European Journal of Clinical Nutrition (1999) 53, 831±839
ß 1999 Stockton Press. All rights reserved 0954±3007/99 $15.00
http://www.stockton-press.co.uk/ejcn
Coffee, caffeine and blood pressure: a critical review
M-L Nurminen1*, L Niittynen2, R Korpela2 and H Vapaatalo1
1
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland; and 2Valio Ltd,
Research and Development Centre, Helsinki, Finland
Objective: We review the published data relating to intake of coffee and caffeine on blood pressure in man. We
also refer to studies on the possible mechanisms of actions of these effects of caffeine.
Design: The MEDLINE and Current Contents databases were searched from 1966 to April 1999 using the text
words `coffee or caffeine' and `blood pressure or hypertension'. Controlled clinical and epidemiologic studies on
the blood pressure effects of coffee or caffeine are reviewed. We also refer to studies on the possible mechanisms
of action of these effects of caffeine.
Results: Acute intake of coffee and caffeine increases blood pressure. Caffeine is probably the main active
component in coffee. The pressor response is strongest in hypertensive subjects. Some studies with repeated
administration of caffeine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not
increase blood pressure. Epidemiologic studies have produced contradictory ®ndings regarding the association
between blood pressure and coffee consumption. During regular use tolerance to the cardiovascular responses
develops in some people, and therefore no systematic elevation of blood pressure in long-term and in population
studies can be shown.
Conclusions: We conclude that regular coffee may be harmful to some hypertension-prone subjects. The
hemodynamic effects of chronic coffee and caffeine consumption have not been suf®ciently studied. The
possible mechanisms of the cardiovascular effects of caffeine include the blocking of adenosine receptors and the
inhibition of phosphodiesterases.
Descriptors: coffee; caffeine; blood pressure; hypertension; adenosine receptors; phosphodiesterases
Introduction
Coffee is one of the most widely used non-alcoholic
beverages in industrialized countries. Caffeine is an important component of this drink: a 150 ml cup of coffee
contains about 60 ± 120 mg of caffeine (Barone & Roberts,
1996). Other common dietary sources of caffeine are tea
and cola soft drinks. The caffeine content in tea is aproximately 20 ± 40 mg per 150 ml cup, and that of cola soft
drinks ranges from 15 to 24 mg per 180 ml serving. The
consumption of coffee in Nordic countries is among the
highest in the world; for instance, in Denmark the mean
daily caffeine intake is approximately 7 mg=kg (Barone &
Roberts, 1996). In addition, caffeine is used as an adjuvant
in many prescription and over-the-counter drugs, e.g. in
combination with nonsteroidal anti-in¯ammatory drugs in
analgesic formulations and with ergotamine in drugs for
treating migraine (Chou & Benowitz, 1994). Combination
of caffeine and ephedrine has also been reported to reduce
weight in obese subjects, whereas both substances given
alone had no effect (Astrup et al, 1992).
Caffeine exerts a variety of stimulatory effects upon the
central nervous system, and it is probably the most widely
used psychoactive substance. It also increases the respiratory rate and causes bronchodilatation, stimulates lipolysis,
and increases diuresis (Robertson et al, 1978; Chou &
*Correspondence: M-L Nurminen, Institute of Biomedicine, Department
of Pharmacology and Toxicology, PO Box 8, FIN-00014 University of
Helsinki, Finland. E-mail: marja-leena.nurminen@helsinki.®.
Guarantor: M-L Nurminen.
Contributors: L Niittynen wrote the chapter dealing with acute intake of
coffee and caffeine, R Korpela and H Vapaatalo wrote the chapter dealing
with the mechanisms and M-L Nurminen is responsible for the other parts
of the manuscript.
Benowitz, 1994). Caffeine produces a variety of adverse
effects, including gastrointestinal disturbances, tremor,
headache and insomnia (Chou & Benowitz, 1994). It can
also induce palpitations and sometimes even cardiac
arrhythmias (Mehta et al, 1997), and it has been suggested
that caffeine may be potentially hypertensive (James 1997;
Jee et al, 1999).
Caffeine is readily absorbed from the gastrointestinal
tract and rapidly distributed in all the body ¯uids (Chou &
Benowitz, 1994). There is, however, considerable interindividual variability in the rate of absorption. The peak
plasma concentrations of caffeine are usually obtained
within 30 ± 120 min of oral intake (Robertson et al, 1978;
Smits et al, 1985, 1986a). Caffeine is extensively metabolized in the liver via a complex set of reactions. The
primary pathway is oxidative N-demethylation to paraxanthine, theobromine, theophylline and direct ring oxidation to 1,3,7-trimethyluric acid (Tang-Liu et al, 1983). The
elimination half-life of caffeine in man ranges from 2 ±
10 h, with a mean of about 4 ± 5 h (Robertson et al, 1981;
Tang-Liu et al, 1983; Smits et al, 1985). A dose-dependent
pharmacokinetics may occur, which means that enzymes
involved in metabolism become saturated (Tang-Liu et al,
1983). The metabolism is slowed during pregnancy (Knutti
et al, 1981) and in women taking oral contraceptives
(Callahan et al, 1983). On the other hand, the clearance
rate of caffeine is greater in smokers than in non-smokers
(Parsons & Neims, 1978).
