Download Omega-3 Fatty Acid Supplementation Augments

Omega-3 Fatty Acid Supplementation Augments
Sympathetic Nerve Activity Responses to Physiological
Stressors in Humans
Kevin D. Monahan, Thad E. Wilson, Chester A. Ray
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Abstract—An inverse relation exists between omega-3 fatty acid intake and risk of cardiovascular disease development/
mortality and sudden cardiac death in humans. Mechanisms underlying this cardioprotective effect are unknown, but
could involve the autonomic nervous system. We tested the hypothesis that omega-3 fatty acid supplementation (“fish
oil”) would reduce muscle sympathetic nerve activity (MSNA) at rest and attenuate increases during physiological
stressors. MSNA (peroneal microneurography) was measured during rest, ischemic handgrip to fatigue (IHG), and a
cold pressor test (CPT). Measurements were obtained before (PRE) and after (POST) 1 month of daily ingestion of
either fish oil (experimental group, n⫽9) or olive oil capsules (control group, n⫽9). MSNA at rest was comparable PRE
and POST in control (3⫾1 versus 3⫾1 bursts/30 seconds) and experimental (4⫾1 versus 5⫾1 bursts/30 seconds)
subjects. IHG and CPT increased MSNA in both groups PRE and POST. MSNA, arterial blood pressure, and heart rate
responses to the stressors were similar PRE and POST in the control group. In contrast, MSNA responses to IHG (⌬4⫾2
and ⌬9⫾2 bursts/30 seconds; P⬍0.05 for PRE and POST, respectively) and CPT (⌬4⫾1 versus ⌬10⫾2 bursts/30
seconds; P⬍0.05) were augmented after omega-3 fatty acid supplementation whereas arterial blood pressure and heart
rate responses were unchanged. These data indicate that 1 month of omega-3 fatty acid supplementation does not change
MSNA at rest but augments sympathetic outflow to physiological stressors. The mechanism underlying augmented
MSNA responses to physiological stressors after omega-3 fatty acid supplementation is unknown, but may involve
impaired peripheral vasoconstriction. (Hypertension. 2004;44:732-738.)
Key Words: autonomic nervous system 䡲 blood pressure 䡲 fatty acids 䡲 cardiovascular diseases
A
n inverse relation exists between omega-3 fatty acid
intake and risk of cardiovascular disease development/
mortality and sudden cardiac death in humans.1– 8 The mechanisms underlying the cardioprotective effects of omega-3
fatty acids are likely to be multifactorial9 –16 and may involve
the autonomic nervous system. Data suggesting a link between omega-3 fatty acids and the autonomic nervous system
include favorable associations between indices of cardiac
autonomic outflow and omega-3 fatty acid intake.17,18 Additionally, sympathetic nervous system outflow may be reduced
by omega-3 fatty acids as suggested by decreased plasma
norepinephrine levels after increased dietary intake of fish or
fish oils.19,20 Presently the effect of omega-3 fatty acid
supplementation on directly recorded efferent sympathetic
nerve activity at rest and in response to sympathoexcitatory
stressors is unknown.
Accordingly, in the present study we tested the hypothesis
that 1 month of omega-3 fatty acid supplementation would
reduce muscle sympathetic nerve activity (MSNA) at rest and
in response to physiological stressors. Moreover, we hypoth-
esized that these effects on MSNA would attenuate the
magnitude of the pressor response to physiological stressors.
These data should expand our knowledge of how omega-3
fatty acids influence the autonomic nervous system and
possibly reduce cardiovascular disease associated morbidity/
mortality in humans.
Methods
Subjects
Eighteen young (age 18 to 35 years) subjects were studied. Subjects
were normotensive, nonsmoking, nonobese (body mass index
⬍27kg/m2), nonmedicated, and otherwise healthy based on medical
history and physical examination.
Written informed consent was obtained on Pennsylvania State
University College of Medicine Institutional Review Boardapproved forms.
Experimental Design
This study was randomized, placebo-controlled, and double-blinded.
Subjects were studied supine and fasted (12 hours) on 2 occasions
separated by 1 month. The time of day of the testing differed
between, but not within subjects.
Received August 4, 2004; first decision August 12, 2004; revision accepted September 7, 2004.
