Habitual coffee and tea drinkers experienced increases in blood pressure after consuming low to moderate doses of caffeine; these increases were larger upright than in the supine posture

Abstract

Caffeine users have been encouraged to consume caffeine regularly to maintain their caffeine tolerance and so avoid caffeine's acute pressor effects. In controlled conditions complete caffeine tolerance to intervention doses of 250 mg develops rapidly following several days of caffeine ingestion, nevertheless, complete tolerance is not evident for lower intervention doses. Similarly complete caffeine tolerance to 250 mg intervention doses has been demonstrated in habitual coffee and tea drinkers' but for lower intervention doses complete tolerance is not evident. This study investigated a group of habitual caffeine users following their self-determined consumption pattern involving two to six servings daily. Cardiovascular responses following the ingestion of low to moderate amounts caffeine (67, 133 and 200 mg) were compared with placebo in a double-blind, randomised design without caffeine abstinence. Pre-intervention and post-intervention (30 and 60 min) 90 s continuous cardiovascular recordings were obtained with the Finometer in both the supine and upright postures. Participants were 12 healthy habitual coffee and tea drinkers (10 female, mean age 36). Doses of 67 and 133 mg increased systolic pressure in both postures while in the upright posture diastolic pressure and aortic impedance increased while arterial compliance decreased. These vascular changes were larger upright than supine for 133 mg caffeine. Additionally 67 mg caffeine increased dp/dt and indexed peripheral resistance in the upright posture. For 200 mg caffeine there was complete caffeine tolerance. Cardiovascular responses to caffeine appear to be associated with the size of the intervention dose. Habitual tea and coffee drinking does not generate complete tolerance to caffeine as has been previously suggested. Both the type and the extent of caffeine induced cardiovascular changes were influenced by posture.

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Introduction

Caffeine is a widely used behavioural stimulant^1,2 consumed primarily in the beverages tea, coffee, and caffeinated soft-drinks.^3,4 It is also present in a wide range of pharmaceuticals.⁵Caffeine stimulates the cerebral cortex in doses up to 200 mg with larger doses affecting also the medulla where neurons controlling cardiovascular and respiratory activity are located.⁴

Studies have shown that with daily use caffeine's pressor effect on blood pressure diminishes or disappears within several days, a process referred to as tolerance.⁶ Tolerance is short-lived and may be lost after a period of 12 to 24 h abstinence.⁷ When studies relating to caffeine tolerance are scrutinized the phenomenon of tolerance appears to be dependent on the size of the intervention dose and it remains to be established if complete tolerance exists for habitual coffee and tea drinkers outside of controlled laboratory studies. This study investigates whether or not habitual coffee and tea drinkers experience acute cardiovascular responses following the ingestion of low and moderate doses of caffeine (67, 133 and 200 mg) while engaging in their self-determined consumption pattern.

Caffeine consumption

In the USA approximately 90% of adults are daily caffeine consumers and the average daily intake is estimated at 192 mg.⁸ Similarly in the UK an estimated 91% of adults consume a minimum of 40 mg caffeine per day and the average adult daily intake is estimated at 240 mg.⁹ Most caffeine is derived from the beverages tea and coffee though there is a wide variation in caffeine levels per serving depending on raw material, type of preparation and personal preferences. The average and range of caffeine levels (excluding decaffeinated preparations) per serving are: tea 40 (1 to 90) mg, instant coffee 54 (21 to 120) mg and ground coffee 105 (15 to 254) mg.¹⁰ Plant derived caffeine is widely used by the beverage industry for the production of colas (30 to 50 mg caffeine per serving) and energy drinks (50 to 500 mg caffeine per serving).¹¹ The use of caffeine in pharmacological preparations is extensive with doses of 50 to 200 mg being used to reduce fatigue, increase alertness and delay the onset of sleep.⁵ It is also present in products generally not associated with central stimulation including allergy preparations, analgesics, antacids, cold medications, headache and weight reduction preparations.⁴ Moderate daily caffeine consumption of up to 400 mg is not associated with toxicity, cardiovascular effects or behavioural changes.⁷

