(Hypertension. 2000;36:264.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Nitric Oxide and Cardiac Autonomic Control in Humans
From the Departments of Cardiovascular Medicine (S.C., J.C.V., J.N.T.) and Physiology (J.F., H.F.R., J.H.C.), University of Birmingham, UK.
Correspondence to Dr S. Chowdhary, Department of Cardiovascular Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. E-mail S.Chowdhary{at}bham.ac.uk
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Abstract |
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Abstract—Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23±5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with NG-monomethyl-L-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (
) in
high-frequency (HF) indexes of heart rate variability were smaller with
L-NMMA in comparison to an equipressor dose of the control
vasoconstrictor phenylephrine (12 to 42 µg/kg per hour):
root mean square of successive RR interval differences
(RMSSD)=23±32 versus 51±48 ms (P<0.002);
percentage of successive RR interval differences >50 ms
(pNN50)=5±15% versus 14±12% (P<0.05); and HF
normalized power=-2±7 versus 9±8 normalized units
(P<0.01), respectively. Relative preservation of these
indexes was observed during unloading of the baroreflex with sodium
nitroprusside compared with a matched fall in blood pressure produced
by a control vasodilator, hydralazine (9 to 18 mg/h):
RMSSD=-8±8 versus -24±15 ms (P<0.001);
pNN50=-6±11% versus -15±19% (P<0.01); HF
normalized power=-7±13 versus -13±11 normalized units
(P<0.05), respectively. The change in cross-spectral
-index calculated as the square root of the ratio of RR interval
power to systolic spectral power in the HF band (although not
-index calculated in the same way for the low-frequency bands or
baroreflex sensitivity assessed by the phenylephrine bolus
method) was attenuated with L-NMMA compared with
phenylephrine (=4±8 versus 14±15 ms/mm Hg,
respectively; P<0.02) and with sodium nitroprusside
compared with hydralazine (=-7±6 and -9±7 ms/mm Hg,
respectively; P<0.05). In conclusion, these data
demonstrate that NO augments cardiac vagal control in humans.
Key Words: nitric oxide • heart rate • baroreceptors • autonomic nervous system • blood pressure
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Introduction |
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The powerful influence of autonomic control on the natural history of cardiac disease is evidenced by large trials showing that reduced heart rate variability (HRV) and baroreflex sensitivity (BRS) are independent indicators of adverse prognosis.1 2 However, the mechanisms controlling cardiovascular autonomic function remain poorly defined.
The initial suggestion that nitric oxide (NO) may be an important mediator in cardiac autonomic control came from the demonstration of discrete neuronal populations that possess NO synthase at numerous sites within known cardiac autonomic pathways.3 Animal evidence suggests that the NO synthesized at these sites is active in modulating activity within both limbs of the autonomic nervous system. NO appears to act as a sympatholytic agent, decreasing activity within sympathoexcitatory brain stem nuclei and reducing central sympathetic outflow,4 5 as well as attenuating cardiac responses to sympathetic stimulation.6 Conversely, NO increases activity in central vagal motoneurons7 and enhances the cardiac response to vagal stimulation.6 8 In addition, NO donors may increase sinoatrial nodal discharge rate directly.9 However, the results of animal experiments have not been consistent, and the influence of NO on human cardiac autonomic control remains to be determined.
Cardiac autonomic control can be assessed noninvasively from the measurement of HRV and of BRS. This study was designed to determine the effects on these indexes of the systemic administration of (1) the inhibitor of endogenous NO synthesis NG-monomethyl-L-arginine (L-NMMA) and (2) the exogenous NO donor sodium nitroprusside in healthy human subjects. Investigation of the autonomic effects of these agents is hampered by their influence on blood pressure and consequently on baroreceptor loading. We have therefore made comparisons with the effects of equal changes in blood pressure produced by vasoactive drugs that do not act via the NO pathway, namely, phenylephrine and hydralazine.
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Methods |
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Subjects
Twenty-six healthy male volunteers aged 18 to 36 years (mean age, 23±5 years) were studied. All subjects were normotensive (supine cuff blood pressure measurement <140/90 mm Hg at initial screening visit), with no symptoms or signs of cardiovascular disease and on no medication. Subjects were asked to abstain from food or drink for at least 2 hours before the study and from caffeine and alcohol for 24 hours. Experimental protocols were approved by the South Birmingham local research ethics committee, and individual written consent was obtained.
