Renal and cardiovascular effects of caffeine: a

Clinical Science(l987)72, 749-756
749
Renal and cardiovascular effects of caffeine:
a dose-response study
A. P. PASSMORE, G. B. KONDOWE AND G. D. JOHNSTON
Department of Therapeuticsand Pharmacoloo, The Queen’s University of Belfast, Belfast, N. Ireland, V.K.
(Received 28 Ocrober/s December 1986; accepted 16 January 1987)
Caffeine is also an adjuvant in many drug formulations at doses between 15 mg and 200 mg per
1. The effects of increasing oral doses of caffeine tablet. It is estimated that 20-30% of adult Ameri(45, 90, 180 and 360 mg) on effective renal plasma
cans consume over 500 mg of caffeine daily, while
flow (ERPF), plasma renin activity (PRA), serum
10%ingest over 1 g per day [2].
electrolytes, plasma noradrenaline, blood pressure
Theophylline has a diuretic efficacy comparable
and heart rate were studied in eight healthy male
with thiazide diuretics [3]. Although it has been
volunteers.
suggested that an increase in effective renal plasma
2. Urine volume was increased by 360 mg of
flow (EFWF) and glomerular filtration rate (GFR)
caffeine only. At caffeine doses greater than 90 mg
are the main factors responsible for the diuresis
urinary sodium excretion was significantly produced by theophylline [4], it has been proposed
increased. There were no changes in ERPF.
that an inhibition of tubular reabsorption of sodium
3. Serum potassium was significantly reduced by
is more likely [5].Acute caffeine ingestion [250 mg)
360 mg of caffeine.
results in increased urine volume and sodium excre4. Caffeine increased systolic pressure in a dose tion in humans [6], but since there are no dose
related manner. Diastolic pressure was also
ranging studies on the renal effects of caffeine, it is
increased, but not in relation to dose. A 360 mg
unclear whether low doses have any diuretic effect.
dose of caffeine produced a late increase in heart
Hypokalaemia is common in theophylline overrate. These changes were not associated with any
dosage [7] and has recently been noted at
alterations in PRA or in plasma noradrenaline.
theophylline concentrations within the therapeutic
range [8]. This effect appears to be independent of
Key words: blood pressure, caffeine, noradrenaline,
diuresis.
As far as we are aware there is no informapotassium, renal circulation,. renin-angiotensin
tion
on
the
effects of caffeine on serum potassium.
system.
The conflicting literature on the cardiovascular
effects of caffeine was resolved to some extent by
Abbreviations: ERPF, effective renal plasma flow;
studies on caffeine-free subjects which showed
GFR, glomerular filtration rate; PRA, plasma renin
increases in blood pressure and a tendency to
activity.
bradycardia, along with rises in plasma renin
activity (PRA) and plasma catecholamines [6].
Introduction
These changes did not occur with regular consumption, suggesting tolerance developed to humoral and
Caffeine is a major dietary constituent with a daily
haemodynamic effects of caffeine [9],and that at
consumption per person in the U.S.A. estimated at
210 mg, 75% of which is derived from coffee [l]. least 24 h abstinence was necessary for tolerance to
disappear. There are few dose ranging studies on
the cardiovascular and humoral responses to
Correspondence: Dr G. D. Johnston, Department of
caffeine.
Therapeutics and Pharmacology, The Queen’s University
This study was undertaken to determine the
of Belfast, The Whitla Medical Building, 97 Lisburn
effect of increasing doses of caffeine on ERPF,
Road, Belfast BT9 7BL, N. Ireland, U.K.
Summary
750
A. l? Passmore et al.
cardiovascular responses, PRA, plasma noradrenaline and serum electrolytes.
Methods
Design
Eight healthy, non-smoking, male volunteers,
aged 21-38 years, were studied, having given full
informed consent to the protocol which had been
approved by the local Ethical Committee. All
subjects had full clinical and biochemical assessment before inclusion. For eligibility subjects were
required to show compliance to a fiied sodium
intake ( 150 mmo1/24 h) for 5 days. Compliance was
assessed by measuring a 24 h urinary sodium output at the end of this period.