From the Departments of Medicine (Cardiology) and Cellular and Molecular Physiology, General Clinical Research Center, Pennsylvania State
University College of Medicine, Hershey, Pa.
Correspondence to Kevin Monahan, PhD, Penn State College of Medicine, Division of Cardiology H047, The Milton S. Hershey Medical Center, 500
University Dr, Hershey, PA 17033-2390. E-mail [email protected]
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000145292.38579.f4
732
Monahan et al
Protocol
After establishing an MSNA site, a 5-minute recording was obtained
to quantify MSNA at rest. After obtaining these data, responses to
physiological stressors was assessed in a randomized fashion. Fifteen
minutes elapsed between stressors.
Ischemic Handgrip to Fatigue
After a 2-minute baseline period, subjects performed ischemic
handgrip (IHG) at 30% of their maximal voluntary contraction to
fatigue. Maximal voluntary contraction force was assessed in triplicate at the beginning of the protocol. IHG was stopped when target
force could not be maintained for ⬎3 seconds. IHG was performed
to fatigue to allow comparisons at the same physiological time
points.
Cold Pressor Test
After a 2-minute baseline period, subjects submerged their hand up
to the wrist in a bucket of ice and water for 90 seconds. This was the
cold pressor test (CPT).
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Omega-3 Fatty Acids Supplementation
After obtaining the aforementioned measurements, subjects were
given a container filled with capsules and instructed to ingest 10
capsules per day for 1 month. Containers were filled with 1-gram
capsules containing either omega-3 fatty acids (Pharmacist’s Ultimate Health, Saint Paul, Minn; 300 mg eicosapentaenoic acid [EPA]
and 200 mg docosahexaenoic acid [DHA]) or placebo (olive oil). A
local compounding pharmacist assembled the placebo capsules.
Efforts to increase/verify compliance to pill ingestion included
review of subject pill ingestion diary, pill count, and phone-based
contacts.
After this 1-month period, subjects returned to the laboratory and
the experimental measurements were repeated in the same order as in
testing before 1 month of oil ingestion. Subjects were asked not to
ingest any capsules the day of testing after 1 month of oil ingestion.
Measurements
Multifiber recordings of MSNA were obtained by inserting a
tungsten microelectrode in the peroneal nerve of the leg.21 Raw
nerve recordings were amplified, filtered, full wave-rectified, and
integrated to obtain mean voltage neurograms.
Arterial Blood Pressure and Heart Rate
Resting arterial blood pressure (BP) was determined (Dinamap XL,
Johnson & Johnson) after a 5-minute period of rest (5 times at
1-minute interval). BP measurements during physiological stressors
were made using a Finapres (Ohmeda). Heart rate was determined
with ECG.
Blood Samples
Venous blood samples were obtained before and after the 1-month
period. Analyses included blood lipids, C-reactive protein (using an
immunoturbidimetric assay),22 and prostanoids (6-Keto-PGF1␣ and
thromboxane B2).23,24
Data Analysis
Physiological data were displayed and recorded (MacLab 8e, ADInstruments) at 400 Hz for later analysis.
Resting MSNA was quantified from 5-minute recordings as bursts
per 30 seconds. Burst frequency is a highly reproducible method of
reporting MSNA within the same subject across periods of weeks to
months.25 Additionally, MSNA was quantified as the sum of the area
under individual MSNA bursts (total MSNA: arbitrary units [au]/30
seconds). Quantifying MSNA in this manner is dependent on both
burst frequency and the size of individual bursts. Importantly, the
latter is influenced by system amplification and microelectrode
position within the nerve. Neurograms are normalized by assigning
the largest burst at rest an arbitrary amplitude of 1000 and a portion
of the nerve recording in which neural silence occurs for ⬇5 seconds
Fish Oil and Sympathetic Nerve Activity
733
a value of zero. This normalization technique assumes that the
largest bursts at rest represent an equal amount of neural outflow
day-to-day and between subjects. Based on this assumption comparing absolute levels of total MSNA between subjects or across days in
the same subject may not be appropriate. For this reason, we
generally report the relative magnitude of sympathoexcitation to
provide further additional support for the data derived from the burst
frequency data (which are not dependent on such assumptions). This
approach appears appropriate, because each individual subject’s
baseline level of total MSNA will serve as a control level for the
response to the stressors. Accordingly, responses to the physiological
stressors were quantified as: (1) absolute burst frequency (bursts/30
seconds); (2) as change in burst frequency from baseline (⌬ bursts/30
seconds); (3) as percent change from baseline in total MSNA (%⌬
total MSNA); and (4) as the change in total MSNA (⌬ au/30
seconds). BP was quantified as systolic, diastolic, and mean BP.