Procedures
All protocols were of a single-blind, random-order, crossover
design. Subjects attended an initial habituation and training visit to
our dedicated clinical autonomic research laboratory. At this visit
they were trained to breathe to an audio signal set close to the
individual’s resting respiratory frequency. All studies were performed
at the same time of day and with an ambient temperature of
24±1°C.
A standard 3-lead ECG signal was amplified, processed (high-frequency [HF] signal noise filter >500 Hz), and digitized at 500 Hz with the use of a National Instruments NB/MI0/16XH/18 analog-to-digital converter board (National Instruments Corporation). A continuous arterial pressure signal was obtained with the Portapres device (TNO Biomedical Instrumentation) and was similarly digitized. Respiratory excursion was recorded from the amplified output of a standard strain gauge attached to an elastic strap around the subject’s chest. All signals were displayed on the screen of a personal computer running Laboratory View 5.0 software (National Instruments Corporation).
At the start of each study, a venous cannula was inserted into an antecubital vein for drug administration. Subjects were rested for 30 minutes, after which selected periods from all 3 signals were stored to disk during breathing at the predetermined frequency. Two 5-minute recordings were taken during a 30-minute normal saline infusion and an additional 2 at steady-state (<10% deviation in the mean heart rate and arterial pressure over two 60-second periods, 5 minutes apart) during the vasoactive infusion. Results were calculated as the mean of the 2 recordings. Target increments and decrements in mean arterial pressure were assessed from a continuously updated 60-second integrated mean of the Portapres signal and by intermittent arm cuff sphygmomanometry with an automated oscillometric system. All drugs were diluted in normal saline or 5% glucose immediately before the experiment.
Protocol 1: Effects of Inhibition of NO Synthesis on HRV
Fourteen subjects were randomly assigned to receive
intravenous infusions of either L-NMMA (3 mg/kg per hour)
or a control infusion of the pressor agent phenylephrine
(12 to 42 µg/kg per hour) during the first of 2 studies. The second
agent was given during a separate study visit 7 to 14 days later. At
each study visit the subject rested semisupine, and data were acquired
at baseline and during the drug infusion after the target rise in mean
arterial pressure of 
10 mm Hg had been
achieved.
Protocol 2: Effects of Exogenous NO on HRV
In a similar experimental design, 12 subjects received
random-order infusions of the NO donor sodium nitroprusside (1 to 3
mg/h) and, as a control, hydralazine (9 to 18 mg/h) on separate
days. Each infusion was titrated to achieve a drop in mean
arterial pressure of 5 to 10 mm Hg. Initial
experiments showed that in the supine position the dose of
hydralazine required to achieve this target was occasionally
associated with headache and nausea. Using a mild degree of
orthostatic stress considerably reduced the cumulative dose
required and side effects. Both experiments were therefore performed
with subjects at 30° of head-up tilt during all phases of the
experiment. Recordings were made, as before, at baseline and
during a 60- to 90-minute infusion of each of the hypotensive
agents.
To test the effect of time on this protocol, in 6 volunteers we assessed changes in mean arterial pressure and HRV during normal saline infusion (30 mL/h) at 30° head-up tilt. Data were acquired at baseline (30 minutes) and at 2 hours. No significant changes over time were observed in mean arterial pressure, RR interval, or any HRV index.
Measurement of BRS
BRS was assessed by 2 methods. The -index, describing the
transfer function of variability in the systolic pressure
signal to variability in the RR interval, was assessed by
cross-spectral analysis in protocols 1 and 2. In addition, we
used the Oxford method of measuring the RR interval response to a
transient rise in blood pressure generated by an
intravenous bolus injection of
phenylephrine.10 The value of the regression
line of RR interval against the preceding systolic blood
pressure was accepted as baroreflex gain only if the correlation
coefficient was >0.8. Quoted values represent the mean of at
least 3 results.
Data Analysis
Initial Processing
The ECG series for analysis were coded so that the
investigator performing the analysis was blinded to the
vasoactive agent under study. All ECG series were reviewed and if
necessary edited to exclude ectopic and artifact signals. The RR
intervals before and after any ectopic beats were replaced by
interpolation from the previous and following sinus intervals. No
signal containing >1% of ectopic beats was used for analysis.
R waves were detected by an individually adjusted threshold, and the
fiducial point was determined by fitting a quadratic polynomial to
sequential groups of 7 data samples. HRV was analyzed off-line
on data lengths of 256 RR intervals.