Subjects were then studied on five occasions at
least 7 days apart and received single doses of
caffeine (45, 90, 180 and 360 mg) and matching
placebo capsules according to a randomized
double-blind cross-over design. For 5 days before
each study day subjects were brought into sodium
balance by taking a diet containing approximately
150 mmol of sodium daily (according to a diet
sheet). Total fluid intake each day was 2 litres. Subjects were also asked to standardize their caffeine
intake to four cups of coffee or six cups of tea per
day (approximately 240 mg daily) for the 5 day
period. For the 24 h before each study day all
methylxanthine containing food and drink was
avoided and all urine was collected. If urinary
sodium excretion was outside 100-200 mmol per
24 h the study day was repeated at a later date as
specified beforehand in the protocol. This was
necessary on five occasions and resulted in a change
in the planned sequence of treatments without
compromising the double-blind nature of the study.
Study day
After a light breakfast subjects presented at
09.00 hours with their 24 h collection of urine. The
volume was recorded and an aliquot stored for subsequent measurement of sodium. An intravenous
cannula was positioned for blood sampling. Subjects remained semi-supine throughout except for
sitting to micturate, and received 100 ml of water
hourly.
After 1 h ERPF was measured using a single
intravenous injection of ~-['~'I]iodohippurate
[lo].
Plasma samples were obtained at 5 min intervals for
20 min and at 10 min intervals up to 60 min. At the
end of this period heart rate and blood pressure
were measured. Blood was drawn for subsequent
assay of plasma caffeine, plasma noradrenaline,
PRA and serum electrolytes. Subjects then emptied
their bladders. The volume of urine was recorded
and a portion was reserved for measurement of
sodium. Study medication was then administered
orally.
Thirty minutes later blood was taken for assay of
plasma caffeine and for determination of residual
radioactivity from the previous injection. A further
injection of radioisotope was given and blood
sampled over a 1 h period as described above. The
plasma curves were analysed using non-linear computer assisted analysis which assumed a two compartmental model [ll]. For the second
measurement of EFWF, correction for persistent
background activity from the first injection was
necessary and was performed by extrapolation of
the first curve using the slope of the terminal elimination phase and the zero sample of the second
study. At 1 , 2 , 3 and 4 h after medication, heart rate
and blood pressure were measured, blood was
taken for measurement of plasma caffeine, PRA,
plasma noradrenaline and serum electrolytes, and
at each interval subjects emptied their bladders.
The volume was noted and an aliquot stored for
measurement of sodium. The study finished 4 h
after administration of drug or placebo.
Assay methods
Heart rate was determined as the mean of 10
beats recorded on an electrocardiograph; blood
pressure was the mean of three readings using a
Hawksley Random Zero sphygmomanometer
(observations were made by the same observer,
using the same arm, at the antecubital fossa with the
arm at the level of the heart, taking phase V
diastolic). Electrolytes were measured using a computer controlled multi-channel biochemical
analyser with lithium internal standard (coefficient
of variation 2.4%); and urinary sodium was
analysed using a Corning flame photometer.
PRA was measured using the technique of Haber
et al. [ 121 and was expressed as pmol of angiotensin
I h-I ml-l of plasma at pH 6.4 and 37°C. Angiotensin I was measured by radioimmunoassay with a
Gamma Coat kit.
Plasma noradrenaline was measured according
to the method of Krstulovic et al. [13] using high
performance liquid chromatography with electrochemical detection.
Blood samples for caffeine were analysed as
follows. Internal standard (j3-hydroxyethyltheophylline) was added to the samples and the plasma was
passed through a Bond-Elut C18 column (Analytichem International) which had previously been conditioned with methanol and double-distilled water.
