Download Effect of adenosine on heart rate variability in

Clinical Science (1999) 96, 597ñ604 (Printed in Great Britain)
Effect of adenosine on heart rate variability
in humans
Gerard A. RONGEN, Steven C. BROOKS, Michael J. POLLARD, Shin-ichi ANDO,
Hilmi R. DAJANI, Catherine F. NOTARIUS and John S. FLORAS
Division of Cardiology, Mount Sinai and Toronto Hospitals, and the Centre for Cardiovascular Research, University of Toronto,
Toronto, Ontario, Canada
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By stimulating afferent nerve endings in skeletal muscle, heart, kidney and the carotid body,
adenosine infusion evokes a receptor-specific sympatho-excitatory reflex in humans that
overrides its direct negative chronotropic effect. We tested the hypothesis that adenosine
increases heart rate by suppressing parasympathetic and augmenting sympathetic components of
heart rate variability. High-frequency (PH ; 0.15–0.50 Hz) and low-frequency (PL ; 0.05–0.15 Hz)
components of heart rate variability total power (PT) were determined by spectral analysis. The
ratios PH/PT and PL/PH respectively were used to estimate parasympathetic and sympathetic input
to the sino–atrial node. Heart rate was recorded before and during a 5 min intravenous infusion
of adenosine (140 µg:min−1:kg−1) in seven healthy men. Adenosine did not affect blood pressure,
but increased heart rate by 33p6 beats/min, and reduced PT, PH, PL and PH/PT. In contrast, there
was an increase in PL/PH. In a second experiment in nine men, brachial artery infusion of adenosine
(15 µg:min−1:100 ml−1 forearm tissue) increased heart rate by 3 beats/min, had no effect on PT,
PH, PL or PH/PT, yet increased PL/PH. Intra-arterial adenosine exerts a modest effect on heart rate
by modulating cardiac sympathetic indices, without affecting parasympathetic indices, of heart
rate variability, whereas intravenous infusion of adenosine reduces heart rate variability and
raises heart rate by decreasing parasympathetic and increasing cardiac sympathetic tone. These
reflex effects may become clinically relevant during adenosine stress testing, or when
endogenous adenosine is increased, such as during ischaemia, exercise or vasodepressor
reactions, or in heart failure.
INTRODUCTION
The cardiovascular actions of adenosine are a topic of
current interest [1]. Adenosine can act directly on the
sinus node to reduce heart rate and slow conduction
within the atrial–ventricular node [2]. These properties
are the basis for one clinical application of adenosine,
namely the interruption of supraventricular tachycardia
by bolus injection. However, when infused intravenously
into conscious humans, to achieve lower plasma concentrations, adenosine increases both heart rate and sympathetic nerve traffic to muscle [3,4]. There are two
stimuli to this activation of the sympathetic nervous
system : peripheral vasodilation, which reduces baroreceptor afferent nerve discharge, and a receptor-specific
sympatho-excitatory reflex elicited by stimulating afferent nerve endings in the carotid body, skeletal muscle,
heart and kidney [4–10].
Key words : adenosine, blood pressure, heart rate variability, parasympathetic nervous system, sympathetic nervous system.
Abbreviations : PT, total spectral power ; PH, high-frequency power ; PL, low-frequency power ; R–R interval, interval between
successive R waves on ECG.
Correspondence : Dr John S. Floras, Suite 1614, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G
1X5.
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Under resting conditions, there is a good correlation
between sympathetic nerve traffic to skeletal muscle and
biochemical estimates of sympathetic outflow to the
human heart [11]. Whether this relationship persists
when sympathetic nerve traffic to skeletal muscle is
activated reflexively by adenosine is unknown. If so, the
tachycardia observed during adenosine infusion could
arise from a concordant increase in sympathetic neural
drive to the heart, which would override the direct
negative chronotropic effects of this purine. On the other
hand, decreased parasympathetic tone [12] could also
contribute to this increase in heart rate. Indeed, in a study
involving six young healthy subjects given intravenous
propranolol and atropine, Conradson et al. [13] concluded that the heart rate response to an infusion of
120 µg of adenosine:min−":kg−" was due to a reduction
in vagal tone. However, the chronotropic response to
adenosine tended to be less after β-adrenoceptor blockade
alone. Thus the relative contributions of sympathetic
nervous system activation and parasympathetic nervous
system withdrawal to the increase in heart rate observed
when adenosine is infused in normal humans for clinical
purposes is unclear.