Time Domain Analysis
We used the standard time domain measures of standard deviation
of RR interval values (SDNN), root mean square of successive RR
interval differences (RMSSD), and percentage of successive RR interval
differences >50 ms (pNN50). Overall variability is expressed by SDNN,
whereas those indexes based on successive differences in RR intervals,
ie, pNN50 and RMSSD, assess HF ("beat-to-beat") variation
associated with respiratory sinus arrhythmia mediated
principally by the vagus nerve.11
Frequency Domain Analysis
Stationarity of the time series was tested by calculation of the
mean and variance of the first and last 128 beats of each
recording period to verify a difference of <10% in the values
for each time series. Power spectral analysis was performed
with the use of the Burg algorithm (autoregressive modeling), with a
model order between 8 and 20 selected to minimize the Akaike
information criterion. The power at each underlying frequency was
quantified by decomposing the total variability signal according to the
method of Zetterberg. Powers at low frequency (LF) (centered at
0.1 Hz) and at HF (corresponding to the observed respiratory
frequency) were thus determined. Power was expressed in absolute and
normalized units (nU) (power/total power >0.04 Hz)12 and
as the coefficient of component variance (square root of power/mean RR
interval).13
Baroreflex Sensitivity
In the assessment of BRS by cross-spectral analysis, the
recordings of RR interval and systolic blood pressure
were interpolated (with a cubic spline) and then resampled at 1 Hz to
produce a uniform time base. A cross spectrum of 256 samples was then
analyzed by fast Fourier transforms with the use of a Hanning
window on successive overlapping records of 64 samples each. The
-index was calculated as the square root of the ratio of RR interval
power to systolic spectral power in both the HF (-HF) and LF
bands (-LF).14 In each case the -index was computed
only when the squared coherence between these 2 signals was >0.5.
Statistical Analysis
Data for mean arterial pressure and RR interval were
compared by a 2-tailed paired Student’s t test. Differences
between groups for time and frequency domain indexes of HRV and BRS
were determined with the Wilcoxon signed rank test for paired
data. Statistical significance was defined by a P value
<0.05. Numerical values are expressed as mean±SD.
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Results |
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Effects of Inhibition of Endogenous NO on HRV
The frequency of metronomic breathing was within the range of 0.17 to 0.22 Hz. Baseline values for mean arterial pressure, RR interval, and indexes of HRV were not significantly different between the groups before administration of L-NMMA or phenylephrine (Table 1). Infusion of L-NMMA and phenylephrine resulted in similar rises in mean arterial pressure (11±5 and 11±3 mm Hg, respectively). Both agents increased the mean RR interval, but this increase tended to be lower with L-NMMA (+101±55 ms) than with phenylephrine (+156±110 ms) (P=0.08).
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However, measures of HF, vagally mediated HRV in both time and frequency domains were significantly lower during L-NMMA infusion than during phenylephrine (absolute values are shown in Table 1). A comparison of the magnitude of change in HRV from baseline values emphasizes the markedly discrepant responses between the 2 equipressor infusions (Figure 1). The increases in HF HRV in both domains (ie, RMSSD, pNN50, and HF power) were significantly smaller in response to L-NMMA than to an equipressor phenylephrine infusion. The fall in LF power in normalized (although not absolute) units was significantly less with L-NMMA than with phenylephrine infusion (Figure 1). The LF/HF ratio was higher during L-NMMA than during phenylephrine administration (Table 1).
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Effects of Exogenous NO on HRV
Baseline levels of mean arterial pressure and RR
interval were not significantly different before administration of
sodium nitroprusside or hydralazine. Indexes of HRV were
comparable at baseline except for RMSSD and HF absolute power, which
were lower in the sodium nitroprusside group (Table 2).
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The hypotensive responses to infusions of sodium nitroprusside and hydralazine were well matched (change in mean arterial pressure=-8±2 and -7±3 mm Hg, respectively) but produced discrepant effects on heart rate, with less acceleration during sodium nitroprusside than during hydralazine infusion (change in mean RR interval=-98±58 versus -212±81 ms, respectively; P<0.0001). The HRV responses were also significantly different. HF, vagally mediated indexes of HRV in the time domain (ie, RMSSD and pNN50) were significantly greater during sodium nitroprusside infusion than during hydralazine infusion (Table 2). It can be seen that despite the fall in blood pressure, there was relative preservation of HF HRV with sodium nitroprusside. In the frequency domain, the pattern is less clear because of a large reduction in total power with hydralazine. In absolute units, both HF and LF powers appeared to be higher with sodium nitroprusside than hydralazine, although there were no significant differences when the change in total power was corrected for by the use of normalized units. However, when changes from baseline are examined, it can be seen that the effects of the 2 agents on HF variability in both domains were discrepant with smaller changes during sodium nitroprusside than during hydralazine administration (Figure 2).