Coffee and other caffeine-containing beverages are
widely consumed on a daily basis. It is therefore important
to de®ne the possible risks and bene®ts associated with
caffeine intake, in order to be able to better inform
both health professionals and the public. The possible
association between coffee consumption and increased
Coffee, caffeine and blood pressure
M-L Nurminen et al
832
risk of coronary heart disease has been debated for decades
without any clear agreement of causal relation (Wilson et
al, 1989; Greenland, 1993; Chou & Benowitz, 1994;
Kawachi et al, 1994; Thompson, 1994). Possible risk
factors predisposing consumers to caffeine-induced coronary heart disease may include blood pressure and plasma
cholesterol levels elevated by coffee.
The objective of this overview is to summarize current
knowledge of the effects of coffee and caffeine intake on
blood pressure. The possible mechanisms of these
responses will also be discussed. The relation between
coffee consumption and plasma lipids has been reviewed
elsewhere (Thelle et al, 1987; Pirich et al, 1993, Thompson, 1994) and is therefore not included in this article.SBP,
systolic blood pressure; DBP, diastolic blood pressure.
Methods
The MEDLINE and the Current Contents literature
searches for published articles in English from January
1966 to April 1999 were carried out using the keywords
`coffee or caffeine' and `blood pressure or hypertension'.
Articles concerning human epidemiological and controlled
clinical studies that have relevant data on the effects of
coffee or caffeine on blood pressure were included in the
present review. In addition, reference lists were reviewed to
obtain applicable articles. We also referred to animal and in
vitro studies that dealt with the possible mechanisms of
actions of the cardiovascular effects of coffee or caffeine.
The inclusion criteria for clinical trials were a controlled
study design and random assignment. Exclusion criteria
were an open study design, the numerical values of the
blood pressure not given or statistical analysis not performed.
Epidemiologic studies on coffee and blood pressure
Several cross-sectional and longitudinal epidemiologic
studies have evaluated the effects of coffee and caffeine
intake on blood pressure (Table 1). However, the results
have remained inconsistent. Some of these studies found
that habitual consumption of coffee or caffeine was associated with slightly elevated blood pressure (Lang et al,
1983a, b; Birkett & Logan, 1988; LoÈwik et al, 1991; Burke
et al, 1992; Narkiewicz et al, 1995). However, many of the
epidemiologic studies showed no relation (Shirlow et al,
1988; Wilson et al, 1989; HoÈfer & BaÈttig, 1993; Lewis et
al, 1993), and some even showed a small inverse association between self-reported coffee consumption and blood
pressure (Periti et al, 1987; Stensvold et al, 1989; Salvaggio et al, 1990; Gyntelberg et al, 1995; Wakabayashi et al,
1998). Consumption of coffee appears to be positively
associated with an increased risk of thromboembolic
stroke in middle-aged hypertensive men (Hakim et al,
1998).
Development of tolerance during habitual use may
explain why coffee consumption in some epidemiologic
studies did not appear to have a clear effect on blood
pressure. However, a large cross-sectional study with over
5000 participants found that caffeine consumption within
the last 3 h was associated with signi®cantly higher blood
pressure than when caffeine was not consumed in the last
9 h (Shirlow et al, 1988). A smaller study with 338 female
subjects also con®rmed that recent coffee consumption was
related to increased blood pressure (HoÈfer & BaÈttig, 1993).
In some of the epidemiologic studies blood pressure measurements were taken under conditions when fasting was
required from the participants (Salvaggio et al, 1990; Lewis
et al, 1993; Gyntelberg et al, 1995). This may have led to
an underestimation of the blood pressure levels in the
studies with negative results, because caffeine deprivation
has been associated with lower blood pressure in habitual
consumers (James, 1994; Phillips-Bute & Lane, 1998).
Thus, the inverse association between coffee intake and
blood pressure observed in some epidemiologic studies
(Salvaggio et al, 1990; Gyntelberg et al, 1995) is consistent
Table 1 Epidemiologic studies on coffee and blood pressure
Reference
Country
Population
Age (y)
Main results
2 436 M ‡ F
843 M ‡ F
> 17
60 ± 87
DBP increased by 1 mmHg at usual level of caffeine intake (181 mg=day)
BP was positively related to coffee drinking in subjects treated with antihypertensive
drugs. No signi®cant association between coffee drinking and BP in untreated
subjects was found
Actual coffee consumption on the testing day was associated with elevated BP
(0.7 ± 2 mmHg per cup of coffee). Habitual coffee consumption was unrelated to BP
DBP was 2 mmHg higher among coffee drinkers than among nondrinkers
SBP was 2 ± 4 mmHg higher among coffee drinkers than among nondrinkers
Caffeine intake (up to 800 mg=day) was unrelated to BP
Coffee consumption was positively correlated with BP among women
Daytime SBP was 2.5 mmHg higher in men who consumed coffee 4 cups=day
than in men who did not drink coffee
SBP and DBP were 0.8 and 0.5 mmHg lower per daily consumed cup of coffee
Increasingly lower BP with increases in coffee consumption; those who drank 4 ± 5
cups=day had SBP and DBP 2 ± 3 and 1 mmHg lower than nondrinkers
A positive correlation between plasma levels of caffeine and BP in infrequent
caffeine users but not in habitual users
Caffeine intake within the last 3 h was associated with 2 ± 4 mmHg higher BP.