Spectral analysis can provide quantitative information
on the relative balance between the parasympathetic
neural and sympathetic neural contributions to heart rate
variability [14–16]. Dipyridamole inhibits the cellular
uptake of adenosine, leading to its accumulation [2]. The
effects of dipyridamole on frequency-domain indices of
heart rate variability have been studied in both normal
subjects and patients with ischaemia [17], but the effects
of the purine itself on heart rate variability have not been
reported. Our objective in the present study was to test
the hypothesis that adenosine reduces the parasympathetic and augments the sympathetic components
of heart rate variability in healthy subjects.
Two series of experiments were performed. In the first
series, we determined the effect of a systemic infusion of
adenosine, as given commonly during myocardial perfusion imaging [18], on heart rate variability. In the
second series, we determined the effect on heart rate
variability of brachial artery infusion of adenosine at a
dose that is without systemic haemodynamic effect, but
which has a demonstrated reflex sympatho-excitatory
action [9].
(meanspS.D.)], known to consume at least two cups of
coffee per day, were enrolled in this series [19]. All
subjects provided written informed consent for this
study, and the study was approved by the Ethics
Committee of our Institute.
Protocol
Because caffeine is a competitive antagonist that inhibits
virtually all actions of adenosine studied, adenosine was
infused after 30 h of abstinence [19,20]. All studies were
performed in the same quiet temperature-controlled
room at the same time of day (afternoon), at least 2 h after
subjects’ last food intake. An antecubital vein of the left
arm was cannulated, and a blood sample was collected for
measurement of total (protein-bound plus free) serum
caffeine concentration by a homogeneous enzyme
immunoassay technique using a commercially available
kit (Emit Caffeine Assay ; Syva Canada, Kanata, Ontario,
Canada). The limit of detection of this assay is 5 µg\ml.
In our clinical laboratory, the batch-to-batch coefficient
of variation is 4.2 % at a concentration of 77.2 µmol\l.
Lead II of the ECG was recorded continuously during
spontaneous respiration, inscribed on to paper by an ink
recorder and digitized at 1000 Hz into a personal
computer for data analysis. Blood pressure was measured
at 1 min intervals, using a non-invasive oscillometric
technique with an inflatable cuff applied on each occasion
to the right arm (Dinamap ; Kritikon, Tampa, FL,
U.S.A.). At 20 min after the intravenous cannulation, a
5 min baseline was recorded. Adenosine was infused to a
maximum concentration of 140 µg:min−":kg−", which
was sustained for 5 min (this being the dose most
commonly administered during myocardial perfusion
imaging [18]).
Series 2 : effect of intra-arterial adenosine
infusion on heart rate variability
Subjects
Nine healthy, non-smoking, male volunteers (age 33p9
years ; weight 79p6 kg ; height 178p5 cm) were enrolled
in this series, which was approved by our institutional
Ethics Committee [9]. All subjects provided written
informed consent prior to their participation.
Protocol
METHODS
Series 1 : effect of intravenous adenosine
infusion on heart rate variability
Subjects
Seven healthy, non-smoking, male volunteers [age
37p10 years ; weight 82p10 kg ; height 178p5 cm
# 1999 The Biochemical Society and the Medical Research Society
All studies were performed in the same quiet
temperature-controlled laboratory, at the same time of
day, after 24 h of caffeine abstinence, with subjects
supine. Lead II of the ECG was recorded continuously,
inscribed on to paper by an ink recorder and digitized at
1000 Hz into a personal computer for data analysis. After
local anaesthesia, the brachial artery of the non-dominant
arm (mean volume 1156p151 ml) was cannulated (5 cm ;
Adenosine and heart rate variability
20 G catheter) for the continuous recording of intraarterial blood pressure, and for intra-arterial infusions.
Forearm blood flow was measured by venous occlusion
strain gauge plethysmography. After a rest period of at
least 30 min, saline (as vehicle) was infused into the
brachial artery for 5 min, followed by adenosine, which
was infused to a maximum concentration of
15 µg:min−":100 ml−" forearm tissue, which was sustained for 5 min. After a further rest period of at least
30 min, glucose (5 %, w\v ; as vehicle) was infused into
the brachial artery for 5 min, followed by sodium
nitroprusside, which was infused as a time and vasodilator
control
to
a
maximum
concentration
of
0.6 µg:min−":100 ml−" forearm tissue, which was sustained for 5 min. In five subjects (randomly allocated),
adenosine was infused before nitroprusside. In the
remainder, the order of infusions was reversed.