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Effects of NO on BRS
Cross-spectral analysis of RR interval and
systolic blood pressure variability revealed that the -LF
index was not calculable because of noncoherence for 25% of data in
protocol 1 and 14% of data in protocol 2, whereas -HF was
calculable for all data. Baseline values of -HF and -LF were not
significantly different for either protocol. -HF (although not
-LF) was both significantly lower and increased less during infusion
of L-NMMA than during infusion of phenylephrine (Table 1 and Figure 1). Sodium nitroprusside resulted in
significantly less attenuation of -HF (although not of -LF) than
did hydralazine (Figure 2).
Assessment of BRS by the phenylephrine bolus method revealed similar baseline values before L-NMMA and phenylephrine infusion (17.4±6.3 and 15.6±6.1 ms/mm Hg, respectively; P=0.2). When L-NMMA and phenylephrine infusion were compared, values were not significantly different (18.6±4.7 and 18.4±6.5 ms/mm Hg, respectively; P=0.9). Compared with baseline, BRS did not change significantly in response to L-NMMA, whereas there was a significant (18%) rise in BRS with phenylephrine (P=0.02).
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Discussion |
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Direct recording of cardiac vagal and sympathetic activity is not possible in humans, but there is good evidence that HF indexes of HRV in both time and frequency domains reflect vagal modulation of heart rate in the conscious human. This includes the demonstration that HF variability is proportional to efferent vagal activity in anesthetized dogs15 and in humans is strongly correlated with heart rate acceleration in response to atropine.13 16 Furthermore, HF variability is virtually abolished by atropine.16 17 We have shown that despite a rise in blood pressure equal to that obtained with phenylephrine, systemic inhibition of NO synthase by L-NMMA was associated with less bradycardia and lower measures of HF HRV. We suggest that this is a result of removal of a tonic excitatory effect of NO on baroreflex-mediated cardiac vagal activity. In support of this, we found that infusion of the exogenous NO donor sodium nitroprusside was associated with less tachycardia and relative preservation of cardiac vagal control (as measured by HF HRV) compared with a control infusion of hydralazine. These data constitute the first controlled evidence of an important role for NO in cardiac vagal control in human subjects.
Although we have shown that NO appears to modulate cardiac vagal control of heart rate, we cannot exclude the possibility of a sympathetic nervous influence on our results. LF power has been used as an index of sympathetic activity (especially when expressed in normalized units),18 but there is undoubtedly a large vagal component to this oscillation.17 Similarly, use of the LF/HF ratio as a measure of "sympatho-vagal balance"12 has been the subject of recent debate.19 Thus, we are reluctant to draw any firm conclusions on the relative activity of the sympathetic nervous system during these drug infusions.
The observed effect of NO on vagal activity during a sustained
rise or fall in blood pressure could have been mediated by effects on
either the sensitivity or "gain" of the baroreflex or a change in
the reflex set point. When BRS was measured by cross-spectral
analysis, -HF was higher during phenylephrine
than L-NMMA infusion and fell less during sodium nitroprusside than
during hydralazine administration, suggesting an enhancement of
baroreflex gain by NO. Changes in -LF were directionally similar but
were not statistically significant (possibly because of the loss of
analyzable data through noncoherence). There may also be differences in
the information held within each -index. Since -HF is determined
at a frequency at which sympathetic influence is not effective, this
index represents gain in the vagal limb of the
baroreflex,20 while the -LF index is open to influence
by both limbs of the autonomic nervous system.20 The
Oxford method of measuring BRS, which is historically the "gold
standard," failed to show a clear influence of NO. Thus, our results
do not allow firm conclusions to be drawn on the possible effects of NO
on human baroreflex gain.