Average daily caffeine consumption was not associated with BP
An inverse U-shaped relation between coffee consumption and BP, the mean values
being lowest for 0 and 9 cups=day
SBP and DBP were 0.6 and 0.4 mmHg lower per daily consumed cup of coffee
Cross-sectional studies
Birkett & Logan (1988)
Burke et al (1992)
Canada
Australia
HoÈfer & BaÈttig (1993)
Switzerland
Lang et al (1983a)
Lang et al (1983b)
Lewis et al (1993)
LoÈwik et al (1991)
Narkiewicz et al (1995)
Algeria
1 491 M ‡ F
France
6 321 M ‡ F
USA
5 115 M ‡ F
Netherlands
255 M ‡ F
Italy
887 M ‡ F
15 ± 70
18 ± 60
18 ± 30
65 ± 79
18 ± 45
Periti et al (1987)
Salvaggio et al (1990)
Italy
Italy
18 ± 62
18 ± 65
Sharp & Benowitz (1990) USA
338 F
500 M ‡ F
9 601 M ‡ F
20 ± 40
247
Shirlow et al (1988)
Australia
5 147 M ‡ F
20 ± 70
Stensvold et al (1989)
Norway
29 027 M ‡ F
40 ± 42
Wakabayashi et al (1998) Japan
3 336 M
Longitudinal studies
Gyntelberg et al (1988)
Wilson et al (1989)
2 975 M
53 ± 74 DBP was negatively associated with coffee consumption in coffee drinkers
5 209 M ‡ F Middle-aged Coffee consumption was unrelated to SBP
Denmark
USA
48 ± 56
SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure.
Coffee, caffeine and blood pressure
M-L Nurminen et al
with the lower blood pressure in regular users of coffee
during caffeine withdrawal.
in hypertensive or hypertension-prone subjects than in
normotensive subjects (Smits et al, 1986a; Greenstadt
et al, 1988; Sung et al, 1994; Lovallo et al, 1996b). The
effect has been shown to be additive or enhanced during
mental and physical stress (Greenstadt et al, 1988; Pincomb
et al, 1988, 1991; Lovallo et al, 1989, 1991, 1996b; Myers
et al, 1989; Lane et al, 1990; France & Ditto, 1992).
It has been suggested that the pressor effect of caffeine
is stronger in older subjects than that seen in the young ones
(Izzo et al, 1983; Massey, 1998). No racial or sex differences have been found in blood pressure responses to
caffeine (Myers et al, 1989; Strickland et al, 1989; Bak
& Grobbee, 1990; James, 1994).
The pressor effect of acute caffeine intake is stronger in
persons who do not normally consume caffeine than in
habitual users of caffeine (Izzo et al, 1983; Casiglia et al,
1992). The degree of blood pressure response associated
with a single dose of caffeine seems to be inversely related
to the plasma caffeine concentration at the time of administration, i.e. the greatest blood pressure response occurs in
those subjects with the lowest caffeine concentration
(Robertson et al, 1981).
Acute intake of coffee or caffeine and blood pressure
A rise in blood pressure after acute intake of coffee has
been shown in many studies (Table 2). It seems that
caffeine is the active component responsible for this
effect, because in several studies regular coffee intake
increased blood pressure, whereas decaffeinated coffee
had no effect (Smits et al, 1985; Ray et al, 1986; Myers
et al, 1989; Nussberger et al, 1990). In addition, no
differences between the pressor effects of regular coffee
and caffeine have been found (Casiglia et al, 1992).
A single dose of caffeine (200 ± 250 mg, equivalent to
two to three cups of coffee) increases systolic blood
pressure by 3 ± 14 mmHg and diastolic blood pressure by
4 ± 13 mmHg in normotensive subjects (Table 2). The
pressor effect coincides with the increase in plasma caffeine concentrations (Robertson et al, 1978; Haigh et al,
1993; Sung et al, 1994). Blood pressure usually elevates
within 30 min, and the maximal increase occurs 60 ±
120 min after caffeine intake (Robertson et al, 1978; Freestone & Ramsay 1982; Izzo et al, 1983; Nussberger et al,
1990; Sung et al, 1994). The increase in blood pressure
may last over 2 ± 4 h (Freestone & Ramsay 1982; Casiglia
et al, 1992; Sung et al, 1994; Bender et al, 1997). The
pressor response to caffeine seems to be more pronounced
Repeated coffee or caffeine intake and blood pressure
Despite the well-described pressor response to acute intake
of coffee or caffeine, the evidence for long-term effects on
blood pressure is inconclusive. The results of the studies
Table 2 Controlled studies on the effects of coffee or caffeine on systolic blood pressure (SBP) and diastolic blood