Heart rate was determined at 30-second intervals and is reported as
beats per minute.
Statistical Analysis
Differences in baseline subject characteristics were determined by t
test, and repeated measures ANOVA was used to determine effects
of the intervention. Statistical significance was established at
P⬍0.05.
Results
Subject Characteristics
Subject characteristics in the experimental (omega-3 fatty
acid) and control (olive oil) groups before and after the
intervention are shown in the Table. Importantly, MSNA at
rest (in any expression) and BP at rest were unchanged by
either intervention.
Responses to Physiological Stressors
Autonomic and cardiovascular parameters were similar before each of the stressors before and after the intervention.
IHG to Fatigue
MSNA, BP, and heart rate increased (P⬍0.05) during IHG to
fatigue before and after the intervention in experimental and
control subjects (Figure 1). Increases in MSNA, BP, and heart
rate were time-dependent and maximal in the final 30 seconds
of IHG. In control subjects, MSNA (⌬ burst frequency, ⌬
total MSNA, and %⌬ total MSNA), mean BP, and heart rate
responses to IHG were similar before and after the intervention (Figure 1). In contrast, MSNA responses were augmented in the experimental group after the intervention
(⌬9⫾2 bursts/30 seconds, ⌬355⫾83%, and ⌬1463⫾360
au/30 seconds for burst frequency, %⌬ total MSNA, and ⌬
total MSNA, respectively) compared with before the intervention (⌬4⫾2 bursts/30 seconds, ⌬104⫾48%, and
⌬585⫾264 au/30 seconds; P⬍0.05 for burst frequency and
%⌬ total MSNA and P⫽0.06 for ⌬ total MSNA) (Figure 1).
Increases in mean BP (⌬34⫾6 versus ⌬33⫾6 mm Hg) and
heart rate (⌬22⫾4 versus ⌬22⫾5 bpm) were similar before
and after the intervention in the experimental group (Figure
1). Because of variations in total MSNA at baseline, the
effects are less pronounced than when data are expressed as
percent change (%⌬) in total MSNA and change (⌬) in total
MSNA (Figure 1). The limitations associated with the expression of total MSNA have been discussed (see Methods).
Collectively, these data indicate that IHG-induced increases
in MSNA (burst frequency, and %⌬ total MSNA), but not in
734
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November 2004
Subject Characteristics
Olive Oil
Gender, m/f
Age, y
Height, cm
Body mass, kg
Fish Oil
Before
After
Before
After
Interaction
4/5
—
—
6/3
—
24⫾1
171⫾2
—
25⫾1
171⫾2
179⫾2
—
179⫾2
—
0.80
67⫾4
67⫾4
79⫾4
80⫾4
0.79
BMI, kg/m2
22.7⫾1.1
22.9⫾1.1
24.8⫾1.0
24.9⫾1.0
0.44
Systolic BP, mm Hg
112⫾2
109⫾1
113⫾4
111⫾3
0.66
Diastolic BP, mm Hg
64⫾2
64⫾2
62⫾1
59⫾2
0.24
Heart rate, bpm
59⫾2
54⫾2
60⫾4
59⫾4
0.07
3⫾1
3⫾1
4⫾1
5⫾1
0.19
0.05
MSNA, bursts/30, s
Total cholesterol, mg/dL
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145⫾8
147⫾7
144⫾11
157⫾13*
HDL, mg/dL
54⫾4
51⫾3
52⫾6
57⫾5
0.04
LDL, mg/dL
76⫾7
80⫾6
67⫾9
80⫾12*
0.13
Triglycerides, mg/dL
82⫾8
79⫾8
82⫾20
55⫾9
0.20
0.80⫾0.05
0.90⫾0.05
0.90⫾0.05
0.94⫾0.05
0.30
90⫾5
82⫾4
83⫾3
87⫾6
0.21
Thromboxane B2, pg/mL
169⫾10
177⫾17
152⫾11
205⫾26
0.96
IHG time to fatigue, s
210⫾13
194⫾15
238⫾24
250⫾20
0.18
C-reactive protein, mg/dL
6-Keto-PGF1␣, pg/mL
Values are mean⫾SE.