Pharmacology

The daily consumption of caffeine worldwide ranges from 80 to 400 mg per adult. Caffeine usage at these levels produces blood plasma concentrations of 5 to 20 μM which are sufficient to block the tonic activation of the adenosine receptors A₁ and A_2A² while doses in the range of 2 to 3 mg kg⁻¹ (130 to 195 mg for a 65kg person) are sufficient to fully block adenosine receptors in the vascular system.¹²Caffeine is rapidly and completely absorbed from the gastrointestinal tract with the rate of absorption (99%) similar across the range of caffeine doses used in clinical experiments.¹³Caffeine is distributed throughout the body's tissues including the central nervous system with peak plasma levels occurring 15 to 60 min after ingestion.^4,14Caffeine blocks the activity of the neurotransmitter adenosine with the dose-response function following a standard log dose-response curve.² In the peripheral blood circulation where adenosine acts as a vasodilator the blocking of adenosine receptors by caffeine causes blood pressure increases.^15,16 Studies on non-caffeine users and caffeine abstainers ingesting caffeine at doses of 250 mg report increases in systolic pressure of 5 to 15 mmHg and diastolic pressure of 5 to 10 mmHg with the effect more pronounced in smokers, the elderly and hypertensives.⁷

Caffeine tolerance

In controlled laboratory testing 250 mg caffeine produced a marked pressor effect (10/6 mmHg) following caffeine abstinence, yet complete tolerance to this intervention developed after several days of ingesting 250 mg caffeine three times a day.¹⁷ However, similar studies with both smaller conditioning doses (3 × 1.75 mg kg⁻¹ (≈ 3 × 115 mg)¹⁸ and 3 × 150 mg¹⁹) and smaller intervention doses (150 mg and 1.75 mg kg⁻¹ respectively) have reported blood pressure increases of 6/5 and 6/7 mmHg respectively after a period of conditioning. In studies with habitual coffee and tea drinkers' complete tolerance was exhibited to large intervention doses of ≥250 mg^20–22 but not to the smaller intervention doses of 1.5 mg kg⁻¹ (≈95 mg)²² and 125 mg,²³ were blood increased by 10/5 and 0/5 mmHg respectively. Although caffeine users have been recommended “to consume it on a regular basis to minimize any effects it may have on blood pressure”²⁴ there is a lack of evidence to support the viewpoint that regular consumption of the beverages coffee and tea produces complete tolerance across the range of caffeine doses to which consumers are exposed both in beverages and pharmaceuticals.

Aims

This study aims to investigate whether habitual tea and coffee drinkers experience acute cardiovascular responses in the hour following ingestion of caffeine at levels of 67, 133 and 200 mg or approximately 1, 2 and 3 mg/kg. These levels are representative of caffeine levels found in both caffeinated beverages and pharmaceutical formulations and are therefore the dosages relevant to public health issues. Additionally cardiovascular recordings were obtained in the supine and upright postures to ascertain if responses to caffeine were influenced by posture.

Methods

Participants and location

This investigation conforms to the principles outlined by the Declaration of Helsinki and was approved by the University of Westminster Ethics Committee (03/04-08). Written informed consent was obtained from the participants who were healthy volunteers recruited from the staff and students of the University of Westminster, London. All participants were selected as habitual coffee and tea drinkers and agreed to continue their normal usage during the study. Habitual tea/coffee drinking was defined in accordance with previous studies involving habitual users^25–29 as consuming between two and six servings of either tea and/or coffee daily. Hypertensives (systolic pressure >140 mm Hg or diastolic pressure >90 mm Hg), smokers, pregnant women and those on prescribed medication were excluded from the study.