pressure (DBP) after acute administration
Subjects
Change (mmHg)
Reference
n
Age (y)
Dose
Normotensive subjects
Astrup et al (1990)
6
20 ± 32
Bender et al (1997)
Casiglia et al (1992)
12
15
21 ± 26
24 ± 30
France & Ditto (1992)
Haigh et al (1993)
Lane & Williams (1987)
Lane et al (1990)
Lovallo et al (1989)
Lovallo et al (1991)
Lovallo et al (1996b)
Nussberger et al (1990)
Passmore et al (1987)
48
8
30
25
34
39
24
8
8
16 ± 36
67 ± 82
19 ± 28
18 ± 36
21 ± 35
27 1
20 ± 39
24 ± 28
21 ± 38
Pincomb et al (1988)
Pincomb et al (1991)
Ray et al (1986)
Robertson et al (1978)
Smits et al (1983)
Smits et al (1985)
Smits et al (1986a)
Sung et al (1994)
44
34
9
9
12
8
10
12
20 ± 36
20 ± 35
21 ± 30
17 ± 38
21 ± 25
19 ± 37
30 ± 45
Hypertensive or borderline hypertensive subjects
Freestone & Ramsay (1982)
16
Goldstein & Shapiro (1987)
Lovallo et al (1996b)
Smits et al (1986a)
Sung et al (1994)
18
24
10
18
37 ± 60
20 ± 39
18 ± 56
30 ± 45
SBP
DBP
100 mg caffeine
200 mg caffeine
400 mg caffeine
5 mg=kg caffeine
2 cups of coffee
200 mg caffeine
250 mg caffeine
250 mg caffeine
250 mg caffeine
3.5 mg=kg caffeine
3.3 mg=kg caffeine
3.3 mg=kg caffeine
3.3 mg=kg caffeine
250 mg caffeine
90 mg caffeine
180 mg caffeine
360 mg caffeine
3.3 mg=kg caffeine
3.3 mg=kg caffeine
4 mg=kg caffeine
250 mg caffeine
2 cups of coffee
300 ml coffee
2 cups of coffee
3.3 mg=kg caffeine
‡2
‡2
‡6
‡9
‡3
‡6
‡3
‡ 12
‡7
‡8
‡6±7
‡7±8
‡6
‡ 12
‡5
‡7
‡ 11
‡4
‡ 6 ± 10
‡8
‡ 14
‡5
‡4±5
‡5
‡9
‡3
0
‡6
‡4
‡4
‡7
‡6
‡7
‡4
‡8
‡4±8
‡5±7
‡4
‡ 13
‡8
‡7
‡8
‡5
‡ 4 ± 11
‡ 11
‡ 10
‡ 11
‡8±9
‡ 11
‡8
500 ml coffee
( 200 mg caffeine)
200 mg caffeine
3.3 mg=kg caffeine
2 cups of coffee
3.3 mg=kg caffeine
‡ 10
‡7
‡8
‡ 11
‡ 13
‡ 12
‡6
‡8
‡ 11
‡ 11
SBP, systolic blood pressure; DBP, diastolic blood pressure.
833
Coffee, caffeine and blood pressure
M-L Nurminen et al
834
Table 3 Controlled clinical studies on the effects of coffee or caffeine on blood pressure (BP) in habitual coffee users after repeated administration
Subjects
Reference
Daily
dose
Age (y)
Treatments
8
20 ± 30
Bak & Grobbee (1990)
107
18 ± 33
Bak & Grobbee (1991)
69
25 4
Burr et al (1989)
54
18 ± 58
van Dusseldorp et al
(1989)
van Dusseldorp et al
(1991)
45
24 ± 45
54
Instant coffee
Decaffeinated coffee
Filtered coffee
Boiled coffee
No coffee
Caffeine
Placebo
Instant coffee
Decaffeinated coffee
No coffee
Filtered coffee
Decaffeinated coffee
Boiled coffee
Boiled and ®ltered coffee
No coffee
Instant coffee
Decaffeinated coffee
Caffeine
Placebo
Filtered coffee
No coffee
Filtered coffee
Decaffeinated coffee
No coffee
Normotensive subjects
Ammon et al (1983)
n
HoÈfer & BaÈttig (1994)
120
39 6
39 9
39 8
20 ± 45
Robertson et al (1981)
18
21 ± 52
Rosmarin et al (1990)
21
35.5
Superko et al (1991)
181
46 11
48 9
45 11
18
20 ± 44
Hypertensive subjects
Robertson et al (1984)
Caffeine
Placebo
8 cups
8 cups
4 ± 6 cups
4 ± 6 cups
75 mg64 ± 6
5 cups
5 cups
5
5
6
6
cups
cups
cups
cups
5.3 cups
5.3 cups
250 mg63
3.6 cups
3 ± 6 cups
3 ± 6 cups
250 mg63
Duration
Main results
4 weeks
4 weeks
9 weeks
9 weeks
9 weeks
9 weeks
9 weeks
4 weeks
4 weeks
4 weeks
6 weeks
6 weeks
11 weeks
11 weeks
11 weeks
9 days
9 days
7 days
7 days
8 weeks
8 weeks
2 months
2 months
2 months
Changing from decaffeinated coffee to
caffeinated coffee increased BP by 3 mmHg
Abstinence from coffee decreased SBP by
3 mmHg. Filtered coffee and boiled coffee
showed a similar BP response
No differences in BP between groups
receiving caffeine and placebo tablets
SBP was 3 mmHg higher when subjects
received caffeinated coffee than whey they
abstained from coffee
Use of decaffeinated coffee decreased SBP
and DBP by 1.5 and 1.0 mmHg
Boiled coffee increased SBP by 3 mmHg
compared with boiled and ®ltered coffee.
Abstinence from coffee had no effect on BP
No differences in BP between groups
receiving caffeinated and decaffeinated coffee
Tolerance developed to the pressor effect of
caffeine within 4 days
Coffee had no signi®cant effect on BP
7 days
7 days
Tolerance developed to the pressor effect of
caffeine after ®rst day
BP did not signi®cantly change following
change to decaffeinated coffee or
abstinence from coffee
SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure.