BMI indicates body mass index; BP, blood pressure; MSNA, muscle sympathetic nerve activity; au,
arbitrary units; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IHG, ischemic handgrip;
Before, before 1 month of oil; After, after 1 month of oil.
Interaction indicates P value of 2-way (group⫻time) repeated measures ANOVA interaction.
*P⬍0.05 from before.
BP and heart rate, are augmented by 1-month ingestion of
omega-3 fatty acids.
CPT
CPT increased MSNA and BP (P⬍0.05) in both groups
before and after the intervention. In the control group,
CPT-induced increases in MSNA (burst frequency, ⌬ total
MSNA, and %⌬ total MSNA), mean BP, and heart rate were
not different before and after the intervention (Figure 2). Peak
CPT-induced increases in MSNA (burst frequency) were
greater (P⬍0.05) after omega-3 fatty acid supplementation
(⌬4⫾1 versus ⌬10⫾2 bursts/30 seconds; change from baseline for before and after the intervention, respectively). When
MSNA was expressed as the absolute increase in total MSNA
(⌬1206⫾300 versus ⌬2021⫾426 au/30 seconds; change
from baseline for before and after the intervention, respectively) and as the relative increase in total MSNA (⌬347⫾93
versus ⌬520⫾175%) responses were greater after the intervention, but not statistically (Figure 2). Increases in MSNA
during CPT elicited similar significant increases in mean BP
(⌬19⫾2 versus ⌬21⫾2 mm Hg) and heart rate (⌬8⫾1 versus
⌬7⫾3 bpm) (Figure 2) before and after the intervention in the
experimental group. Collectively, these data indicate that
CPT-induced increases in MSNA burst frequency, but not in
BP or heart rate, are augmented by 1-month ingestion of
omega-3 fatty acids.
Discussion
The primary new finding from the present study is that
1-month ingestion of omega-3 fatty acids does not alter
MSNA at rest, but does augment stress-induced increases.
Despite the augmented MSNA responses to stress after
ingestion of omega-3 fatty acids, the systemic pressor response was not altered, suggesting that the process by which
increases in MSNA produce vasoconstriction may be impaired by omega-3 fatty acids.
Experimental data indicate that fish consumption and
omega-3 fatty acid supplementation reduce morbidity/mortality associated with cardiovascular disease as well as risk of
sudden cardiac death.8,26 The mechanisms underlying these
effects could involve a number of physiological systems.27
One system that has received limited attention is the autonomic nervous system. In this context, experimental data
suggest favorable associations between omega-3 fatty acid
intake and cardiac autonomic outflow.17,18,28 Moreover,
plasma norepinephrine levels, which provide a gross index of
whole-body sympathetic outflow, have been shown to be
reduced at rest after fish or fish oil intake in some,19,20 but not
all studies.29 Our results using a direct and more powerful
measure of sympathetic outflow (ie, MSNA) do not support
these earlier findings19,20 or the hypothesis that omega-3 fatty
acids reduce MSNA at rest in healthy young adults. It is
possible that different results may be obtained if these
measures were made in populations with elevated baseline
levels (eg, older adults or in congestive heart failure).
Few data exist examining sympathetic nervous system
responses to physiological stress after omega-3 fatty acid
supplementation. Increases in plasma norepinephrine during
hypovolemic stress are not altered by 4-week ingestion of
Monahan et al
Fish Oil and Sympathetic Nerve Activity
735
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Figure 1. Responses to ischemic handgrip to fatigue (IHG) before (Pre) and
after (Post) 1-month intake of omega-3
fatty acids (experimental) or olive oil
(control). Data are plotted at the time
corresponding to 25%, 50%, 75%, and
100% (ie, fatigue) of the task performance. All data are derived from the
30-second period before each time point
and are reported as change from baseline. Note that the muscle sympathetic
nerve activity (MSNA) (⌬ MSNA and ⌬
total MSNA [%]) response to IHG is
greater in the Post condition in the
experimental group. In contrast, the
mean arterial blood pressure (MAP) and
heart rate (HR) responses were not different. Olive oil intake did not affect any
of the physiological responses. *P⬍0.05.
omega-3 fatty acids.29 However, although not statistically
different, these responses were ⬇20% greater after the
intervention. It is possible that use of a direct more powerful
measure of sympathetic outflow (ie, MSNA) allowed us to
observe an effect of omega-3 fatty acids on sympathetic
responses to physiological stressors. However, because
mechanisms mediating increases in sympathetic outflow during central hypovolemic stress and IHG and CPT differ, we
cannot exclude the possibility that our results are specific to
these stressors.