The column was then washed with water and both
caffeine and internal standard were eluted with
methanol, which was then evaporated and reconsti-
'
Renal and cardiovascular effects of caffeine
tuted in the mobile phase before injection on to the
chromatographic column. The mobile phase comprised 35% methanol in 0.01 mmol/l sodium
acetate at pH 4.7. A 15 cm x 0.46 cm Spherisorb 5
ODS column was used, together with a Waters
6000 pump at a flow rate of 1.5 ml/min. The detector was a Waters U.V. absorbance detector (model
440) with a fixed wavelength of 254 run. Retention
times of 4.2 and 2.2 min were recorded on a PerkinElmer 056 recorder for caffeine and fihydroxyethyltheophyllinerespectively.
751
T
T
1
2
Statistical analysis
The aim of the analysis was to compare the five
treatments taking account of the baseline values.
The repeated measures analysis of co-variance [14]
was used on all response variables, taking the predose value of the variable on each study day as the
co-variate. This test compares the response from
each treatment over time adjusting for differences
at the beginning of each study day and allowing for
variation due to volunteers and study days.
Williams’ test [15] was performed on each
parameter measured. This test investigates differences between treatment means when dose levels
are compared with a zero dose control. Williams’
test was also applied to investigate the difference
between treatments at each hour.
Correlations between parameters were assessed
by linear regression analysis.
The results are expressed as means f standard
error. Statistical significance was accepted when P
values were < 0.05.
Results
Plasma caffeine (Fig. 1)
Caffeine was detected beforehand in 18 out of 40
study days. The average level was 0.15 pg/ml and
never exceeded 1 pcglml. Caffeine was. detected
within 30 min of dosing. Maximum concentrations
were seen at 1 h for 45 mg (0.59f0.13 pg/ml), 90
mg (1.54f0.13 pg/ml) and 180 mg (2.76+0.32),
and at 2 h for 360 mg (6.46f0.48 pg/ml). The
greatest individual level was 9.6 pg/ml after 360
mg. Plasma concentrations declined slowly from
peak over the 4 h period. A linear relationship
between peak plasma concentration and dose was
observed (r=0.94, P < 0.001, n=32).
Urine volume and sodium excretion
Urine volume was increased by caffeine at most
time periods although individual means did not
differ sigmficantly from placebo. The cumulative
hourly urine volume was recorded for each dose of
4
3
Time (h)
FIG. 1. Mean ( k SEM) values ( n = 8) of plasma
caffeine concentrations obtained during the 4 h
time period after drug administration. Dose of
caffeine administered: 0 , 45 pg;
90 mg; 180
mg; A , 360 mg.
.,
*,
caffeine and only the cumulative value 3 h after 360
mg differed significantlyfrom placebo ( P< 0.05).
Urinary sodium excretion per hour was
increased significantly over placebo by 90 mg of
caffeine (1-2 h, 1 9 f 4 mmol/h vs 8 f 2 mmol/h,
P < 0.05; 2-3 h, 13 f 3 mmol/h vs 9 f2 mmol/h,
P < 0.05), 180 mgof caffeine( 1-2 h, 16-12 mmol/h
vs 8 f2 mmol/h, P < 0.01; 2-3 h, 15 f2 mmol/h vs
9 f 2 mmol/h, P < O . O l ) and 360 mg of caffeine
(0-1 h, 23 f5 mmol/h vs 12 f 3 mmol/h, P < 0.05;
1-2 h, 26 f 3 mmol/h vs 8 f2 mmol/h, P < 0.01;
2-3 h, 19 & 3 mmol/h vs 9 & 2 mmol/h, P < 0.001;
3-4 h, 19 If: 3 mmol/h vs 11k 2 mmol/h, P < 0.01).
An increased cumulative urinary sodium excretion compared with placebo was evident with 90 mg
of caffeine (4 h, 5 7 f 9 mmol vs 38f 10 mmol, P
< 0.05), 180 mg of caffeine (3 h, 5 0 f 6 mmol vs
29 f8 mmol, P < 0.05; 4 h, 63 f7 mmol vs 38 f 10
mmol, P < 0.01) and 360 mg of caffeine (1 h, 23 f5
mmol vs 1 2 f 3 mmol, P < 0.05; 2 h, 4 9 + 8 mmol
vs 21 f 6 mmol, P<O.Ol; 3 h, 6 8 f 9 mmol vs
2 9 f 8 mmol, P<O.Ol; 4 h, 89&10 mmol vs
38 f 10 mmol, P < 0.01) (Fig. 2).
