Download Attenuated cardiac baroreflex in men with

Clinical Science (2001) 100, 303–309 (Printed in Great Britain)
Attenuated cardiac baroreflex in men with
presyncope evoked by lower
body negative pressure
Duminda N. WIJEYSUNDERA, Gary C. BUTLER, Shin-ichi ANDO,
Michael J. POLLARD, Peter PICTON and John S. FLORAS
Division of Cardiology of the Toronto General and Mount Sinai Hospitals and the University of Toronto, Suite 1614,
600 University Avenue, Toronto, Ontario, Canada M5G 1X5
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Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in
otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA),
blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke
volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven
experienced presyncope at LBNP k15 mmHg. Subjects who tolerated LBNP k15 mmHg
had significantly lower CVP (2n6p1n0 versus 7n2p1n2 mmHg ; meanspS.E.M., P 0n02), HR
(59p2 versus 66p3 beats/min, P 0n05) and MSNA burst frequency (29n0p2n4 versus 39n0p3n5
bursts/min, P 0n05) during supine rest. LBNP at k15 mmHg had no effect on blood pressure,
but caused similar and significant reductions in stroke volume and cardiac output in both groups.
Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency
and burst amplitude with LBNP of k15 mmHg. These responses were absent in those who
experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly
attenuated in pre-syncopal subjects (1n2p0n6 versus 8n8p1n4 bursts/100 heart beats per mmHg ;
P 0n001). Healthy subjects who experience presyncope in response to LBNP appear more
dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic
vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.
INTRODUCTION
The cause of vasodepressor syncope in otherwise healthy
adults remains obscure. Much attention has been directed
at neural events, often sudden, occurring at the time
blood pressure begins to fall [1–4] and at physical or
pharmacological manoeuvres that might unmask any
underlying predisposition to faint [5,6]. A common
theme in such experiments has been the selection of
patients with a prior history of recurrent syncope,
presumably due to a neurally mediated mechanism.
During the course of our investigation of sympathetic
nervous system responses to lower body negative pressure (LBNP) in healthy, middle-aged men, symptoms or
signs of presyncope at levels greater than k15 mmHg
LBNP resulted in premature termination of this stimulus
in 50 % of these subjects. Because none of these individuals had a history of prior syncope, and several were
engaged in occupations requiring a high degree of
alertness, this finding was unanticipated. Our purpose in
conducting the present analysis was to compare the
haemodynamic and sympathoneural characteristics of
those who became pre-syncopal, as opposed to those
who did not, under two conditions : at rest, prior to the
application of LBNP ; and in response to LBNP at
k15 mmHg, which was the stimulus that all subjects
were able to tolerate without developing symptoms.
Differences between these two groups, both at rest and in
Key words : baroreceptor reflex, central venous pressure, heart rate variability, microneurography, sympathetic nervous system.
Abbreviations : LBNP, lower body negative pressure ; MSNA, muscle sympathetic nerve activity ; CVP, central venous pressure ;
HR, heart rate.
Correspondence : Dr John S. Floras (e-mail john.floras!utoronto.ca).
# 2001 The Biochemical Society and the Medical Research Society
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D. N. Wijeysundera and others
response to this simulated orthostatic stimulus, raise
hypotheses concerning neural aspects of circulatory
regulation of individuals at risk of presyncope, which
merit prospective testing in future investigations.
METHODS
Subjects
Healthy, active, middle-aged men (n l 14, 44n5p1n7
years ; meanpS.E.M.) with no prior history of syncope
were studied. Their mean weight was 81n4p3n5 kg and
their height 180n4p1n4 cm. None were taking any medication. All subjects provided informed written consent as
approved by our Institutional Human Subjects Review
Committee, in accordance with the Declaration of
Helsinki.
Procedures
Subjects emptied their bladder, then were placed supine
into a chamber custom-built for recording muscle sympathetic nerve activity (MSNA) from the right peroneal
nerve during LBNP [7]. An airtight seal was obtained by
a neoprene kayak skirt fitted at the iliac crests. The right
leg was held in position by form-fitting supports at
the thigh, knee and ankle, and caudal displacement of the
subject was prevented by bilateral foot plates. Before any
additional recording instruments were applied, a brief
trial of LBNP was performed so as to familiarize subjects
with the sensation of lower body suction and thereby
minimize any inadvertent contraction of leg muscles
during the protocol.