Table 4 Studies on the blood pressure effects of coffee or caffeine using continuous ambulatory blood pressure (BP) monitoring
Subjects
Reference
n
Age (y)
Normotensive subjects
Green & Suls (1996)
13
34.1
James (1994)
36
Jeong & Dimsdale (1990)
12
Lane et al (1998)
19
Myers & Reeves (1991)
25
Rakic et al (1999)
22
Superko et al (1994)
Treatments
Caffeinated coffee
Decaffeinated coffee
18 ± 52 Caffeine
Placebo
29 ± 59 Instant coffee
Decaffeinated coffee
37 7 Caffeine
21 ± 43 Placebo ! Caffeine !
Placebo
54 ± 89 Instant coffee
Caffeine-free diet
150
Caffeinated coffee
Decaffeinated coffee
No coffee
Hypertensive or borderline hypertensive subjects
Eggertsen et al (1993)
23 28 ± 74 Instant coffee
Decaffeinated coffee
MacDonald et al (1991)
50 26 ± 63 Instant coffee
Decaffeinated coffee
No caffeine
Normal diet
Rakic et al (1999)
26 54 ± 89 Instant coffee
Caffeine-free diet
SBP, systolic blood pressure; DBP, diastolic blood pressure.
Daily
dose
ad 8 cups
Duration
Main results
1 day
1 day
1.75 mg=kg63 1 ± 7 days
1 ± 7 days
3 cups
1 day
3 cups
1 day
50 mg6 2
9h
250 mg62
9h
200 mg62
5 cups
4.5 1.1 cups
4.5 1.1 cups
3 ± 4 cups
3 ± 4 cups
3 cups
3 cups
5 cups
Caffeine increased daytime SBP and DBP
maximally by 3.6 and 5.6 mmHg
Caffeine increased SBP and DBP maximally
by 6.0 and 5.2 mmHg after 1 week's consumption
Caffeinated coffee increased SBP and DBP
4 mmHg during the workday
SBP and DBP were 4 and 3 mmHg higher
when the larger dose of caffeine (250 mg62)
was consumed during the workday
5 days
Caffeine increased daytime SBP and DBP by
5 days
3 mmHg during the ®rst day. BP returned to
3 days
baseline by third day (data not shown)
2 weeks No signi®cant differences in BP between
2 weeks
abstainers and coffee drinkers.
2 months Changing from caffeinated to decaffeinated
2 months
coffee increased daytime SBP by 3 ± 5 mmHg.
2 months
Abstinence from coffee decreased SBP and
DBP by 2 ± 4 and 2 ± 3 mmHg
2
2
2
2
2
2
2
2
weeks
weeks
weeks
weeks
weeks
weeks
weeks
weeks
No signi®cant differences in mean 24 h BP
between the treatments
No signi®cant differences in mean 24 h BP
between the treatments
Mean 24 h SBP and DBP was 4.8 and 3.0
mmHg higher in coffee drinkers than in
abstainers
Coffee, caffeine and blood pressure
M-L Nurminen et al
with repeated administration of coffee or caffeine are
summarized in Table 3. The effects of repeated caffeine
intake have also been studied in controlled studies using
continuous ambulatory monitoring to measure blood pressure (Table 4).
Some of the long-term studies have shown that caffeine
induced persistent pressor effects (by 3 ± 6 mmHg) in habitual consumers (Ammon et al, 1983; Burr et al, 1989; James,
1994; Rakic et al, 1999). Changing from caffeinated to
decaffeinated coffee (van Dusseldorp et al, 1989; Superko
et al, 1994) or abstinence from coffee (Bak & Grobbee, 1990;
Superko et al, 1994) resulted in a slight fall (by 2 ± 5 mmHg)
in blood pressure. However, other studies reported that
chronic caffeine consumption or abstinence from caffeine
were not accompanied by signi®cant changes in blood
pressure (Rosmarin et al, 1990; Bak & Grobbee, 1991; van
Dusseldorp et al, 1991; Superko et al, 1991; HoÈfer & BaÈttig,
1994). In one double blind trial in obese subjects, reduction in
blood pressure was observed during an energy-restricted diet
combined with caffeine (200 mg63) for 6 months (Astrup et
al, 1992). However, blood pressure also reduced in the
placebo group, and there was a pronounced weight loss by
more than 10 kg in both groups. Because reduction in body
weight lowers blood pressure in overweight subjects (Stevens et al, 1993), it is very dif®cult to differentiate the
in¯uence of caffeine alone in this study.
Daytime ambulatory blood pressure has generally been
higher on caffeine days than on caffeine-free days (Jeong &
Dimsdale 1990; James 1994; Superko et al, 1994; Green &
Suls, 1996; Lane et al, 1998; Rakic et al, 1999), whereas some
studies which reported ambulatory blood pressure recordings as 24 h means have failed to detect this pressor effect
(MacDonald et al, 1991; Eggertsen et al, 1993) (Table 4).
Most of the long-term studies were of normotensive
subjects, and there is relatively little information on the
long-term effects of caffeine in hypertensive patients
(Robertson et al, 1984; MacDonald et al, 1991; Eggertsen
et al, 1993; Rakic et al, 1999).