Caffeine dosage

The interventions were either a placebo capsule or caffeine capsules at the levels of 67, 133 and 200 mg. It was estimated that the 67 mg dose would be approximately the equivalent of 1 mg kg⁻¹, the 133 mg dose the equivalent of 2 mg kg⁻¹ and the 200 mg dose the equivalent of 3 mg/kg. The capsules were identical and contained varying combinations of caffeine and microcrystalline cellulose together as well as magnesium stearate.

Design and procedure

Participants were tested with each of the intervention doses on four separate occasions in a randomised, double blind design. Finometer recordings were obtained pre-intervention and post-intervention at both 30 and 60 min. Each recording segment commenced with a five minute relaxation period in the supine posture after which 90 s Finometer recordings were obtained first in the supine posture and later standing. To avoid orthostatic influences, the standing posture recording started 90 s after the participant began to change posture. Each participant was required to attend all sessions at a similar time of the day so as to minimise circadian rhythm influences.³⁰ Prior to an experimental session participants were required to abstain from food and drink (excluding water) for two hours. The commonly used procedure of requiring participant caffeine abstinence (usually overnight) was specifically avoided for three reasons: firstly it may produce confounding effects due to varying degrees of caffeine withdrawal which occur 12 to 24 h after the last intake of caffeine,^3,4 secondly participants may avoid caffeine products for a longer period of time than requested and lose their caffeine tolerance i.e. super-compliance²⁴ and thirdly it was intended to test participants in a naturalistic setting where each individual followed their own preferred consumption pattern rather following an imposed intake schedule. Participants were tested without any attempt to control caffeine intake other than to maintain their normal consumption which was verbally confirmed at the beginning of each test session.

Cardiovascular measurement

The Finometer (FMS, Finapres Measurement Systems, Amsterdam, The Netherlands) finger pulse contour recordings together with the accompanying Modelflow software provide the parameters: heart rate, ejection time, dp/dt (contraction force), DPTI/SPTI (the cardiac oxygen supply: demand ratio (the Buckberg index)), stroke volume, cardiac output, systolic,diastolic and mean blood pressure, peripheral resistance, arterial compliance and aortic impedance. Additionally the body surface area adjusted values (Dubois and Dubois formula): indexed stroke volume, indexed cardiac output (cardiac index) and indexed peripheral resistance values are provided.^31–37 The following parameters are reported: heart rate, ejection time, dp/dt, DPTI/SPTI, cardiac index, systolic pressure, diastolic pressure, arterial compliance, aortic impedance and indexed peripheral resistance.

Baroreflex sensitivity measurement

Assessment of the spontaneous baroreflex sensitivity was calculated from the Finometer recordings using the validated time-domain xBRS program with standard settings (p = 0.01).³⁸

Data analysis and statistics

Measurements from the 30 and 60 min recordings were averaged³⁹ to produce a single post-ingestion measures. Planned contrasts, comparing measures from each caffeine condition with measures from the placebo condition, were analysed with repeated measures 2 × 2 (pre/post × placebo/caffeine) ANOVA for each posture using SPSS v15 (Chicago, USA). A 2 × 2 × 2 (pre/post × placebo/caffeine × supine/posture) repeated measures ANOVA was used to assess whether the cardiovascular responses to caffeine were influenced by posture. The significance level was set at p <0.05 and the number of planned contrasts was equal to the number of degrees of freedom. Omnibus F values are also reported when significant.

Results

Participant characteristics

Initially 14 participants were recruited. One participant failed to complete all four sessions due to time commitments and one further participant was excluded from the analysis because of heart irregularities during the placebo session. None of the participants spontaneously reported any discomfort or problems arising during or after experimental sessions. The 12 analysed participants (10 female) had a mean (standard deviation, range) age of 36 (±7.8, 25 to 57) years, mean weight of 61 (±6.4, 49 to 79) kg, mean height (±1.66, 1.53 to 1.79) m and mean BMI of 22 (±0.9, 19 to 26) kg m⁻². As the mean participant weight was 61 kg the caffeine doses of 67, 133 and 200 mg were approximately equivalent to 1.1, 2.2 and 3.3 mg kg⁻¹. The values of the cardiovascular parameter measurements are presented in Table 1.