Spectral analysis
The ECG was sampled at 1000 Hz to determine the
interval between successive R waves (R–R interval). Data
over the last 3.5 min of the baseline period and for each
infusion were subjected to spectral analysis by fast
Fourier transformation, as described in [20]. Extra or
missing beats were edited and replaced with substitute
R–R intervals calculated by linear interpolation from
adjacent cycles. The unequal R–R intervals were aligned
sequentially to obtain equally spaced samples with
spectra that do not differ significantly from heart rate
variability spectra for the interpolated time series [21].
The 3.5 min data set was subdivided into five overlapping
segments. The mean and linear trend were subtracted
from each segment. A cosine tapered window was applied
to each segment to reduce spectral leakage. Power spectra
were obtained and ensemble-averaged over the five
segments using the Coolman–Tukey algorithm. Total
spectral power (PT) and integrated power within the lowfrequency (0.05–0.15 Hz ; PL) and high-frequency (0.15–
0.50 Hz ; PH) regions were then computed. The ratios
PH\PT and PL\PH were used as conventional indices of
parasympathetic nervous system and sympathetic nervous system modulation respectively of sino–atrial node
discharge [14–16].
Statistics
Baseline values and responses to adenosine
(140 µg:min−":kg−" intravenous for Series 1 ;
15 µg:min−":100 ml−" forearm tissue intra-arterial for
Series 2) were compared. Mean values for blood pressure
and heart rate, acquired over the 5 min baseline periods
and during the last 3.5 min of adenosine infusions, were
calculated. Student’s t-test was used for paired comparisons of heart rate and blood pressure, whereas the
Wilcoxon signed rank test was used to assess changes in
frequency-domain indices of heart rate variability from
baseline values. P values of
0.05 were considered
statistically significant. Results are presented as
meanspS.D.
RESULTS
Series 1 : effect of intravenous adenosine
infusion on heart rate variability
All subjects reported complete abstinence from any
caffeine intake during the preceding 30 h, and plasma
caffeine concentrations in all seven subjects were below
the limits of detection. Adenosine (140 µg:min−":kg−",
intravenous) increased heart rate by 33.3p6.2 beats\min
(P 0.001). Systolic (j4.2p8.2 mmHg) and diastolic
(j0.5p5.4 mmHg) blood pressure did not change
significantly (Table 1 ; Figure 1). Adenosine suppressed
PT (P 0.02), PH (P 0.02) and PL (P 0.02), as well as
the parasympathetic nervous system indicator PH\PT (P
0.02). In contrast, there was an increase in the
sympathetic nervous system indicator PL\PH (Table 1 ;
Figure 2).
Series 2 : effect of intra-arterial adenosine
infusion on heart rate variability
Adenosine (15 µg:min−":100 ml−" forearm tissue, intraarterial) increased forearm blood flow from 3.3p0.7 to
20.1p7.1 ml:min−":100 ml−" forearm tissue (P 0.01).
There was no significant effect on systolic blood pressure,
but diastolic blood pressure was increased by
2.7p2.4 mmHg (P 0.01). Mean heart rate rose from 58
to 61 beats\min (P 0.02) (Table 2). Adenosine had no
effect on PT, PH or PL, or on the parasympathetic nervous
system indicator PH\PT. In contrast, there was a
significant increase in the sympathetic nervous system
indicator PL\PH (P l 0.04) (Table 2 ; Figure 2).
Sodium nitroprusside (0.6 µg:min−":100 ml−" forearm
tissue, intra-arterial) had no significant effect on
Table 1 Influence of intravenous adenosine infusion on
blood pressure, heart rate and its variability
Adenosine was infused intravenously at a concentration of 140 µg:min−1:kg−1.
Results are meanspS.D. from seven healthy subjects. BP, blood pressure ; n.s., not
significant (P 0.05).