A volume-clamp cuff (Finapres model 2300 ; Ohmeda,
Rexdale, Canada) was placed on the left-middle finger for
continuous non-invasive beat-by-beat recording of blood
pressure. After local anaesthesia, a central venous catheter
was introduced into an antecubital vein of the right arm
and advanced to an intrathoracic position [7]. A respiratory belt was secured around the abdomen. Central
venous pressure (CVP) and respiratory excursions were
measured continuously by Statham P23ID pressure
transducers (Gould Inc., Cleveland, OH, U.S.A.) and
recorded simultaneously with lead II of the electrocardiogram, heart rate (HR) and the MSNA neurogram
by an ink recorder on to paper. Post-ganglionic MSNA
was recorded from the right peroneal nerve [7,8]. Stroke
volume was calculated over approx. 10 consecutive
cardiac cycles from two-dimensional echocardiographic
and continuous-wave Doppler recordings, using methods reported previously by our group [7,9]. Cardiac
output was determined from HR and stroke volume.
Protocol
Supine bed rest (20 min) was followed by a 10 min
baseline period. LBNP was then applied at k5, k15
k30 and k40 mmHg. If tolerated, each level of LBNP
# 2001 The Biochemical Society and the Medical Research Society
was sustained for 10 min. Blood pressure, HR, CVP and
MSNA were recorded continuously. Stroke volume was
derived over the last 2 min of baseline, each level of
LBNP and the last 2 min of the recovery period.
Subjects were monitored for any sensation or indication of presyncope, such as pallor, tachypnea, yawning, a drop in systolic blood pressure 30 mmHg, or
heart rate 20 beats\min. If these arose, LBNP was
stopped and subjects were instructed to begin mild leg
muscle contractions to facilitate venous return.
Data analysis
Muscle sympathetic nerve activity
Pulse synchronous bursts of MSNA were identified by
inspection of the mean voltage neurogram [7] by two
trained, but blinded, assessors. Any disagreement with
respect to burst identification was resolved by the senior
investigator. MSNA was expressed as burst frequency
(bursts\min), incidence (bursts\100 cardiac cycles) and
units of integrated nerve activity (the product of burst
frequency and mean burst amplitude in mm). The latter
serves as a quantitative representation of the strength of
each burst of post-ganglionic discharge.
Spectral analysis of heart rate variability
A total of 7 min of the ECG (from the second to the
eighth minute of each level of LBNP) for each experimental condition was analysed to determine HR
variability, using coarse-graining spectral analysis. The
specific details of this technique have been reported
previously [10–12]. Total spectral power (PT) was divided
into its fractal power (PF), low-frequency harmonic (0n0–
0n15 Hz ; PL) and high-frequency harmonic (0n15–
0n50 Hz ; PH) components, with total harmonic power
(PHP) comprising the sum of PL and PH. The ratio PH\PT
was used to estimate the contribution of parasympathetic
modulation of HR to total spectral power [13–16], and
ratio PL\PH was applied to estimate the contribution of
sympathetic nervous system modulation of HR, or the
‘ sympathovagal balance ’, to power spectral density
[8,13,15–20]. The non-harmonic component of spectral
power was characterized further by plotting the log of
spectral power as a function of the log of frequency (a
1\fβ plot), with β the slope of this linear regression
[10,11,21].
Statistical analysis
Mean valuespS.E.M. are reported throughout. Subjects
were divided on the basis of their response to LBNP into
pre-syncopal and non-pre-syncopal groups. The principal comparison in this analysis was between baseline
measurements and responses to k15 mmHg LBNP,
which was the highest level tolerated by all subjects.
Within-group responses were assessed, applying Stu-
Attenuated cardiac reflex preceding presyncope
dent’s paired t test to normally distributed data and the
Wilcoxon rank sum test for non-parametric data, whereas
Student’s unpaired t test and the Mann Whitney rank
sum test were used for between-group comparisons.
Statistical significance was accepted if P 0n05.