The failure to detect an increase in blood pressure caused
by repeated adminstration of caffeine may be due to the
development of tolerance. The pressor response has been
reported as diminishing within a few days of the start of
regular intake of caffeine (Robertson et al, 1981, 1984;
Ammon et al, 1983; Myers & Reeves, 1991). However,
the tolerance may be partial, because in some studies
caffeine was still able to elevate blood pressure during
habitual consumption (Burr et al, 1989; Jeong & Dimsdale
1990; James 1994; Green & Suls, 1996). The pressor
response to caffeine may be regained after a relatively
short period of abstinence. Caffeine taken after only an
overnight abstinence of 10 ± 12 h increased blood pressure
in regular coffee drinkers (Freestone & Ramsay, 1982; Isso
et al, 1983; Ray et al, 1986; Goldstein & Shapiro, 1987;
Pincomb et al, 1988, 1991; Myers et al, 1989; Lane et al,
1990; Lovallo et al, 1991, 1996b; Sung et al, 1994). A
pressor response to the second cup of coffee of the day
within 1 ± 2 h of the ®rst morning cup has also been observed
(Lane & Manus, 1989; Goldstein et al, 1990). Thus, the
cardiovascular effects of caffeine may persist, at least in part,
during chronic consumption of caffeine. It is possible that
some people have a higher sensitivity to caffeine or a lesser
susceptibility to the development of tolerance to the pressor
effect of caffeine.
A recent meta-analysis of 11 controlled clinical trial
with 522 participants assessed the effect of coffee intake on
blood pressure by comparing the coffee group with the nocoffee control group (Jee et al, 1999). Studies which
compared caffeine tablets with decaffeinated coffee were
excluded. According to the meta-analysis, systolic and
diastolic blood pressure increased by 0.8 mmHg
(P < 0.001) and 0.5 mmHg (P < 0.01), respectively, for
every cup of coffee during long-term coffee consumption
(Jee et al, 1999).
In hypertensive subjects the combination of coffee and
smoking produced a stronger and more sustained pressor
response than each stimulus alone (Freestone & Ramsay,
1982). Moreover, in a cross-sectional observational study
using 24 h ambulatory blood pressure monitoring, moderate
smokers and coffee drinkers with mild hypertension had
signi®cantly higher daytime blood pressure than nonsmokers and those who did not drink coffee (Narkiewicz
et al, 1995), which suggests that the effect might recur
throughout the day, despite the increased caffeine catabolism in smokers (Parsons & Neims, 1978).
Hemodynamic effects of caffeine
Acute intake of coffee or caffeine increased vascular
resistance, indicating a vasoconstrictor effect (Pincomb
et al, 1985, 1988, 1991; Smits et al, 1986a; Lovallo et al,
1991; Casiglia et al, 1992; Sung et al, 1994). The pressor
effect has often been accompanied by a small decrease in
the heart rate (Izzo et al, 1983; Smits et al, 1983, 1985,
1986a; Robertson et al, 1984; Sung et al, 1994), or heart
rate was not sign®cantly affected even after high doses of
caffeine (Robertson et al, 1981; Ammon et al, 1983;
Casiglia et al, 1992; Bender et al, 1997). The caffeineinduced lowering of the heart rate may be a re¯ectory
bradycardic response to pressor action or a direct effect on
the cardiac or sino-atrial node. The re¯ex activation of
baroreceptors is supported by a recent study using power
spectral analysis, in which an increase in parasympathetic
nerve activity was observed in normotensive subjects
(Hibino et al, 1997). On the other hand, a single dose of
caffeine reduced baroreceptor sensitivity simultaneously
with an increase in blood pressure in normotensive subjects
(Mosqueda-Garcia et al, 1990). The effects were not seen
after multiple doses of caffeine over one week, possibly
due to the development of tolerance to the hemodynamic
effects of caffeine.
Palpitations sometimes associated with caffeine intake
may be explained by an increased level of altertness or by
an increased force of myocardial contraction (Myers &
Reeves, 1991). A positive inotropic effect of caffeine has
been reported (Bender et al, 1997), although in general,
little or no effect on cardiac output at rest has been noted
(Pincomb et al, 1985, 1991; Casiglia et al, 1992; Bender
et al, 1997). However, during stress an enhancement of
myocardial contractility has been found to be accompanied
by an increase in cardiac output (Pincomb et al, 1988;
Lovallo et al, 1991). The chronic effects of caffeine on
cardiac output have not been studied.
Mechanisms of the cardiovascular effects of coffee
and caffeine
The summary of the possible mechanisms of the cardiovascular effects of coffee and caffeine has been presented
in Table 5. The best known pharmacologically active
substance in coffee is trimethylxanthine caffeine. The
835
Coffee, caffeine and blood pressure
M-L Nurminen et al
836
Table 5 Possible mechanisms of the cardiovascular effects of caffeine
Antagonistic effects on adenosine receptors
Inhibition of phosphodiesterases (increase in cyclic nucleotides)
Activation of the sympathetic nervous system (release of
catecholamines from adrenal medulla)
Stimulation of adrenal cortex (release of corticosteroids)
Renal effects (diuresis, natriuresis, activation of the renin-angiotensinaldosterone system)
main metabolite of caffeine, paraxanthine, also increased
blood pressure in man (Benowitz et al, 1995). Some of the
cardiovascular effects of coffee may be mediated by a
variety of substances other than caffeine, such as the lipid
compounds cafestol and kahweol, which have been implicated as the components responsible for the hyperlipidemic
effect of un®ltered coffee (Urgert & Katan, 1997). Other
chemicals identi®ed in coffee include chlorogenic acid,
carbohydrates and peptides (Chou & Benowitz, 1994).
