
0.065
Restored
101±3.31
97±2.77
0.345
L-NMMA
124±4.75†
124±6.02†
0.975
22±2.42
27.5±5.06
0.688
Baseline
61±2.71
58±2.67
0.549
Trimethaphan
57±2.30*
53±3.55
0.183
–4.0±1.63
–5.7±3.41
0.183
Restored
54±4.86
60±2.28
0.378
L-NMMA
72±2.95†
82±4.08†
0.096
∆ L-NMMA
18±4.27
22±4.14
0.224
62±2.08
72±2.83
0.006
97±7.39*
0.116
∆ L-NMMA
DBP, mm Hg
by Mann–Whitney U test, protocol 2). As expected, POTS
patients had higher upright HR (80±3.3, 86±3.1, and 123±5.1
for controls and POTS patients, respectively; P<0.001, Table
1, protocol 2). They also showed a trend toward a lower power
in the low- and high-frequency power spectra of HR. The
greater increase in HR was accompanied by a greater increase
in plasma norepinephrine in POTS patients.
Protocol 1
∆ Trimethaphan
During autonomic blockade with trimethaphan, L-NMMA
and phenylephrine increased SBP from 107±2.8 to 134±3.1
mm Hg (ΔSBPL-NMMA: 27±2 mm Hg) and from 108±4 to 135±5
mm Hg (ΔSBPphe: 27±3 mm Hg), respectively (P=0.861;
Figure 1). Phenylephrine produced only minimal HR changes
(from 83±2 to 82±2 bpm; P=0.093), confirming effective
removal of baroreflex function by trimethaphan. During NOS
inhibition, the same increase in SBP had a greater bradycardic
effect (from 81±2 to 76±2 bpm; P=0.005). The decrease in
HR was greater during NOS inhibition (ΔHRL-NMMA) than during phenylephrine boluses (ΔHRphe) (–4.8±1.2 bpm versus
–0.8±0.4 bpm; P=0.011).
POTS patients and controls showed similar supine blood
pressure values at baseline (95±3/58±3 mm Hg versus
102±3/61±3). The supine HR was significantly higher in
POTS patients than healthy subjects at baseline (72±2 versus
67±3 bpm; P=0.006). Autonomic blockade with trimethaphan
(4 mg/min) produced a significant increase in HR in both
POTS patients and healthy subjects (23±2 and 25±6 bpm;
Table 2) and a decrease in SBP (86±5 versus 99±4 mm Hg;
P=0.024; Table 2). Although SBP in POTS patients was significantly lower than healthy subjects with autonomic blockade, the larger fall in SBP seen in the POTS patients did not
reach statistical significance compared with the healthy subjects (ΔSBPTMT: –9.6±3.4 versus –2.5±2.1 mm Hg; P=0.065;
Figure 2).
All but 2 POTS patients tolerated the 250 µg/kg per min
dose of L-NMMA. The infusion was stopped at 125 µg/kg
per min in one patient who did not want to continue with the
remainder of the study, and in the other because we reached
POTS
(n=9)
SBP, mm Hg
∆ Trimethaphan
Protocol 2
Controls
(n=14)
HR, bpm
Baseline
Trimethaphan
85±2.12*
22.8±1.77
24.7±5.56
1.000
Restored
83±1.61
96±5.36
0.030
L-NMMA
79±1.88†
90±4.21†
0.016
∆ L-NMMA
–4.4±1.27
–5.9±1.72
0.477
Amount of L-NMMA, mg
219±18.24
253±34.29
0.516
DBP indicates diastolic blood pressure; HR, heart rate; POTS, postural
tachycardia syndrome; and SBP, systolic blood pressure.
Values are presented as mean±SEM.
*P<0.05 when comparing trimethaphan with baseline.
†P<0.05 when comparing final with restored.
our predetermined systolic blood pressure safety limit of 150
mm Hg. To account for this, we gave a dose of 125 µg/kg per
min to 3 control subjects. Cumulative doses of L-NMMA were
not different between POTS and controls (219±18 and 253±34
mg; P=0.516). The maximal tolerated dose of L-NMMA
produced an increase in SBP in POTS (ΔSBPL-NMMA: 28±5
mm Hg) that was similar to equivalent doses in controls (22±2
mm Hg; P=0.688). Increases in diastolic blood pressures were
also similar (ΔDBPL-NMMA: 22±4 and 18±4 mm Hg; P=0.224).
HR decreased to a similar extent in both POTS and controls
(ΔHRL-NMMA: –5.9±1.7 versus –4.4±1.3 bpm; P=0.477).
Discussion
There are 2 main new findings in the present study. The first
one is that, after removing autonomic influences, inhibition of
endogenous NO synthesis with L-NMMA results in significant
bradycardia. This effect is not explained by its pressor effect
or baroreflex responses, as the same increase in SBP with
phenylephrine did not reduce HR during autonomic blockade. These data show that NO has a tonic effect on human HR
in vivo, and that this effect is independent of the autonomic
Gamboa et al Nitric Oxide in Postural Tachycardia Syndrome 5
60
Systolic BP
p=0.0705
20
40
0
-10
20
-20
5
C
P
p=0.9749
C
P
p=0.901
-30
60
0
-5
-10
40
20
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-15
-20
SBP L-NMMA(mmHg)
HRL-NMMA, mm Hg
p=0.9728
10
0
B
Heart Rate
SBPTrMT (mmHg)
HRTrMT, mm Hg
A
0
Figure 2. Hemodynamic changes during autonomic blockade (A)
and NOS inhibition+autonomic blockade (B) on heart rate (HR,
left y-axis, open dots) and systolic blood pressure (SBP, right
y-axis, closed dots) in postural tachycardia syndrome (POTS)
patients (P, squares) and age- and sex-matched controls (C,
circles). Patients with POTS showed a trend toward a greater
drop in systolic blood pressure during autonomic blockade (A).