ERPF
Values for EMF after caffeine did not differ
significantly from placebo response at any of the
doses (Table 1).
Serum electrolytes
There were no significant changes in sodium,
chloride or urea after caffeine or placebo. An
A . l? Passmore et al.
g
unexpected finding was the fall in serum potassium
with caffeine (Fig. 3). The decrement was more
evident with increasing dosage and time and s i d cantly lower than placebo 4 h after 360 mg (decrease of 0.44 mmol/l, P<O.O5). The greatest
reduction of 0.8 mmol/l occurred with 360 mg.
100-
Y
8
.a
5
80-
60'
0
.U
40-
-
20-
.->
Blood pressure and heart rate
0-1
0-2
0-3
0-4
Time period after caffeine or placebo (h)
FIG. 2. Cumulative urinary sodium excretion
at the four time periods after
( m e a n z k s ~ n=8)
~,
caffeine (El, 45 mg; 0, 90 mg; El, 180 mg; B, 360
mg) or placebo (W). Significant differences vs
placebo:*P< 0.05; **P< 0.01.
TABLE
1. Effective renal plasma flow before and afier
treatment with caffeine or placebo in eight subjects
Results are meanszks~.There are no differences
between caffeine and placebo.
Dose of caffeine
(ms)
Placebo
45
90
180
360
ERPF (ml m i d 1.73 d)
Pretreatment
Post treatment
838 f77
827 f 60
752 f 89
757 f 49
806 f 60
754 f54
788f51
695 f 37
747 f 33
733 f 52
Systolic pressure increased with increasing dose
of caffeine. A linear relationship to dose was
observed ( r = 0.4, P < 0.05). When mean values at
each hour were compared with placebo, systolic
pressure was significantly increased 1 h after 90 mg
(increase of 4.5 mmHg, P < 0.05), 180 mg (increase
of 7 mmHg, P<O.Ol) and 360 mg of caffeine
(increase of 10.6 d g , < 0.01). The increase in
systolic pressure decreased with time after 45 and
90 mg of caffeine but was sustained with 180 and
360 mg of caffeine and significant increases were
observed after 360 mg of caffeine at 2 h (increase of
8.6 mmHg, P < 0.05), 3 h (increase of 10 mmHg,
P<O.O5) and 4 h (increase of 14 mmHg,
P < 0.001) (Fig. 4). Significant increases in diastolic
pressure were observed (Fig. 4)at 1 h with 90 mg
(increase of 8 mmHg, P < 0.01), 180 mg (increase
of 6.5 mmHg, P < 0.01) and 360 mg of caffeine
(increase of 8 mmHg, P < 0.01). No relationship
was evident between dosage and the change in diastolic pressure.
There was no significant change in heart rate
after placebo or after 45, 90 and 180 mg of
caffeine. There was a significant increase in heart
rate at 3 h (increase of 6 beatslmin, P < 0.05) and
4 h (increase of 5.5 beats/min, P < 0.05) after 360
mg of caffeine (Fig. 4).
0.2-
PRA plasma noradrenaline
There was no significant change in PRA (Table 2)
or plasma noradrenaline (Table 3) at any time point
after caffeine.
E -0.2
Discussion
Caffeine is used as an ingredient in prescription and
non-prescription drugs for its diuretic effect and to
-0.4~
enhance the therapeutic effect of analgesics and
c
stimulants. There is no information on the diuretic
O - 0.5 1
effects of low doses of caffeine. Robertson et al. [6]
n n n n showed that 250 mg of caffeine increased urine
1
2
3
4
volume and sodium excretion. The mechanism of
Time (h)
the diuretic effect has been implied from work with
theophyllines. The diuresis may be due to increased
FIG.3. Mean ( k SEM, n = 8) change in serum potasGFR or renal blood flow [4],but it has been
sium at each time point after caffeine (El, 45 mg; 0,
suggested that diminished tubular reabsorption of
90 mg; H, 180 mg; R, 360 mg) or placebo (W). Sigsodium is more likely [5], in particular at the dilutnificant differences vs placebo: * P < 0.05.