Table 1 Cardiovascular parameter measures in the pre-ingestion and post-ingestion phases for both postures.^a

Parameter	Caffeine	Supine Posture		Upright Posture
		Pre-ingestion	Post-ingestion	Pre-ingestion	Post-ingestion
		Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
a HR: heart rate, DPTI/SPTI: the cardiac oxygen supply: demand ratio, CI: cardiac index, SP: systolic pressure, DP: diastolic pressure, AC: arterial compliance, AI: aortic impedance; PRI: indexed total peripheral resistance,,BRS: spontaneous baroreflex sensitivity, SD: standard deviation, bpm: beats per minute, MU = medical unit = mmHg.s/ml, * p < 0.05, ** p < 0.01.
HR (bpm)	placebo	67.3 ± 8.7	63.3 ± 10.5	85.2 ± 11.3	79.9 ± 10.3
	67 mg	67.0 ± 10.5	62.3 ± 12.1	83.6 ± 10.7	76.2 ± 9.0
	133 mg	65.2 ± 9.4	60.5 ± 10.0	82.9 ± 13.0	75.0 ± 10.6
	200 mg	66.9 ± 9.6	61.3 ± 9.8	81.2 ± 7.4	77.4 ± 10.9
ET (ms)	placebo	332 ± 20	342 ± 17	265 ± 19	275 ± 20
	67 mg	335 ± 13	339 ± 18	267 ± 21	281 ± 18
	133 mg	339 ± 14	346 ± 18	271 ± 24	283 ± 20
	200 mg	335 ± 18	340 ± 16	273 ± 20	275 ± 23
dp/dt (mmHg/s)	placebo	942 ± 257	1003 ± 242	1220 ± 348	1188 ± 296
	67 mg	900 ± 260	1056 ± 267	1112 ± 212	1241 ± 258*
	133 mg	889 ± 258	1030 ± 222	1102 ± 268	1205 ± 291
	200 mg	979 ± 264	1093 ± 226	1124 ± 208	1155 ± 217
DPTI/SPTI (%)	placebo	145 ± 23	152 ± 33	149 ± 18	154 ± 19
	67 mg	148 ± 43	161 ± 39	152 ± 23	161 ± 24
	133 mg	148 ± 31	160 ± 34	153 ± 26	164 ± 24
	200 mg	144 ± 25	161 ± 32	152 ± 18	163 ± 22
CO (l min^−1)	placebo	3.4 ± 0.6	3.3 ± 0.8	2.8 ± 0.7	2.8 ± 0.6
	67 mg	3.5 ± 0.8	3.2 ± 0.9	3.0 ± 0.8	2.7 ± 0.8
	133 mg	3.2 ± 0.7	3.2 ± 0.6	2.7 ± 0.6	2.6 ± 0.6
	200 mg	3.5 ± 0.5	3.2 ± 0.5	3.0 ± 0.5	2.8 ± 0.6
SP (mmHg)	placebo	116.2 ± 11.7	119.3 ± 6.8	133.5 ± 14.1	131.5 ± 11.8
	67 mg	115.2 ± 10.4	124.1 ± 9.4*	127.6 ± 9.1	135.6 ± 10.1*
	133 mg	115.3 ± 10.3	124.4 ± 8.5*	126.9 ± 11.1	137.6 ± 14.1**
	200 mg	120.6 ± 12.1	126.1 ± 9.8	127.5 ± 10.2	132.7 ± 10.7
DP (mmHg)	placebo	68.1 ± 6.6	67.5 ± 6.8	86.4 ± 8.7	82.9 ± 8.4
	67 mg	67.0 ± 5.3	68.1 ± 6.6	81.9 ± 6.7	84.7 ± 6.0*
	133 mg	66.7 ± 5.8	69.9 ± 4.5	81.4 ± 7.7	86.5 ± 8.2**
	200 mg	69.8 ± 6.4	71.1 ± 3.7	81.1 ± 5.5	83.5 ± 8.2
AC (MU)	placebo	2.01 ± 0.35	2.03 ± 0.30	1.52 ± 0.28	1.61 ± 0.27
	67 mg	2.04 ± 0.38	1.92 ± 0.41	1.65 ± 0.33	1.54 ± 0.34**
	133 mg	2.06 ± 0.42	1.97 ± 0.34	1.67 ± 033	1.61 ± 0.29**
	200 mg	1.98 ± 0.37	1.94 ± 0.35	1.67 ± 0.28	1.62 ± 0.30
AI (mMU)	placebo	63.0 ± 8.1	62.8 ± 7.7	68.6 ± 8.1	67.0 ± 7.5
	67 mg	63.0 ± 8.0	63.1 ± 7.6	66.7 ± 8.1	67.8 ± 8.3*
	133 mg	62.8 ± 8.4	63.4 ± 8.1	66.5 ± 8.4	68.7 ± 8.7**
	200 mg	63.3 ± 8.0	63.5 ± 7.9	66.3 ± 7.6	67.2 ± 8.6
PRI (MU/m^2)	placebo	0.58 ± 0.15	0.61 ± 0.17	0.86 ± 0.26	0.84 ± 0.19
	67 mg	0.61 ± 0.12	0.67 ± 0.17	0.77 ± 0.19	0.89 ± 0.23*
	133 mg	0.62 ± 0.20	0.64 ± 0.11	0.83 ± 0.21	0.94 ± 0.19
	200 mg	0.58 ± 0.11	0.65 ± 0.11	0.74 ± 0.13	0.87 ± 0.19
BRS (ms/mmHg)	placebo	19.4 ± 11.6	23.3 ± 14.7	7.3 ± 3.5	8.3 ± 3.6
	67 mg	16.2 ± 8.5	20.2 ± 9.6	6.9 ± 2.7	8.4 ± 3.4
	133 mg	17.3 ± 8.6	22.1 ± 10.7	6.9 ± 3.4	9.0 ± 3.3
	200 mg	16.9 ± 9.2	22.7 ± 10.5	7.5 ± 3.5	9.6 ± 4.0