Variable
Baseline
jAdenosine
P
Systolic BP (mmHg)
Diastolic BP (mmHg)
Heart rate (min−1)
PT (ms2)
PH (ms2)
PL (ms2)
PH/PT
PL/PH
122p6
68p8
67p4
1696p1829
440p421
437p385
0.28p0.11
1.15p0.36
126p12
68p9
100p6
280p410
32p56
43p41
0.08p0.05
3.00p1.54
n.s.
n.s.
0.001
0.02
0.02
0.02
0.02
0.03
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Figure 1
Effects of intravenous adenosine infusion on heart rate variability
Shown are representative tracings in a single subject of pulse (RR) intervals over 5 min (A) and corresponding coarse graining power spectra across the frequency range
0ñ0.5 Hz (B) under supine rest (baseline ; left panels) and during intravenous infusion of adenosine at 140 µg:min−1:kg−1 (right panels).
Figure 2
Effects of intravenous and intra-arterial adenosine infusion on heart rate variability
Shown are group mean values for heart rate, PT, PH/PT as an index of heart rate modulation by the parasympathetic nervous system, and PL/PH as an index of heart rate
modulation by the sympathetic nervous system, at baseline and during intravenous (i.v.) infusion of adenosine (140 µg:min−1:kg−1 ; left panels) (n l 7 ;
meanpS.D.), and at baseline and during intra-arterial (i.a.) infusion of adenosine (15 µg:min−1:100 ml−1 forearm tissue ; right panels) (n l 9 ; meanpS.D.).
Significance of differences : *P 0.05 ; **P 0.02 ; ***P 0.001.
systolic or diastolic blood pressure, or on heart rate.
Forearm blood flow rose from 3.2p0.7 to
14.0p3.5 ml:min−":100 ml−" forearm tissue (P 0.01).
# 1999 The Biochemical Society and the Medical Research Society
This increase in forearm blood flow (j10.9p
8.8 ml:min−":100 ml−" forearm tissue) was not significantly different from that caused by adenosine
Adenosine and heart rate variability
Table 2 Influence of intra-arterial adenosine infusion on
blood pressure, heart rate and its variability
Adenosine was infused intra-arterially at a concentration of
15 µg:min-1:100 ml−1 forearm tissue. Results are meanspS.D. from nine
healthy subjects. BP, blood pressure ; n.s., not significant (P 0.05).
Variable
Baseline
Systolic BP (mmHg)
119p20
Diastolic BP (mmHg)
67p11
Heart rate (min−1)
58p9
PT (ms2)
4668p6424
PH (ms2)
1200p178
PL (ms2)
978p990
PH/PT
0.22p0.10
PL/PH
1.65p0.92
jAdenosine
P
120p22
69p11
61p9
3833p3051
839p1050
1042p859
0.18p0.12
2.24p1.29
n.s.
0.01
0.02
n.s
n.s
n.s.
n.s.
0.04
(j16.8p19.5 ml:min−":100 ml−" forearm tissue ; P l
0.15). Nitroprusside had no effect on PT, PH or PL, or on
the ratios PH\PT and PL\PH. The latter was 1.69p1.24
during dextrose infusion and 1.81p1.44 during sodium
nitroprusside infusion.
DISCUSSION
In conscious humans, adenosine evokes a receptorspecific sympatho-excitatory reflex by stimulating afferent nerve endings in the carotid body, skeletal muscle,
heart and kidney [3–8]. Several independent, yet complementary, methods have been used to characterize the
reflex adrenergic response to adenosine infusion : peroneal muscle sympathetic nerve traffic [3,4], plasma
noradrenaline concentration [22] and total body noradrenaline spillover [23]. However, the effect of exogenous adenosine on cardiac sympathetic neural drive,
as assessed by heart rate variability, has not been
described. From experiments in six healthy volunteers in
which intravenous propranolol plus atropine abolished
the increase in heart rate elicited by adenosine, but
propranolol alone did not, Conradson et al. [13] concluded that vagal inhibition is the primary mechanism by
which adenosine infusion increases heart rate. However,
these authors did not report on the interaction of
adenosine with atropine alone. Moreover, the combination of propranolol and atropine increased baseline
heart rate significantly, complicating the interpretation of
the results.