.-0
-0.3
1
Renal and cardiovasculizr effects of caffeine
201
-5J
154
-5-1
10
-5’
1
T
n nn n
1
2
3
4
Time (h)
FIG. 4. Effect of caffeine on haemodynamic
responses. The change ( m e a n z k s ~n=
~ , 8) in each
variable (systolic pressure, diastolic pressure and
heart rate) from baseline is plotted at the individual
time points after administration of study medication
(W, placebo; 8, 45 mg of caffeine; 0, 90 mg of
caffeine; 8, 180 mg of caffeine; B, 360 mg of
caffeine). Significant differences vs placebo:
*P<0.05; **P<0.01.
ing segment and possibly at the proximal tubule [5].
The present study has demonstrated significant
increases in urinary sodium excretion after 90, 180
and 360 mg of caffeine. These results suggest that
the amount of caffeine used in drug formulations
753
could have a diuretic effect. We have not shown any
change in ERPF, implying that a haemodynamic
change is not an important factor in caffeine
induced natriuresis, and that a change in tubular
reabsorption of sodium is more likely, although an
increase in GFR or an intrarenal redistribution of
blood flow have not been excluded.
The increases in PRA with caffeine [6,9] are not
always seen [16, 171, especially in patients with
autonomic failure [18] nor after chronic dosing [9].
Under the present conditions caffeine did not
change PRA.
There is now evidence that caffeine actions are
mainly mediated by antagonism of adenosine receptors [19], while there are subsidiary effects on
adenylate cyclase [20], inhibition of phosphodiesterase [21] and intracellular calcium [22]. Animal
studies suggest a possible role for adenosine in the
control of renin release, renal haemodynamics and
electrolyte metabolism [23]. These studies imply
that the sensitivity of the kidney to adenosine is
related to the level of the renin-angiotensin system
and if the analogy is applicable to man, then adenosine antagonism by caffeine may result in increased
GFR, urine flow and sodium excretion, while
changes in ERPF and PRA would be dependent on
sodium balance. We have noted increased urine
volumc and sodium excretion but the lack of change
in PRA or EFWF in the present study may have
been due to the normal salt balance of the volunteers.
The hypokalaemia was unexpected. This is a
prominent finding in theophylline overdosage [7]
but has only recently been described at therapeutic
concentrations of theophylline [8]and has not been
reported with caffeine. The mechanism of this effect
is unclear and it is only possible to speculate on
aetiology. Since 250 mg of caffeine had no kaliuretic effect [6] we feel that a change in potassium
excretion is unlikely. A caffeine induced rise in
plasma adrenaline [6] may reduce serum potassium
by stimulation of &adrenoceptors [24]. This
possibility has ndt been addressed in the present
study. Another possible explanation is an effect on
the Na+/K+-ATPase pump such as produced by
adenosine antagonism, adenylate cyclase inhibition
or phosphodiesterase inhibition [25].
There is only one dose ranging study [26] using
caffeine where both systolic and diastolic pressure
increased but neither response was related to dose.
The present study showed a dose-response relationship with systolic pressure only. Pressure
responses in patients with autonomic failure [18]
that are unaccompanied by changes in
sympatho-adrenal or renin system activity, are
similar to those seen in normal subjects [6]. This
suggests that the neuroendocrhe system is not the
A . P. Passmore et al.
754
TABLE
2. Plasma renin activity after caffeine orplacebo in eight subjects
Results are means It SE. The response to caffeine is not significantly different from
placebo.