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Cardiac parameters

The dp/dt omnibus F was significant for all conditions F(3,33) = 3.627, p = 0.023. Dp/dt increased in the upright posture for 67 mg by 161 mmHg/s (F(1,11) = 5.848, p = 0.034).

There were no changes in heart rate, ejection time, DPTI/SPTI or the cardiac index.

Vascular parameters

The systolic pressure omnibus F was significant for all conditions F(3,33) = 4.876, p = 0.006, and upright F(3,33) = 5.332, p = 0.004. Systolic pressure increased in the supine posture for 67 mg by 5.8 mmHg (F(1,11) = 4.892, p = 0.049) and for 133 mg by 6.0 mmHg (F(1,11) = 6.299, p = 0.029). Systolic pressure increased in the upright position for 67 mg by 10.0 mmHg (F(1,11) = 8.223, p = 0.015) and for 133 mg by 12.7 mmHg (F(1,11) = 17.246, p = 0.002).

The diastolic pressure omnibus F was significant for all conditions F(3,33) = 4.285, p = 0.012, and upright F(3,33) = 3.806, p = 0.019. Diastolic pressure increased in the upright posture for 67 mg by 6.4 mmHg (F(1,11) = 5.591, p = 0.038) and for 133 mg by 8.6 mmHg (F(1,11) = 14.953, p = 0.003).

The arterial compliance omnibus F was significant for all conditions F(3,33) = 3.063, p = 0.042, and upright F(3,33) = 4.197, p = 0.013. Arterial compliance decreased in the upright posture for 67 mg by 0.20 MU (F(1,11) = 10.214, p = 0.009) and for 133 mg by 0.23 MU (F(1,11) = 120.968, p = 0.001).