Both normal and decaffeinated coffee have been shown
to contain muscarinic compound(s) that constricted coronary arteries in vivo (Kalsner, 1977). An extract which
produced an abrupt depression of blood pressure and
heart rate in rats and relaxed aortic rings in vitro has also
been isolated from regular and decaffeinated instant coffee
(Tse, 1992).
Inhibition of phosphodiesterases
Caffeine could in¯uence vascular tone by inhibiting phosphodiesterases, with consequent increases in cyclic AMP
and cyclic GMP levels (Kramer & Wells, 1979). However,
caffeine is a non-speci®c inhibitor of phosphodiesterases
and is only effective in vitro at much higher concentrations
(50% inhibitory concentration of 390 ± 500 mmol=l; Kramer
& Wells, 1979) than are achieved in vivo in plasma after
two to three cups of coffee (20 ± 40 mmol=l; Izzo et al,
1983; Smits et al, 1983; Cassiglia et al, 1992). Caffeine
induced vasoconstriction in humans, whereas enprofylline,
a xanthine derivative which has prominent phosphodiesterase inhibiting effects, caused vasodilatation (Smits et al,
1989). Thus, inhibition of phosphodiesterases appears not
to be the major mechanism mediating the cardiovascular
effects of caffeine.
Antagonism of adenosine receptors
Caffeine exerts many of its actions by antagonizing adenosine receptors, of which four subtypes have been cloned
and characterized (Fredholm, 1995; Olah & Stiles, 1995).
Adenosine dilates several vascular beds (Ohah & Stiles,
1995). Based on studies with knockout mice lacking A2areceptors and having elevated blood pressure (Ledent et al,
1997), adenosine seems to act as a physiological vasodilator. Thus, caffeine may cause an increase in blood
pressure by antagonizing this effect of adenosine. The
major targets of caffeine are A1 and A2a receptors, which
can be blocked by caffeine at low micromolar concentrations similar to those that occur in plasma after consumption of a few cups of coffee (Fredholm, 1995). In
normotensive men, intravenous caffeine has been shown
to reduce the hemodynamic effects of adenosine infusion
(Smits et al, 1989).
Adenosine A1 and A2a receptors have partially opposite
cellular effects. Stimulation of A1 receptors causes the
inhibition of adenylate cyclase and some types of calcium
channels, and the activation of several types of potassium
channels, as well as phospholipases C and D (Fredholm,
1995; Olah & Stiles, 1995). Stimulation of A2a receptors
activates adenylate cyclase and probably voltage-sensitive
calcium channels. The two subtypes of receptors may be
co-expressed and activated simultaneously in the same cells
(Fredholm, 1995). The actions of caffeine are therefore
complicated.
Adenosine also inhibits the release of many neural
transmitters, e.g. noradrenaline, dopamine, acetylcholine,
glutamate and GABA (Fredholm & Dunwiddie, 1988). The
excitatory transmitter release seems to be more inhibited
than that of the inhibitory ones (Fredholm, 1995). This may
be related to activation of potassium channels via the A1
receptors. By blocking these receptors, caffeine may facilitate the release of neurotransmitters.
Caffeine not only acts at the receptor level on the
adenosine system, but in rats it can increase plasma concentration of adenosine, probably via a receptor-mediated
mechanism at concentrations achieved by the daily human
use of coffee (Conlay et al, 1997).
Vascular effects and calcium
Caffeine produced transient contractions of arterial smooth
muscle at millimolar concentrations in vitro (Kalsner,
1971; Karaki et al, 1987; Sato et al, 1988; Moriyama et
al, 1989), which were more marked in preparations from
spontaneously hypertensive rats than from normotensive
rats (Moriyama et al, 1989). Caffeine-induced vascular
contractions were reduced or blocked by removal of extracellular calcium or by the inhibition of calcium release
from the sarcoplasmic reticulum (Sato et al, 1988; Moriyama et al, 1989). It has been suggested that the mobilization of intracellular calcium by the so-called calciuminduced calcium release mechanism is crucial in caffeineinduced vasoconstriction (Karaki et al, 1987). On the
venous side in vitro, caffeine induced phasic contractions,
which were dependent on both the in¯ux of extracellular
calcium and the release of intracellular calcium (Shimamura et al, 1991).
Studies on the role of calcium in¯ux through calcium
channels in the pressor response to caffeine in man have
been contradictory, because pretreatment with the slow Ltype calcium channel antagonist verapamil had no effect
(Smits et al, 1986b), whereas nifedipine reversed the
increase in blood pressure caused by caffeine in normotensive subjects (van Nguyen & Myers, 1988).
In addition to vasoconstriction, caffeine has also been
shown to inhibit contractions in vascular smooth muscle
(Ahn et al, 1988; Sato et al, 1988), partly due to reduced
cytoplasmic calcium and partly due to reduced sensitivity
of the contractile elements to calcium (Sato et al, 1988).
Caffeine-induced relaxations in rat aortic rings consist
partly of a nitric-oxide-dependent component and also of
a component involving the inhibition of phosphodiesterases
(Hatano et al, 1995).