RESULTS
All subjects completed the k5 and k15 mmHg LBNP
segments of the protocol, but three developed presyncope
at k30 mmHg and four at k40 mmHg. Characteristics,
at baseline, of subjects who completed the full protocol
and subjects who developed presyncope appear in Table
1. A continuous measure of CVP was obtained in 12
subjects, six in each group.
There was no significant difference in mean age, blood
pressure, stroke volume or cardiac output between
Table 1
subjects who completed the full protocol and those who
experienced presyncope. However, the latter group was
characterized by significantly higher sympathetic burst
frequency, heart rate and CVP (Table 1). A comparison
of baseline power spectral analysis data did not detect any
difference in the initial indices for heart rate variability in
these two groups (Table 2). Five of these subjects had
participated in previous research studies and were familiar with these procedures. Of these, three developed
presyncope and two did not.
Responses to k15 mmHg LBNP
This level of LBNP did not significantly affect systolic or
diastolic blood pressure in either group. As anticipated,
there were significant reductions in CVP, stroke volume
and cardiac output in both groups. LBNP at k15 mmHg
Haemodynamics and muscle sympathetic nerve activity in subjects without and with presyncope
n l 7 for each group, an l 6 for each group ; meanspS.E.M. *P
§P 0n005 for within-group differences.
0n05 ; **P
0n02 for differences between groups at baseline. †P
Without presyncope
0n05 ; ‡P
0n01 ;
With presyncope
Variable
0 mmHg
k15 mmHg
0 mmHg
k15 mmHg
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse pressure (mmHg)
CVP (mmHg)a
Stroke volume (ml)
Heart rate (beats/min)
Cardiac output (L/min)
MSNA (bursts/min)
MSNA (bursts/100 heart beats)
MSNA burst amplitude (mm)
MSNA (units/min)
MSNA (units/100 heart beats)
125p6
80p4
45p3
2n6p1n0
71p6
59p2
4n1p0n4
29n0p2n4
47n7p3n2
6n8p0n4
201p19
328p36
121p5
76p4
46p3
0n3p0n2†
60p4‡
64p3‡
3n8p0n3†
41n5p1n1§
62n2p3n4§
10n5p1n4†
441p70†
651p89‡
119p3
76p2
42p2
7n2p1n2**
67p7
66p3*
4n4p0n5
39n0p3n5*
58n1p5n4
7n7p0n5
302p38*
456p62
115p4
76p2
39p3
3n0p1n2§
54p5†
69p3
3n8p0n3†
42n0p3n4
65n2p5n6†
8n6p1n2
405p84
589p124
Table 2
R–R interval and heart rate variability in subjects without and with presyncope
n l 7 for each group ; meanspS.E.M. *P
0n05, **P
0n01 for within-group comparisons.
Without presyncope
With presyncope
Variable
0 mmHg
k15 mmHg
0 mmHg
k15 mmHg
R–R interval (ms)
PT (ms2)
PF (ms2)
PF/PT
PHP (ms2)
PH (ms2)
PH/PT
PL (ms2)
PL/PH
β
987p67
1493p459
828p243
0n62p0n07
664p278
241p121
0n11p0n03
423p160
3n8p1n3
1n15p0n10
912p51*
1208p188
870p151
0n71p0n03
337p57
72p28
0n06p0n02
266p42
18n7p8n0
1n46p0n10**
896p38
825p163
591p118
0n74p0n05
234p64
61p20
0n07p0n02
175p56
7n0p4n1
1n33p0n10
868p41*
1724p793
1258p566
0n74p0n04
481p228
52p21
0n04p0n01
422p207
22n3p10n8
1n53p0n16
# 2001 The Biochemical Society and the Medical Research Society
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D. N. Wijeysundera and others
heart beat increase in MSNA for every 1 mmHg decrease
in CVP and a 17n0p19n2 units\100 heart beat increase in
MSNA for each mmHg decrease in CVP (P 0n001 and
P l 0n027 respectively).
DISCUSSION
Figure 1
Gain of cardiac reflex control of MSNA
Means of ratios between increases in MSNA (response) and decreases in CVP
(stimulus) in response to k15 mmHg LBNP in subjects with or without
presyncope above k15 mmHg LBNP (n l 7 for each group). Note log scale.
lowered CVP in subjects who did not tolerate hypotensive LBNP to the initial level observed during supine
rest in the other group (P 0n05 for comparison between
groups). At these similar levels of CVP, stroke volume
tended to be lower in the pre-syncopal group (55p5 ml
versus 71p6 ml ; P l 0n053).