The aortic impedance omnibus F was significant in upright conditions F(3,33) = 5.118, p = 0.005. Aortic impedance increased in the upright posture for 67 mg by 2.6 mMU (F(1,11) = 5.591, p = 0.038) dose and for 133 mg by 3.8 mMU (F(1,11) = 14.953, p = 0.003).

Indexed peripheral resistance increased in the upright posture for 67 mg by 0.13 MU/m² (F(1,11) = 5.134, p = 0.045.

Baroreflex sensitivity

There was no change in spontaneous baroreflex sensitivity.

Posture

For 133 mg the systolic pressure (F(1,11) = 11.080, p = 0.007), diastolic pressure (F(1,11) = 6.171, p = 0.030), arterial compliance (F(1,11) = 5.935, p = 0.033) and aortic impedance (F(1,11) = 8.254, p = 0.015) changes were larger in the upright than the supine posture. For the 67 mg dose aortic impedance (F(1,11) = 14.467, p = 0.003) changes were also larger upright.

Discussion

The principal finding of this study was that the habitual drinkers of tea and coffee experienced acute blood pressure increases following the ingestion of 67 and 133 mg whereas they exhibited complete caffeine tolerance following the 200 mg intervention. These increases in blood pressure resulted predominantly from vasoconstriction in the arterial structures rather than from vasoconstriction in the resistance vessels or changes in cardiac output. An additional key finding was that posture can influence both the type and the extent of the cardiovascular responses to caffeine ingestion. Both diastolic pressure and arterial compliance increased only in the upright posture while the pharmacological effects of caffeine on systolic pressure, diastolic pressure, arterial compliance and aortic impedance were all more pronounced in the upright than the supine posture. This result suggests that the tonus of the vascular system, which is greater in the upright than the supine posture, modulates caffeine's pharmacodynamics. Furthermore the study found that 67 mg caffeine increased dp/dt and peripheral resistance in the upright posture suggesting that low levels of caffeine may modulate autonomic outflow.

Blood pressure responses to caffeine

Caffeine levels in the range of 30 to 150 mg per serving are present in the beverages coffee and tea as well as carbonated beverages and pharmaceutical products.⁴Caffeine induced maximal blood pressure increases occur approximately 60 min after intake for both non-users⁴⁰ and overnight abstaining nonusers.⁴¹ This study's findings indicate that habitual coffee and tea drinkers, consuming two to six servings daily, as well as non-drinkers (i.e. nearly everyone) can be expected to experience transient blood pressure increases within half an hour to an hour of consuming products containing roughly 67 mg to 133 mg caffeine. These blood pressure increases may corrupt blood pressure measurements either undertaken in clinical patients or collected in epidemiological research. Notably smokers, the elderly, hypertensives and the caffeine-naive experience greater pressor effects from caffeine ingestion.⁷ It has been recommended that clinical blood pressure measurements should be adjusted to account for recent caffeine intake;⁴² however, this approach is problematical due to the inconsistent levels of caffeine present in coffee and tea (see Introduction) as well as the risk that testees unknowingly consume caffeine in pharmaceutical preparations. Consequently we suggest that where accurate blood pressure measurements are critical measurements could be obtained after at least two hours of fasting or before breakfast.