Systemic infusion of adenosine could affect heart rate
variability through a number of pathways : by a direct
negative chronotropic action on the sino–atrial node ; or
indirectly, either by a central neural action or reflexively
by unloading arterial baroreceptors or by stimulating
adenosine-sensitive afferent nerve endings in the carotid
body, myocardium, kidney and skeletal muscle. Previously we reported that intra-arterial infusion of
adenosine increased total body noradrenaline spillover,
presumably by stimulating selectively the latter set of
afferents [9]. In the present series, we determined whether
selective stimulation of skeletal muscle afferent nerve
endings by local infusion of adenosine has similar reflex
effects on the sympathetic neural modulation of heart
rate variability. If so, this mechanism could assume
importance during local ischaemia or exercise.
In the first series of experiments, systemic infusion of
adenosine caused a 50 % rise in heart rate and increased
the PL\PH ratio, a frequency-domain representation of
heart rate modulation by the sympathetic nervous system. Because diastolic blood pressure did not fall significantly, arterial baroreflex unloading [23] is probably less
important than the stimulation of adenosine-receptor
sympathetic neural afferents in mediating these
sympathoneural responses. In the second series, intraarterial infusion of adenosine also increased the sympathetic nervous system indicator PL\PH ; this increase
occurred in the setting of a much more modest (3
beats\min) increase in heart rate. This was not a time
effect, or a non-specific response to forearm vasodilation,
since nitroprusside infusion did not alter either variable.
High local concentrations of adenosine, as may be
achieved clinically by bolus adminstration, have a direct
negative chronotropic effect and a direct inhibitory action
on cardiac noradrenergic neurotransmission [24,25], yet
heart rate increased during the intravenous and the intraarterial infusions. Thus observations with both protocols
are consistent with the concept that the cardiac adrenergic
nervous system participates in the efferent reflex
sympatho-excitatory response to infused adenosine.
Systemic infusion of adenosine reduced spectral power
across all frequency bands. This effect, not observed
during local infusion, can be attributed to the additional
stimulation of adenosine-sensitive neural afferents in
other skeletal muscle vascular beds, and in the heart,
kidneys and carotid bodies. Several mechanisms could
account for this broad-band decrease in spectral power.
First, by acting directly on the sinus node [2], adenosine
could exert a damping effect that would render the heart
rate less responsive to neural modulation. Secondly,
adenosine reduced two generally accepted indices of the
parasympathetic modulation of heart rate : PH and the
ratio PH\PT. These actions were not observed during
intra-arterial infusion, indicating that the reflex stimulated by adenosine-receptor-specific neural afferents in
the forearm does not include the parasympathetic nervous system in its efferent limb. Observations during
systemic infusion indicate that sympathetic activation
and vagal withdrawal are important effectors of the
marked chronotropic response to adenosine. Such parasympathetic withdrawal could occur through several
mechanisms, or their interactions : as an appropriate
arterial baroreflex-mediated efferent response to peripheral vasodilation, via central inhibition of acetyl# 1999 The Biochemical Society and the Medical Research Society
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G. A. Rongen and others
choline release [26], or as a direct inhibitory effect of
adenosine on vagally induced bradycardia [12].
Chemoreceptor reflex stimulation is an important
component of the sympatho-excitatory response to the
systemic infusion of adenosine in humans [5,27].
Adenosine infusion at 140 µg:min−":kg−" increases tidal
volume and causes respiratory alkalosis, but does not
change breathing frequency [5]. Increasing the depth of
respiration will increase vagal drive reflexively (which
should augment power within the high-frequency spectral band) and decrease sympathetic outflow [28], i.e.
effects opposite to those observed. Because tidal volume
(and hence these additional respiratory influences) was
not controlled in the present experiments, our results
might have underestimated both the potential inhibitory
effect of exogenous adenosine on parasympathetic tone
and its excitatory influence on cardiac sympathetic neural
drive.
The effects of adenosine infusion on heart rate variability in normal subjects have not been reported, but
Petrucci et al. [17] assessed heart rate variability changes,
using a time variant spectral algorithm, during the
infusion of dipyridamole, which inhibits the cellular
uptake of adenosine, leading to its accumulation [2]. In
control subjects without objective evidence for coronary
artery disease, dipyridamole infusion increased heart
rate, and decreased PT, PH and PL [17]. The last parameter
decreased to 31 % of its baseline value. The sympathetic
nervous system indicator PL\PH tended to increase, but
this was not significant. These results indicate that our
observations during adenosine infusion are qualitatively
similar to the actions of endogenous adenosine on heart
rate variability in healthy subjects. In contrast, during
ischaemia, when adenosine accumulates, there was a 15fold increase in PL in their experimental group of patients
with functionally important coronary artery disease [17],
consistent with an enhanced, adenosine-induced,
sympatho-excitatory response under these conditions
[10].