Subjects who tolerated hypotensive LBNP (i.e.
k15 mmHg) responded to k15 mmHg LBNP, with a
significant increase in heart rate, sympathetic burst
frequency, incidence, amplitude and integrated nerve
activity. In contrast, in those who subsequently experienced presyncope, there were no significant reflexive
increases in heart rate or these several representations of
MSNA, with the exception of sympathetic burst incidence (see Table 1).
LBNP at k15 mmHg did not affect harmonic power
spectra in either group. However, there was a significant
increase in the slope of the log power–log frequency
relationship in the non-presyncopal group (Table 2).
Cardiac reflex control of MSNA
Because LBNP at k15 mmHg did not have any significant effect on arterial blood pressure, or on PH\PT, the
principal representation of parasympathetic withdrawal
in response to arterial baroreceptor unloading, the
primary analysis of reflex control of MSNA focused on
the gain of the cardiac reflex. To estimate this, a ratio
relating changes in MSNA to changes in CVP was
constructed. Regardless of the representation of MSNA
selected, there was a marked attenuation in the calculated
gain of this reflex in those subjects who experienced
presyncope at higher levels of LBNP (Figure 1). In the
group who tolerated LBNP without presyncope, there
was an 8n8p1n4 unit increase in burst incidence for every
mmHg decrease in CVP and a 248p87 unit incidence
increase for every mmHg decrease in CVP. In contrast, in
the pre-syncopal group, there was a 1n2p0n6 burst\100
# 2001 The Biochemical Society and the Medical Research Society
Our objective in this analysis was to compare the
haemodynamic and sympathoneural characteristics of
healthy, middle-aged subjects, with no prior history
of unexplained syncope, who did or did not experience
presyncope in response to graded LBNP. The two groups
differed significantly in the following three respects.
Subjects who became pre-syncopal : (1) had higher initial
CVP, heart rate and MSNA burst frequency, prior to the
application of LBNP ; (2) did not increase heart rate,
MSNA burst frequency, amplitude, or integrated MSNA
in response to k15 mmHg LBNP ; and (3) displayed
marked attenuation of the gain of the cardiac baroreflex
control of MSNA in response to this stimulus. For
similar levels of CVP, stroke volume was substantially
lower in subjects who subsequently experienced presyncope.
These observations suggest that subjects with a predisposition to presyncope in response to an orthostatic
stimulus are more dependent on central sympathetic
outflow to skeletal muscle, to maintain preload, and on
sympathetic nerve traffic to the sino-atrial node to
maintain cardiac output. Venous pooling and withdrawal
of preload by graded LBNP would therefore predispose
these subjects to syncope unless countered by reflex
sympathetic activation. However, these individuals were
unable to mount the appropriate additional increase in
sympathetic vasoconstrictor discharge in response to this
stimulus, presumably due to impairment of their cardiac
baroreflex control of MSNA. Right atrial pressure
remained higher in the pre-syncopal group throughout
LBNP, and there was no abrupt cut-out of MSNA
during the course of the experiment, which argues against
the ‘ collapse-firing ’ hypothesis of neurogenic syncope.
Young subjects with borderline or mild essential
hypertension also have increased MSNA burst frequency
and incidence, often in the setting of higher central blood
volume, heart rate, cardiac output and decreased venous
distensibility [22–25]. However, in contrast to the present
findings, their reflex forearm vasoconstrictor and MSNA
responses to non-hypotensive LBNP are either augmented, or unchanged, when compared with agematched normotensive counterparts [26,27].
Because all were healthy, active individuals with no
prior history of fainting, the pre-syncopal response to
hypotensive LBNP was unanticipated. This may be a
feature unique to this specific protocol, in which, initially,
there was greater unloading of low pressure than high
pressure mechanoreceptors. In contrast, standing or tilt
Attenuated cardiac reflex preceding presyncope
unloads simultaneously both low pressure cardiopulmonary and high pressure aortic baroreceptor afferent
nerve endings. This redundancy, which provides two
independent pathways for reflex increases in efferent
sympathetic vasoconstrictor discharge, may be sufficient
to protect healthy individuals from presyncope during
standing, but not during the stimulus of graded LBNP.