PRA (pmol of ANG I h-'
Dose of caffeine
(md
Time post treatment (h)... 0
Placebo
45
90
180
360
1.20f0.25
0.87f0.23
1.1 3 f 0.13
1.22f0.28
1.20f0.24
d - I )
1
2
3
4
1.21 f 0 . 2 9
0.70f0.16
1.04f 0.16
0.86f0.14
0.8650.13
1.23f0.29
0.83f0.17
0.84 f 0.27
1.12f0.31
0.93f0.13
1.27f0.36
0.96f0.20
1.09f 0.17
1.03f0.23
0.87f0.17
1.46f0.34
0.8950.18
1.73f 0.41
1.03f0.23
0.81f0.15
TABLE
3. Plasma noradrenaline concentrationsafter caffeine or placebo in eight subjects
Results are m e a n s k s ~ .The response to caffeine is not significantly different from
p Iaceb 0.
Dose of caffeine
(mfd
Time post treatment (h)... 0
Placebo
45
90
180
360
1.20f0.11
1.24f 0 . 0 9
1.18 f 0 . 0 9
1.19f0.11
1.07f0.08
Plasma noradrenaline (pmol/ml)
1
2
3
4
1.21 f0.08
1.30f 0.12
1.26 f0.11
1.41f0.14
1.30fO.11
1.22f0.08
1.30 f 0.12
1.24 f0.11
1.40f0.12
1.20f0.11
1.41 f 0 . 1 4
1.30f 0.1 1
1.42f 0 . 1 8
1.28f0.14
1.12f0.15
1.31 f 0 . 1 4
1.20 f 0.1 1
1.15 f 0 . 1 5
1.3910.14
1.21f0.12
primary mediator of these pressor effects. There
were no changes in PRA nor in plasma noradrenaline in the present study. The possibility of a change
in adrenaline [6] has not been excluded. Adenosine
is a vasodilator in vivo [27] and lowers the blood
pressure when infused into humans [28]. Blockade
of vasodilator adenosine receptors by caffeine
could result in the drug's pressor effect.
Caffeine has direct effects on the heart which
may result in tachycardia [29], but as a result of its
pressor action elicits a vagally mediated bradycardia secondary to baroreceptor activation, and
this latter effect appears to predominate [6, 17, 30,
311. However, late increases in heart rate have been
detected [6, 311 and it is possible that the reflex
bradycardia declines with time, unmasking any direct
cardioaccelerator effect. This may account for the
late increment in heart rate produced by 360 mg of
caffeine, which could contribute to the pressor
response at 3 h and 4 h by increasing cardiac
output.
The extensive ingestion of caffeine has led to
increasing concern about its effect on health. It has
been unclear whether lower doses of caffeine have
any effect on renal or cardiovascular function. The
present study has shown the responses to acute
administration of caffeine orally (45-360 mg).
Tolerance develops to these effects and these
results must be viewed with this in mind. The tolerance to the cardiovascular responses may account
for the lack of epidemiological evidence for caffeine
as an independent risk factor in the incidence of
hypertension [32] or myocardial infarction [33],
although conflicting evidence has recently emerged
in relation to the former [34].
Tolerance may be overcome by doubling the
dose of caffeine [35]. Since a cup of coffee may contain up to 333 mg of caffeine [36], many people may
ingest large quantities, for example first thing in the
morning, having abstained for 8-12 h overnight,
when tolerance may be reduced [17]. The acute
responses we have observed may well be relevant.
This hypothesis is supported by the findings of one
study in hypertensive patients [37], where blood
pressures were lower after overnight abstention
from caffeine, but increased after caffeine was
given, suggestidg that tolerance had worn off.
Hypokalaemia after caffeine has not been previously described and was somewhat unexpected.
The decrement was large in a few individual cases,
even at low doses. The exact nature of this effect is
unclear but such a change may have sigruficant
implications in patients with hypokalaemia. Further
research is necessary to see whether tolerance
develops to this, to determine the mechanisms
involved and to identify any risk to patients.
Renal and cardiovasccular effects of caffeine
Acknowledgment
We are grateful to the Boots Company p.1.c. for
supplies of the drug and for financial assistance.
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