The mechanism(s) mediating the augmented MSNA response to the physiological stressors in the present study is
unknown. Previously, 4- to 6-week ingestion of omega-3
fatty acids was shown to blunt forearm vasoconstrictor
responses to intrabrachial infusion of norepinephrine.30,31
Extending these findings, it is possible that the augmented
MSNA response to physiological stressors we observed was
appropriate if end-organ responsiveness was impaired. For
instance, during IHG the body increases MSNA in an attempt
to increase perfusion pressure in the active limb (“flow
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Hypertension
November 2004
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Figure 2. Responses to cold pressor test
(CPT) before (Pre) and after (Post)
1-month intake of omega-3 fatty acids
(experimental) or olive oil (control). All
data are derived from the 30-second
period before each time point and are
reported as change from baseline. Note
the Post MSNA response to CPT is
greater (⌬ MSNA) in the experimental
group. In contrast, the MAP and HR
responses were not different. Olive oil
intake did not affect any of the physiological responses. *P⬍0.05.
error”) and systemic BP secondary to baroreflex resetting
(“pressure error”).32 If forearm vascular responsiveness to
increases in MSNA were attenuated, then greater increases in
MSNA would be necessary to elicit the same pressor effect
and to appropriately respond to these error signals. Data from
the IHG trial are consistent with this concept. Specifically,
the systemic pressor response to IHG was not influenced by
ingestion of omega-3 fatty acids, but the reflex increase in
MSNA was. In lieu of a change in central hemodynamic
responses, these data suggest that end-organ responsiveness
was impaired by omega-3 fatty acids. Future studies measur-
ing limb blood flow and central hemodynamics before and
after omega-3 fatty acid supplementation are needed to
definitively address this question.
If end-organ responsiveness was impaired (ie, the ability of
skeletal muscle to vasoconstrict in response to an increase in
MSNA) by omega-3 fatty acid supplementation, then it is
possible that factors locally produced contributed to this
effect. Two local factors that may be influenced by omega-3
fatty acid supplementation and that may impair vasoconstrictor responses are nitric oxide33 and prostanoids.34 We have no
measure, index, or assay of nitric oxide in the present study.
Monahan et al
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Therefore, we cannot determine if nitric oxide production was
increased after the intervention or if it contributed to any of
our findings. Additionally, prostaglandins may have influenced our results. However, we were unable to document any
effect of omega-3 fatty acids on several markers of prostanoid
synthesis (ie, 6-Keto-PGF1␣ and thromboxane B2) (Table).
These findings suggest that our results may not be dependent
on changes in prostanoids. However, to definitively determine the role of prostanoids or nitric oxide on the present
findings would require repeating the present study while
inhibiting cyclooxygenase and/or nitric oxide synthase.
These previous discussions suggest that postsynaptic
mechanisms explain augmented MSNA responses to physiological stressors. However, modulators of neurovascular norepinephrine levels, such as release, uptake, or spillover,
cannot be excluded. If altered, these could reduce end-organ
exposure to neurotransmitter, resulting in a reduced vasoconstrictor signal. Consistent with this concept, DHA enhances
purine release in rats, which may act to inhibit sympathetic
nerve terminal release of norepinephrine.20 This reduced
norepinephrine release would necessitate a greater neural
impulse to produce the same neurovascular concentration of
norepinephrine. Thus, we cannot exclude the possibility that
factors associated with modulation of neurovascular norepinephrine levels contributed to our findings.
Several limitations are associated with the present study.
First, gender balance was not even between groups. However,
we are not aware of any data suggesting that gender influences responses to omega-3 fatty acids. Second, no measure
of peripheral blood flow was obtained. Therefore, we cannot
be certain that for a given change in MSNA, end-organ
response was impaired by omega-3 fatty acids. Third, the
number of subjects studied was small. Fourth, we examined
sympathetic outflow innervating skeletal muscle arterioles.