Previous information on the effects of NO on autonomic activity in humans is limited. Studies comparing the response of muscle sympathetic nerve activity to an infusion of L-NMMA with appropriate baroreflex controls indicated an inhibitory action of endogenous NO on sympathetic nerve activity in humans.21 Castellano et al22 studied the effects of L-NMMA on HRV in 7 healthy volunteers. No controls for alterations in blood pressure were studied, making the results difficult to interpret, but in agreement with our results, there were no significant changes in absolute values of HF or LF RR interval powers or in cross-spectral BRS despite a clear rise in blood pressure.
Our data appear to indicate that NO exerts a tonic enhancing effect on human cardiac vagal control. The site of action cannot be determined from our results, but animal data suggest that this may be due to actions of NO synthesized within neurons at a number of sites. NO has been shown to increase neuronal activity within the nucleus tractus solitarius5 (the primary relay site for baroreceptor afferent fibers), as well as enhancing the activity of medullary vagal motoneurons.7 In the efferent limb of the reflex, NO has been shown to enhance the bradycardic effects of efferent vagal8 and muscarinic stimulation.6 "Indirect" vagal activity (the ability of the efferent vagus to antagonize sympathetic cardiac responses) is also enhanced by NO.23
In vitro studies have shown that NO may also have direct nonneurally
mediated effects on the sinus node, increasing heart rate by
stimulating the If current.9 In our
study the NO donor (sodium nitroprusside) caused less
tachycardia than the non–NO-dependent agent
hydralazine, while inhibition of NO synthesis caused less
bradycardia than the 1-adrenergic agonist
phenylephrine. Thus, any direct effects of NO on the sinus
node in humans would appear to have been overwhelmed by opposing
effects of NO on cardiac autonomic control.
There are a number of limitations to our study. It is not possible for us to be certain that the stimulus to the baroreceptor was identical between our study drugs and their controls. We chose to use mean arterial pressure to control for baroreceptor stimulus because there is good evidence that this value (rather than pulse pressure or rate of pressure change) is the main determinant of baroreceptor discharge.24 Furthermore, we did not measure central aortic pressure directly but assessed blood pressure in the upper limb. However, the avoidance of invasive procedures permitted a more accurate estimation of resting cardiac autonomic tone.
It is also possible that the vasoactive drugs we used may exert different mechanical effects on the arterial baroreceptors. In dogs phenylephrine was found to constrict carotid arteries, resulting in augmentation of the baroreceptor response.25 However, in humans phenylephrine appears to cause dilatation rather than constriction of the carotid artery.26 Furthermore, in dogs there was no significant difference in baroreceptor firing whether intraluminal pressure was raised by phenylephrine, angiotensin II, or an aortic balloon,27 and Hirooka et al28 showed that the baroreceptor response was independent of the effects of drugs on aortic diameter. We therefore believe that it is unlikely that any mechanical effects on arterial baroreceptors could explain our results.
Clinical Implications
Our study provides the first demonstration that both
endogenous and exogenous NO modulate baroreflex-mediated
cardiac vagal control in humans, as indicated by measures of HRV and
BRS. The clinical relevance of this finding is emphasized by the clear
demonstration that both of these measures of cardiac autonomic control
are of prognostic importance in patients with cardiac
disease.1 2 Further work is required to assess whether
these prognostic markers can be favorably influenced by manipulation of
the NO pathway in patients with cardiac disease. Finally, until
recently it was common to assess BRS in humans with the use of
nitrovasodilators to unload the reflex. Our data raise doubts about the
results obtained by this method because of the possibility of a direct
autonomic effect of the NO donor itself.
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Acknowledgments |
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This research was supported by a grant from the British Heart Foundation. Dr Chowdhary is a British Heart Foundation Junior Research Fellow, and Dr Townend is a British Heart Foundation Senior Lecturer.
Received November 22, 1999; first decision December 27, 1999; accepted February 28, 2000.