The sympathetic nervous system responds to some
internal or external challenges in a highly selective and
organ-specific manner, whereas, under other circumstances, such stimuli elicit a generalized sympathoexcitatory response [29–31]. When considered in the
context of previous reports that adenosine, infused at the
dose used in the present study, increases muscle sympathetic nerve activity and heart rate [3,4], these observations with respect to heart rate variability indicate that
the systemic infusion of adenosine evokes a generalized
reflex sympatho-excitatory response involving the heart,
in addition to other vascular beds.
The capacity to vary the heart rate appropriately allows
the cardiovascular system a broad repertoire of responses
to maintain stability when faced by acute pathology or
external challenges. A reduction in the variability or
complexity of heart rate is a risk factor for early mortality
# 1999 The Biochemical Society and the Medical Research Society
following myocardial infarction [32]. The increases in
heart rate, reductions in heart rate variability and
augmented adrenergic drive to the heart observed during
adenosine infusion may be clinically relevant in the
setting of adenosine-radiotracer stress testing, and may
contribute to its pro-arrhythmic effects, as observed in
clinical practice [33]. These actions may also have
relevance for cardioprotective interventions involving
adenosine or molecules designed to replicate or potentiate
its local actions [34]. In conditions such as congestive
heart failure or coronary artery disease, tissue ischaemia
or relative hypoperfusion of skeletal or cardiac muscle
could stimulate the local production of endogenous
adenosine and cause reflex increases in sympathetic
outflow to the heart and other vascular beds [9]. In a
recent report, 10–20-fold increases in plasma adenosine
concentrations were described in patients with NYHA
(New York Heart Association) Class III and Class IV
heart failure, as compared with healthy control subjects
[35]. Decreases in both the variability and the complexity
of the heart rate in heart failure [36] have been attributed
to impaired neural circulatory control, and to decreased
sino–atrial responsiveness to autonomic input in this
condition. Increased interstitial and plasma adenosine
concentrations might underlie both alterations.
In summary, exogenous adenosine reduces heart rate
variability by decreasing parasympathetic and increasing
cardiac sympathetic nervous system tone. These actions
overwhelm adenosine’s direct negative chronotropic
effects, resulting in a marked increase in heart rate.
Brachial artery infusion of adenosine has a more modest,
positive, effect on heart rate, and increases its modulation
by the cardiac sympathetic nervous system without
affecting parasympathetic tone. These findings indicate
concordance between this purine’s reflex actions on the
heart and on sympathetic discharge to other vascular
beds. These reflex effects override its direct negative
chronotropic and sympatho-inhibitory actions, and may
be clinically relevant in the setting of exercise, vasodepressor syncope [37], congestive heart failure or
myocardial ischaemia, or during adenosine-radiotracer
stress testing.
ACKNOWLEDGMENTS
The expert technical assistance of Beverley L. Senn is
gratefully acknowledged. This work was supported by an
Operating Grant from the Medical Research Council of
Canada (MT9721). G. A. R. was the recipient of a Research Fellowship from the Department of Medicine
Research Fund of the Mount Sinai Hospital, a grant from
Janssen-Cilag B.V. (Tilburg, The Netherlands), and travel
grant R95114 from the Dutch Heart Foundation (‘ De
Gelderfonds ’ ; The Hague, The Netherlands). S. C. B.
received a John D. Schultz Science Student Scholarship
Adenosine and heart rate variability
from the Heart and Stroke Foundation of Ontario. S-i.A.
was the recipient of a Canadian Hypertension Society\
Merck Frosst Fellowship. C. F. N. was supported by a
Research Fellowship from the Department of Medicine,
Mount Sinai Hospital, and by Fellowship Awards from
the Department of Medicine and the Centre for Cardiovascular Research of the University of Toronto. J. S. F.
is a Career Investigator of the Heart and Stroke Foundation of Ontario.
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Received 12 October 1998/4 January 1999; accepted 12 March 1999
# 1999 The Biochemical Society and the Medical Research Society