For several decades incremental LBNP has been used to
isolate reflexes arising from the atria, pulmonary veins
and the left ventricle (which sense changes in filling
pressures and chamber volumes and elicit reflex changes
in sympathetic discharge to skeletal muscle) from reflexes
arising from afferent nerve endings situated in the aortic
arch and carotid sinus (which sense changes in blood
pressure and stroke volume) [28–30]. Both the haemodynamic changes observed in the present protocol, and
the absence of any significant drop in parasympathetic
heart rate modulation, imply that unloading of these low
pressure receptors was the predominant stimulus to
sympathetic activation k15 mmHg LBNP.
In a retrospective comparison of healthy subjects,
Jacobs et al. [31] reported a significant increase in forearm
noradrenaline spillover, in response to k15 mmHg in
subjects who tolerated k40 mmHg LBNP, whereas
there was a non-significant trend to lower forearm
noradrenaline spillover in those who experienced presyncope during that stimulus. There were no differences
between these two groups, at baseline, in blood pressure,
heart rate, plasma beta-endorphin concentrations, arterial
catecholamines, total body noradrenaline spillover or
forearm noradrenaline spillover into plasma. These
authors did not record CVP, and therefore could not
quantify cardiac reflex gain.
Mosqueda-Garcia et al. [4] performed a detailed study
of responses to incremental tilt in three groups of
subjects : controls, healthy subjects with no prior history
of syncope, but who consistently fainted during tilt, and
subjects under investigation for recurrent neurally
mediated syncope. They described a progressive reduction, across these three groups, in the gain of the
relationship between the absolute change in CVP and
the relative (%) increase in MSNA induced by progressive
tilting. Reductions in CVP and systemic blood pressure
with this stimulus also differed in their time course and
magnitude. In those with recurrent neurogenic syncope,
they observed attenuation of the MSNA response at low
tilt angles, followed by a gradual decline and then an
abrupt cut-off. (However, in our experience, it is difficult
to discriminate between abrupt reflex cessation of central
sympathetic outflow and displacement of the microelectrode by leg movement during negative pressure.)
The greatest fall in CVP was observed in the otherwise
healthy subjects in whom repeated tilt-testing evoked
syncope, i.e. analogous to the response observed in our
pre-syncopal subjects. Although, in contrast to the
present findings, MSNA increased significantly, in re-
sponse to tilt, in this group. However, no statistical
comparison between these three calculated gains was
performed ; relative, rather than absolute increases in
MSNA were plotted on the ordinate ; and the tilt stimulus
applied was not specific to cardiac mechanoreceptor
unloading.
Morillo et al. [2] also examined responses to tilt in
subjects with a history of orthostatic syncope. Approx.
40 % of these developed recurrent syncope during this
experiment. At baseline, heart rate, blood pressure and
MSNA were similar in pre-syncopal and non-syncopal
patients, but parasympathetic responses to nitroprussideinduced reductions in blood pressure were attenuated.
The arterial baroreflex control of MSNA was not
different between these two groups. Since CVP was
not determined, these authors could not comment on
cardiac reflex gain.
Our demonstration of markedly lower cardiac reflex
control of MSNA in subjects who experienced presyncope would therefore appear to be a novel finding. This
may reflect long-standing differences in the discharge
characteristics of the afferent nerve endings, perhaps due
to altered compliance of the cardiac chambers or large
vessels which house these mechanoreceptors, or differences in the distribution of blood volume [32] between
these two groups. If so, this could explain why the
significantly higher CVP did not appear to reflexively
suppress MSNA under resting conditions. It is also
possible that LBNP stimulated the release of sympathoinhibitory peptides, such as vasopressin, atrial natriuretic
peptide and endogenous endorphins. Plasma concentrations of these peptides increase markedly prior to
syncope, or when orthostatic maneouvers elicit nausea,
light-headedness and related symptoms of impending
faint [3,31,33]. An inhibitory interaction between such
peptides and the sympathetic nervous system, centrally,
or at the ganglionic level [7,34–36], could reset the cardiac
baroreflex acutely, causing a gradual or abrupt loss of
sympathetic vasoconstrictor discharge to skeletal muscle.