Sympathetic nervous system
Acute administration of coffee or caffeine increases the
plasma concentrations of catecholamines, particularly adrenaline, and the urinary excretion of catecholamines
(Robertson et al, 1978; Izzo et al, 1983; Smits et al,
1985; Pincomb et al, 1988; Lane et al, 1990; Nussberger
et al, 1990; Narkiewicz et al, 1995). The increase in plasma
adrenaline is similar in normotensive and hypertensive
subjects (Smits et al, 1986a).
Coffee, caffeine and blood pressure
M-L Nurminen et al
In animal experiments caffeine activates tyrosine hydroxylase (Snider & Waldeck, 1974; Datta et al, 1996), the ratelimiting enzyme in catecholamine biosynthesis. In addition,
caffeine releases adrenal catecholamines, both directly and
through neurogenic stimulation (Berkowitz & Spector,
1971; Snider & Waldeck, 1974). It has also been speculated
that the caffeine-induced increase in plasma catecholamines is due to inhibition of the extraneuronal metabolism
of catecholamines (Kalsner, 1971).
An increase in blood pressure by caffeine was seen in
some normotensive (Izzo et al, 1983) and hypertensive
subjects (Potter et al, 1993) as well as in adrenalectomized
patients (Smits et al, 1986a) without an increase in plasma
catecholamines. Caffeine also elevates blood pressure in
subjects with autonomic dysfunction, in whom sympathetic
responsiveness is lacking (Onrot et al, 1985; van Soeren
et al, 1996). Therefore, the pressor response to coffee is not
purely the result of an increase in circulating catecholamines or the activation of the sympathetic nervous system.
Effects on adrenal cortex
In normotensive and hypertensive subjects, caffeine
caused stress-like increases in plasma adrenocorticotropin
(ACTH) and cortisol concentrations (Lovallo et al, 1996a)
and potentiated stress-related increases in plasma cortisol
(Pincomb et al, 1988; Lovallo et al, 1989; Lane et al,
1990). Corticosteroids can in¯uence vascular tone, e.g. by
enhancing reactivity to other vasoactive substances, such as
catecholamines (Walker & Williams, 1992).
Renal effects
Acute ingestion of caffeine slightly increased urinary
volume and sodium excretion in humans (Robertson et al,
1978; Passmore et al, 1987; Nussberger et al, 1990). The
role of atrial natriuretic peptide (ANP) in the diuretic and
natriuretic effects of caffeine is unclear, because the plasma
concentrations of ANP were not affected by acute intake of
caffeine (Nussberger et al, 1990), whereas a signi®cant
increase in circulating ANP was observed during 2 weeks
of regular caffeine consumption (Eggertsen et al, 1993).
The plasma concentrations of antidiuretic hormone (vasopressin) remained unchanged after an acute intake of
caffeine (Izzo et al, 1983; Nussberger et al, 1990). On
the other hand, in rats caffeine caused a marked dosedependent increase in renal prostaglandin excretion (Engelhardt, 1996), which could, at least partly, explain the
caffeine-induced diuresis.
Repeated administration of caffeine for one week caused
renal vasoconstriction and lowered renal plasma ¯ow in
normotensive volunteers ingesting a high-salt diet (Brown
et al, 1993). Plasma renin activity was increased, which
could have caused the renal vasoconstriction via increased
angiotensin II concentrations. Acutely administered caffeine increased plasma renin activity in experimental animals (Ohnishi et al, 1987) and in man (Robertson et al,
1978, 1981), probably through the antagonism of adenosine
receptors on juxtaglomerular cells (Kuan et al, 1990). In
some studies, however, no signi®cant effect of acute
caffeine intake on plasma renin activity was observed
(Passmore et al, 1987; Nussberger et al, 1990), or else
the increase was attenuated after chronic administration of
caffeine (Robertson et al, 1981, 1984; Eggertsen et al,
1993). A decrease in plasma renin activity after an acute
intake of coffee has also been reported (Smits et al, 1983,
1986a,b). Moreover, an inverse association between
chronic coffee consumption and plasma renin activity has
been observed in mildly hypertensive men (Palatini et al,
1996). Thus, the importance of the renin ± angiotensin ±
aldosterone system in the cardiovascular effects of caffeine
remains unclear.
Conclusion
The acute pressor effect of coffee and caffeine is well
documented, but the reports on the chronic effects on blood
pressure are inconsistent. Large inter-individual variations
in caffeine metabolism may contribute to the variability in
the hemodynamic responses to chronic caffeine consumption. Differences in the extent of tolerance may also underlie the variations in sensitivity to blood pressure elevation
caused by caffeine. Although there is at present no clear
epidemiologic evidence that coffee consumption is causally
related to hypertension, high intake of coffee may be an
additional risk factor in the development of hypertension at
the individual level, because some people seem to have a
higher sensitivity to the cardiovascular effects of caffeine,
e.g. due to long-lasting stress or to a generic susceptibility
to hypertension. We conclude that coffee and caffeine in
large doses may be harmful to some hypertensive or
hypertension-prone subjects. Before more de®nite conclusions can be drawn, long-term clinical trials, as well as
prospective epidemiologic studies with large numbers of
participants, are needed.
Acknowledgements ÐSupported by grants from the Academy of Finland
and the Biomed-2 (BMH4-CT96-0979). The authors would like to thank
Mrs Mimi Ponsonby for her excellent language revision.
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