Because sympathetic outflow is highly heterogeneous, it is
possible that sympathetic outflow to other organs may not
have been similarly affected by omega-3 fatty acids. In this
regard, it may be important to examine sympathoexcitatory
responses to other organs important in mediating stress
responses (eg, cardiac) in future studies.
Lastly, it is important to emphasize that the most consistent
effect of omega-3 fatty acid supplementation on MSNA
responses to physiological stressors was observed when
MSNA was expressed as burst frequency. The other measures
of MSNA (%⌬ total MSNA and ⌬ total MSNA) produced
similar results to the burst frequency data during IHG, but
less clear results during CPT. Specifically, changes in total
MSNA at fatigue during IHG were greater after omega-3 fatty
acid supplementation when data were expressed as %⌬ total
MSNA (P⬍0.05) and tended to be greater when expressed as
⌬ total MSNA (P⫽0.06), entirely consistent with the burst
frequency data. These augmented MSNA responses after
omega-3 fatty acid supplementation were not as consistently
apparent during the CPT. Despite the fact that the MSNA
burst frequency data indicated an augmented response to the
CPT after omega-3 fatty acids, the total MSNA data (ie, %⌬
total MSNA or ⌬ total MSNA) were not as clear (Figure 2).
Based on this observation, it could be argued that MSNA
responses are not augmented after omega-3 fatty acids,
Fish Oil and Sympathetic Nerve Activity
737
particularly during the CPT trial. We are uncertain as to why
there is a partial disconnect between the burst frequency and
total activity data during the CPT. We can only speculate that
these discrepancies are associated with inherent methodological limitations associated with reporting changes in total
MSNA (either as ⌬ total MSNA or %⌬ total MSNA) in
humans using microneurography especially when measured
on separate days (see Methods). Ultimately gaining insight
into end-organ responsiveness requires that events occurring
within the neurovascular junction be examined. In this regard,
the use of burst frequency as a surrogate for events taking
place in the neurovascular junction in humans is supported by
the strong association between changes in burst frequency
and changes in interstitial norepinephrine concentrations in
humans.35 However, we cannot entirely discount the alternative interpretation that responses were not augmented but
believe that our conclusions are valid based on the available
data. At minimum, our data demonstrate that 1 month of
omega-3 fatty acid supplementation does augment MSNA
responses to physiological stressors when burst frequency is
considered.
Perspectives
These data suggest that 1 month of omega-3 fatty acid
supplementation augments MSNA responses to several distinct physiological stressors but does not alter resting levels.
The augmented MSNA response to physiological stressors
after omega-3 fatty acid supplementation may be caused by
an impaired ability of MSNA to elicit vasoconstriction. This
impairment in vasoconstriction is suggested by the fact that
the augmented MSNA response after omega-3 fatty acid
supplementation was not associated with an augmented systemic pressor response to the stressors. Impaired vasoconstriction could involve numerous factors, including blunted
end organ responsiveness (ie, altered adrenergic receptor
sensitivity), alterations in exposure of the end organ to
neurotransmitter (ie, norepinephrine), or altered local production of factors that may modify vasoconstriction generations
(eg, nitric oxide or prostanoids). Further studies directly
examining these specific mechanisms appear warranted and
may expand our knowledge of how omega-3 fatty acids
reduce cardiovascular disease-associated risks in humans.
Acknowledgments
We thank Erica McHugh, Nathan Kuipers, and Charity Sauder for
technical assistance. Grants supporting this project were received
from the National Institute of Health (HL58503, DC006459, and
HL67624), National Space and Biomedical Research Institute
(CA00207), an Established Investigator Grant from the American
Heart Association, and a Pennsylvania State University Tobacco
Settlement Grant. Additional support was provided by a National
Institutes of Health-sponsored General Clinical Research Center with
National Center for Research Resources Grants M01 RR10732 and
C06 RR016499.
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Omega-3 Fatty Acid Supplementation Augments Sympathetic Nerve Activity Responses to
Physiological Stressors in Humans
Kevin D. Monahan, Thad E. Wilson and Chester A. Ray
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Hypertension. 2004;44:732-738; originally published online September 27, 2004;
doi: 10.1161/01.HYP.0000145292.38579.f4
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