Similar increases in systolic blood pressure during NOS inhibition
produced comparable changes in heart rate in POTS patients
and healthy controls (B).
control of HR. It is well known that NO is produced within the
heart not only by endothelial cells, but also by myocytes.20,21
It has been proposed that NO has a role in the regulation of
cardiac function both under normal and pathological conditions.11,22,23 NOS inhibition was previously shown to reduce
HR in patients with transplanted, and presumably denervated,
hearts.24 Our findings indicate for the first time that endogenous NO tonically regulates HR in healthy subjects. This is
also in agreement with studies in animal models and isolated
human hearts, suggesting that NO provides a direct positive
chronotropic effect. The present study, therefore, contributes
to our understanding of HR modulation by NO without the
confounding effect of the baroreflex.
The second new finding is that NO function is not altered
in POTS patients. After removing autonomic influences,
the effects of NOS inhibition on HR and blood pressure
were comparable between POTS patients, and sex- and agematched controls. This finding indicates a lack of an intrinsic
impairment of NO function in POTS patients. If endogenous
NO were to contribute to the tachycardia observed in POTS,
then NOS inhibition would result in a greater reduction of
HR in this patient population, which was not observed in this
study. One could also speculate that excessive NO-mediated
vasodilation could contribute to tachycardia in POTS through
reflex mechanisms. If indeed endogenous NO did cause
greater vasodilation in POTS patients, then systemic NOS
inhibition would result in a greater increase in SBP for this
group. We did find a nonsignificant trend toward an augmented
blood pressure response in POTS with NOS inhibition, but
the magnitude of this effect is of questionable biological
significance. Assuming that the point estimates from this study
are correct, we would have needed at least 120 POTS patients,
and an equal number of healthy subjects for this difference to
reach statistical significance with 90% power.
It remains possible that a decrease in neuronal NO could
contribute to the sympathetic activation seen in POTS.
Conversely, sympathetic activation can induce a secondary
impairment in NO function. The current experimental paradigm does not allow us to tease out these potential interactions
between NO and the autonomic nervous system.
Finally, this study confirms previous findings22 that POTS
patients have a greater reliance of sympathetic activity to
maintain their blood pressure, as evidenced by their greater
fall in systolic blood pressure during autonomic blockade.
Intrinsic blood pressure (in the absence of autonomic
influences) was about 9 mm Hg lower in POTS than healthy
subjects (86±5 versus 99±3; P=0.039). The cause of this
constitutional hypotension remains unknown. Our findings
raise the possibility that sympathetic activation in POTS is a
compensatory response to these putative mechanisms.
In conclusion, we found that when disengaged from the
autonomic nervous system, NO has a positive tonic effect on
HR in both POTS patients and in healthy subjects. There were
no differences in the response to NOS inhibition in POTS
patients compared with healthy controls, arguing against a
primary NO impairment contributing to the pathophysiology
of POTS. If NO dysfunction plays a role in POTS, it is likely
through its interactions with the autonomic nervous system.
Acknowledgments
We thank all the participants who made this study possible.
Sources of Funding
This work was supported, in part, by National Institutes of Health
(NIH) grants P01 HL056693, U54 NS065736, and UL1 TR000445.
A.G. is supported by NIH grant K23 HL-95905.
Disclosures
None.
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Novelty and Significance
What Is New?
• Nitric oxide synthase has been shown to be present in the heart and
proposed to play a role in the regulation of cardiac function. This is the
first study to show that after removal of autonomic influences, NOS inhibition results in a significant drop in heart rate, implying a direct positive
chronotropic effect in humans.
• It has been postulated that patients with postural tachycardia syndrome
(POTS) have an altered nitric oxide (NO) function. This is the first study of
the effects of systemic NOS inhibitions in POTS patients.
What Is Relevant?
• These data reveals in vivo, the importance of NO on regulation of hear
rate in humans.
• In this study, we did not find differences between POTS patients and
controls in their response to NOS inhibition. If NO dysfunction plays a role
in POTS, it is likely through its interactions with the autonomic nervous
system.
Summary
The present study found that when disengaged from the autonomic
nervous system, NO has a positive tonic effect on heart rate in both
healthy subjects and POTS patients.
We found no evidence of a primary alteration of NO function in
POTS.
Nitric Oxide and Regulation of Heart Rate in Patients With Postural Tachycardia
Syndrome and Healthy Subjects
Alfredo Gamboa, Luis E. Okamoto, Satish R. Raj, André Diedrich, Cyndya A. Shibao, David
Robertson and Italo Biaggioni
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Hypertension. published online January 2, 2013;
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