The vascular effects of caffeine

Blood pressure, rather than being directly regulated, is determined by a mixture of cardiac activity and vascular tonus following feedback from the baroreceptors. The cardiac parameters include heart rate, dp/dt, stroke volume, cardiac output (heart rate x stroke volume) while the vascular parameters include arterial compliance and peripheral resistance. In this study the increases in blood pressure resulted primarily from a decreased arterial compliance. In the upright posture the decreases in arterial compliance were highly significant for both the 67 (p = 0.009) and 133 (p = 0.001) mg interventions and close to significant in the supine posture: p = 0.062 and p = 0.057 respectively. Heart parameters were unchanged except for a relativity small increase in dp/dt (p = 0.034) for 67 mg upright which was accompanied by a relatively small increased indexed peripheral resistance (p = 0.045). These relatively small changes may have resulted from either local effects in both structures or from increases in sympathetic outflow.² In other studies a similar finding, increased aortic stiffness, has been reported following caffeine intake for both normotensives and treated hypertensives.^21,41,43 Subsequently it has been suggested that measures of brachial blood pressure may not accurately represent the cardiovascular responses to caffeine intake and that measure of aorta/arteries are appropriate.²¹ The results of this study indicate that the inclusion of arterial/aortic measurements adds important useful information to studies investigating responses to cardiovascular agents.

The biphasic response

The finding that for habitual coffee and tea drinkers the lower doses of 67 and 133 mg increase blood pressure, indicating a lack of complete tolerance, but not higher dose of 200 mg follows a pattern that is consistent with previous research but that has not previously been noted in the literature. This pattern of blood pressure increases is similar to the results from other studies using an intervention dose of low (<100 mg or < 1.6 mg(kg) to moderate (100 to 200 mg) caffeine levels where blood pressure increases were reported^18,19 and other studies using high (200 to 300 mg) or very high (≥300 mg) intervention doses which reported complete tolerance.^{17,20,21,26,27} The present findings present a similar pattern to another study using the multiple intervention doses of 1.5, 3 and 6 mg kg⁻¹ (for a 65 kg person this equates to 95, 190 and 380 mg respectively). Complete tolerance was reported at the highest dose while increases of ≈ 10/5 and ≈ 8/4 mm/Hg were reported for the 1.5 and 3.0 mg kg⁻¹ respectively.

The observed pattern of blood pressure changes in response to caffeine is a biphasic response which is in stark contrast to the anticipated standard log dose-response curve.² The biphasic response indicates that at the lower doses caffeine's pressor effect is active while at the higher dose some other mechanism reduces the pressor effect resulting in the phenomenon of tolerance. As caffeine's pressor effect is not fully active at the lower doses of 67 and 133 mg the mechanism responsible for caffeine tolerance at higher doses is unlikely to be an increased number of adenosine receptors, a conclusion which is consistent with pharmacological reviews.² It has been demonstrated that the baroreflex system develops tolerance with continuous caffeine usage⁴⁴ however there were no changes noted in spontaneous baroreflex sensitivity for any the doses. Furthermore there no changes in either heart rate or cardiac output so there is no evidence that the baroreflex system was involved in producing tolerance at the 200 mg dose. Other actions of caffeine, including adrenal activation,¹² inhibition of phosphodiesterases, blockade of GABA receptors and the release of intracellular calcium,² have only been reported at doses much greater than 200 mg.

A possible mechanism to account for the biphasic response is that higher doses of caffeine simultaneously produce vasodilation. Caffeine doses of 300 mg have been shown to produce acute forearm blood flow vasodilation in response to acetylcholine leading the authors to suggest that acute administration of caffeine augments endothelium-dependent vasodilation through an increase in nitric oxide production”.⁴⁵ However, as yet caffeine has not been shown to effect basal nitric oxide release in the vasculature.⁴⁶ Thus on the basis of current knowledge the observed biphasic response remains unexplained as is the phenomenon of tolerance itself.

Posture

Posture affected both the type and the extent of the vascular responses but had virtually no effect on the cardiac responses. Compared to supine measures arterial compliance decreased 20% and indexed peripheral resistance increased 35% in the upright posture. We postulate that the reason why the pharmacological effects of caffeine on systolic pressure, diastolic pressure, arterial compliance and aortic impedance were all more pronounced in the upright than the supine posture was that the endothelium was sensitised by the increased tonus of the vascular system making it more susceptible to caffeine's pressor effects. The effect of posture on pharmacodynamics is unclear but this study's findings indicate that posture has a major influence on the pharmacodynamics of caffeine and perhaps other cardiovascular drugs.