If these peptidergic responses differed within subjects,
from one test stimulus to the next, such variability could
explain why subjects differ in their tolerance to repeated
orthostatic stress.
In a previous report [37], subjects with unexplained
syncope who developed recurrent symptoms during tilttesting had a decrease in their PL\PH ratio, whereas this
ratio increased in those without symptoms. We therefore
explored frequency domain characteristics of heart rate
variability. There was no difference in baseline values for
this ratio between the two groups, and k15 mmHg
LBNP had no effect in either group, supporting our
previous conclusion that this proposed power spectral
estimate of efferent sympathetic outflow to the sinoatrial node is insensitive to significant between-group
differences in the magnitude of sympathetic nervous
system activation [8].
# 2001 The Biochemical Society and the Medical Research Society
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D. N. Wijeysundera and others
There are several limitations to the present analysis.
First, this was a post hoc comparison of subjects who did
or did not develop presyncope in response to a protocol
of LBNP applied for another purpose, rather than a
prospective study of subjects predisposed to recurrent
syncope. Secondly, it is not known whether these
observations would be reproducible within subjects if
this protocol were to be repeated. Thirdly, our observations do not permit us to determine the mechanisms
responsible for these baseline differences between groups,
their contrasting sympathoneural responses to LBNP
and the attenuated cardiac reflex control of MSNA.
These may reflect long-standing differences in neurogenic cardiovascular control in such individuals. Alternatively, they may arise from day-to-day variations in
sodium balance, and therefore cardiopulmonary and total
intravascular blood volume, or reflect an alerting response to the laboratory environment. These differences
may also be due to variations between subjects, in the corelease of sympatho-inhibitory peptides and neurotransmitters, or in their actions. Thus the present report
should be considered as hypothesis-generating. Future
studies of this issue should address questions of reproducibility, predictive value and mechanism. Fourthly, the
two groups were well matched with respect to age,
height, blood pressure and several other baseline characteristics, but differed with respect to their initial CVPs.
However, the higher initial CVP of the pre-syncopal
group would suggest that they were operating at the
steeper portion of the sigmoid CVP–MSNA stimulus–
response relationship, and therefore might be expected to
display an augmented, rather than a diminished,
sympatho-neural response to the fall in CVP elicited by
non-hypotensive LBNP. Fifthly, we did not study
concurrently blood volume, or plasma markers of other
vasoactive systems involved in salt and water balance. It
is possible that these pre-syncopal subjects maintain
increased blood volume or redistribute their blood
volume centrally as a result of a generalized activation of
several neurohormonal mechanisms. Finally, we cannot
comment on whether women predisposed to presyncope
would display the same baseline differences or attenuated
reflex responses to LBNP.
In summary, this analysis would suggest that the
predisposition to presyncope in responses to graded
LBNP is associated with greater dependence on vasoconstriction and venoconstriction in skeletal muscle, to
maintain preload under conditions of supine rest, and
attenuation of the reflex vasoconstrictor response to
preload reduction, subserved by the low pressure cardiopulmonary receptors. This diminished cardiac reflex
control of muscle sympathetic nerve activity would then
result in an inability to maintain stable blood pressure
and cerebral blood flow in the face of sustained displacement of blood volume from the cardiopulmonary
circulation.
# 2001 The Biochemical Society and the Medical Research Society
ACKNOWLEDGMENTS
This work was supported by Grants-in-Aid from the
Heart and Stroke Foundation of Ontario (T3054 and
T4050). J. S. F. holds a Career Investigator Award from
the Heart and Stroke Foundation of Ontario. G. C. B.
received a Fellowship from the Medical Research Council
of Canada. S.A. received a Canadian Hypertension
Society\Merck Frosst Fellowship and was supported, in
addition, by the George R. Gardiner Foundation
(Toronto). We thank Beverley L. Senn, R. N. and Steven
C. Brooks, B.Sc. for their technical assistance.
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Received 3 August 2000/20 October 2000; accepted 24 November 2000
# 2001 The Biochemical Society and the Medical Research Society
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