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 S. Cook, M. Togni, M. C. Schaub, P. Wenaweser, and O. M. Hess High heart rate: a cardiovascular risk factor? Eur. Heart J., October 2, 2006; 27(20): 2387 - 2393. [Full Text] [PDF]
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 F. Iellamo, M. Tesauro, S. Rizza, S. Aquilani, C. Cardillo, M. Iantorno, M. Turriziani, and R. Lauro Concomitant Impairment in Endothelial Function and Neural Cardiovascular Regulation in Offspring of Type 2 Diabetic Subjects Hypertension, September 1, 2006; 48(3): 418 - 423. [Abstract] [Full Text] [PDF]
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 H C Routledge, S Manney, R M Harrison, J G Ayres, and J N Townend Effect of inhaled sulphur dioxide and carbon particles on heart rate variability and markers of inflammation and coagulation in human subjects Heart, February 1, 2006; 92(2): 220 - 227. [Abstract] [Full Text] [PDF]
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M.-C. Irigoyen, J. Paulini, L. J. F. Flores, K. Flues, M. Bertagnolli, E. Dias Moreira, F. Consolim-Colombo, A. Bello-Klein, and K. De Angelis Exercise Training Improves Baroreflex Sensitivity Associated With Oxidative Stress Reduction in Ovariectomized Rats Hypertension, October 1, 2005; 46(4): 998 - 1003. [Abstract] [Full Text] [PDF]
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 K. D. Monahan, I. Eskurza, and D. R. Seals Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2113 - H2117. [Abstract] [Full Text] [PDF]
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S. Chowdhary, A. M. Marsh, J. H. Coote, and J. N. Townend Nitric Oxide and Cardiac Muscarinic Control in Humans Hypertension, May 1, 2004; 43(5): 1023 - 1028. [Abstract] [Full Text] [PDF]
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 J. Fletcher, A. N. Buch, H. C. Routledge, S. Chowdhary, J. H. Coote, and J. N. Townend Acute aldosterone antagonism improves cardiac vagal control in humans J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1270 - 1275. [Abstract] [Full Text] [PDF]
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M. Farias III, K. Jackson, M. Johnson, and J. L. Caffrey Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2001 - H2012. [Abstract] [Full Text] [PDF]
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R. D. Lipman, J. K. Salisbury, and J. A. Taylor Spontaneous Indices Are Inconsistent With Arterial Baroreflex Gain Hypertension, October 1, 2003; 42(4): 481 - 487. [Abstract] [Full Text] [PDF]
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 B. Pitt, C. T Stier Jr, and S. Rajagopalan Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168. [Abstract] [PDF]
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G. Piccirillo, M. Nocco, A. Moise, M. Lionetti, C. Naso, S. di Carlo, and V. Marigliano Influence of Vitamin C on Baroreflex Sensitivity in Chronic Heart Failure Hypertension, June 1, 2003; 41(6): 1240 - 1245. [Abstract] [Full Text] [PDF]
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 B. Pitt Aldosterone Blockade in Patients With Acute Myocardial Infarction Circulation, May 27, 2003; 107(20): 2525 - 2527. [Full Text] [PDF]
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P. J. Fadel, M. Stromstad, D. W. Wray, S. A. Smith, P. B. Raven, and N. H. Secher New insights into differential baroreflex control of heart rate in humans Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H735 - H743. [Abstract] [Full Text] [PDF]
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C. R. Claxton and M. W. Brands Nitric Oxide Opposes Glucose-Induced Hypertension by Suppressing Sympathetic Activity Hypertension, February 1, 2003; 41(2): 274 - 278. [Abstract] [Full Text] [PDF]
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T. Gori, J. S. Floras, and J. D. Parker Effects of nitroglycerin treatment on baroreflex sensitivity andshort-term heart rate variability in humans J. Am. Coll. Cardiol., December 4, 2002; 40(11): 2000 - 2005. [Abstract] [Full Text] [PDF]
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S Chowdhary, D Harrington, R S Bonser, J H Coote, and J N Townend Chronotropic effects of nitric oxide in the denervated human heart J. Physiol., June 1, 2002; 541(2): 645 - 651. [Abstract] [Full Text] [PDF]
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S. Chowdhary, S. L. Nuttall, J. H. Coote, and J. N. Townend L-Arginine Augments Cardiac Vagal Control in Healthy Human Subjects Hypertension, January 1, 2002; 39(1): 51 - 56. [Abstract] [Full Text] [PDF]
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S. D. Katz, D. V. Parums, B. G. Phillips, M. Kato, C. A. Pesek, V. K. Somers, M. Winnicki, D. Davison, and K. Narkiewicz Sympathetic Activation by Sildenafil Response Circulation, November 27, 2001; 104 (22): e119 - e120. [Full Text] [PDF]
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 J. D. Lefrandt, M. C. Mulder, E. Bosma, A. J. Smit, and K. Hoogenberg Relation Between Autonomic Function and Blood Glucose in the Nondiabetic Range Diabetes Care, November 1, 2001; 24(11): 2017 - 2017. [Full Text] [PDF]
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