Implications for public health

This study indicates that caffeine users may experience clinically important blood pressure increases resulting from their normal regular consumption of caffeine. While this finding is relevant to the accuracy of blood measurements which is the basis of hypertension treatments⁴⁷ it does not indicate that the consumption of either caffeine or caffeine containing beverages has a negative impact on health. In fact there is large amount of research indication that habitual coffee and caffeine consumption does not increase cardiovascular risk.^7,48–51

The changes in aortic impedance occurring at both 67 and 133 mg in the upright posture raise the possibility that caffeine present in both energy drinks and some sport supplements may have a negative impact on physically active consumers. In particular if these caffeine induced increases in aortic impedance were amplified with physical activity then extra demands would be placed on the heart. These finding also indicate that aortic/arterial measures have role to play when assessing the pharmacological impact of drugs on the cardiovascular system.

Limitations and robustness of the present study

This study did not include a period of caffeine abstinence and without testing the participants in abstinence conditions it is unclear whether the participants exhibited partial tolerance or not to the 67 and 133 mg doses. However, our aim was to investigate if blood pressure increases occurred rather than to assess the degree of tolerance developed by habitual coffee and tea consumption.

Also no attempt was made to regulate or monitor consumption levels prior to a test session. There were several reasons for this:

1. caffeine levels vary enormously¹⁰ as noted in the Introduction and therefore calculations of individual intake based on averages are inherently accurate;

2. caffeine consumers seem to titrate their caffeine intake and so increase beverage intake when they are caffeine deprived;⁵²

3. the requirement for experimental participants to record their caffeine consumption may modify their consumption pattern;

4. there is a risk that when monitoring caffeine consumption the interpretation of the study's results will be based on this potentially imperfect system e.g. questionnaires are less accurate than diaries in establishing recording the consumption of caffeinated beverages.⁵³ Errors in monitoring may lead to an erroneous data interpretation.

As increases in blood pressure have been reported to be inversely proportional to serum caffeine levels^19,46 it may be the participants had lower caffeine plasma levels prior to the 67 and 133mg test sessions than prior to the 200 mg session. Consequently we cannot exclude the possibility that variable caffeine intake leading to reduced plasma levels prior testing is responsible for the pattern of blood pressure responses. This factor could have been controlled if we had undertaken caffeine salivary testing prior to each test session.

The major strengths of the present study are that the same participants were tested over a range of caffeine levels. Additionally participants were tested at two post-ingestion intervals and in two postures. Furthermore the measurements were derived from 90 s continuously recorded segments which included between 80 and 120 individual measurements.

Conclusion

The results of this study indicate that the habitual coffee and tea drinkers can experience blood pressure increases when consuming caffeine at the doses found in the commonly consumed beverages tea, coffee, cola soft-drinks and energy-drinks as well as in many pharmaceuticals. Consequently it can be anticipated that many people will experience increases of blood pressure, which are larger in the upright posture, in the hour after consuming products containing caffeine whether they are habitual caffeine users or not. Accordingly care should be taken in clinical assessments of blood pressure to exclude the presence of caffeine induced blood pressure changes. Currently the impact of caffeine on blood pressure is underestimated in the literature and caffeine usage does not feature in hypertension discussions.⁵⁴ Tolerance to caffeine's pressor effect appears to be dependent on the size of the intervention dose and there is at best only partial tolerance to caffeine at the levels commonly consumed.

Acknowledgements

Caffeine capsules were donated by Dr Brian Whitton of Whitehorse Nutriceuticals.

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Footnotes

† Trial registration, ISRCTN11339389, http://www.controlled-trials.com/ISRCTN11339389/mcmullen

‡ Sources of support/funding: no funding or sponsoring was involved in this study.

§ Potential conflicts of interest: none

¶ Current address: Box 65, 760 40 Vaddo, Sweden. E-mail: research@micmcmullen.se; Fax: +46 176 52467; Tel: +46 706227384.

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