Dr. Carmen E.

Rexach
10/14/08

Effects of Temperature and Drugs on Frog Heart

Mechanism Effect on heart rate Effect on contractility Clinical applications

Digoxin (Digitalis) Inhibits Na+/K+ Atpase pump Decreases heart rate Increases Used to regulate arrhythmias in
which leads to increased Ca++ in atrial fibrillation or flutter
SR and Increased release of
Ca++ in a/p

Atropine Binds to acetylcholine receptors Increase Increase Dilates pupils, used to treat
nd rd
and inhibits parasympathetic bradycardia, 2 & 3 degree
response heart block, cardiac arrest

Caffeine Adenosine receptor antagonist Increase* Increase* Treat apnea, bronchopulmonary

sympathomimetic dysplasia, & fecal incontinence
CaCl2 Increases available Ca++ No effect Increase Treatment for hypocalcemia,
neonatal tetany, insect bites,
spider bites (esp. Black Widows)
Acetylcholine Hormone or NT binds to Decrease Decrease Parasympathetic response
cholinergic receptors
Epinephrine Hormone binds to adrenergic Increase Increase Sympathetic response
receptors
Nicotine Activates sympathetic ns Increase Increase (in high concentrations) Being investigated as anti-
migraine drug, ADD, Alzheimer’s,
Parkinsons
KCl Stops heart Used for lethal injections

Although these chemicals have fairly consistent behavior when investigated alone, they can produce a variety of effects when used in living systems and
when used in conjunction with, or following the administration of, other chemicals. The following article describes how difficult it can be to assign one type of
response to a particular chemical! At the end of this long paper and the equally long list of references, you will find a small blurb on “vagal inhibition”.

Haemodynamic and cardiovascular effects of caffeine

Amer Suleman M.D., Nasir Hameed Siddiqui M.D.

GENERAL INTRODUCTION.
Waking up in the morning with a cup of coffee is a part of Western culture and caffeine has become one of the most popular and accepted stimulants.
Caffeine has been recognized as the most widely used psychoactive drug in the world1. It has been estimated that 80% of U.S. civilian population
above the age of 20 years drinks caffeine and related methylxanthines on a regular basis2,3. About 90% of this amount results from drinking coffee.
Dr. Carmen E. Rexach
10/14/08

Chronic daily consumption is the usual pattern of intake of caffeine3, and although majority of these individuals drink one to three cups a day, the
mean for all coffee drinkers is 3.2 cups, or 272 mg of caffeine per day2,3. Coffee is extracted from the fruit of Coffea arabica and related species.
At least half the population of the world consumes tea prepared from the leaves of Thea sinensis, a bush native to southern China and now
extensively cultivated in other countries. Cocoa and chocolate are extracted from the seeds of Theobroma cacao4.
Cola-flavored drinks usually contain considerable amounts of caffeine, in part because of their content of extracts of the nuts of Cola acuminata (the
guru nuts chewed by the natives of the Sudan) and in part because of the addition of caffeine as such in their production4. Caffeine is often
incorporated into therapeutic preparations. The caffeine containing beverages have been popular on the basis of the ancient belief that these
beverages had stimulant and antisoporific actions that elevated mood, decreased fatigue, and increased capacity for work.
Depending upon the alkaloid content of the coffee bean and the method of brewing, 1 cup of coffee contains 75 to 200 mg of caffeine, while 1 cup of
tea contains about 50 mg of caffeine and 1 mg of theophylline; cocoa contains about 250 mg of theobromine and 5 mg of caffeine per cup. A 12-oz
(360-ml) bottle of a cola drink contains 30 to 50 mg of caffeine, half of which is added by the manufacturer as the alkaloid.

Table One: AMOUNT OF CAFFEINE IN COMMON SOURCES

INSTANT COFFEE WEAK 27MG PER CUP
MEDIUM 48MG PER CUP

STRONG 68MG PER CUP

NON-INSTANT COFFEE WEAK 53MG PER CUP

MEDIUM 62MG PER CUP

STRONG 71MG PER CUP

DECAFFEINATED COFFEE 2MG PER CUP

TEA 46MG PER CUP

CHOCOLATE DRINKS 4MG PER CUP

SOLID 1MG PER 5GM SQUARE.

COLA DRINKS 34MG PER 370ML.

5
Adapted from Shirlow 1983 .

Personal characteristics and environmental factors influence coffee consumption. Heavy usage (more than five cups a day) was found to be more
prevalent in middle aged adults, in men, and in employed individuals, particularly members of two occupational groups: managers/ administrators and
craftsmen/ kindred workers2. Increases in coffee consumption were also found to be systematically related to periods of heightened occupational
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demands among naval company commanders6. Given such ubiquitous use of caffeine by individuals who are exposed to substantial occupational
stress, investigation of its cardiovascular and related effects is warranted, particularly during periods of heightened stress.

Chemistry

Caffeine is 1,3,7-trimethylxanthine and is structurally related to uric acid. Caffeine is metabolized by demethylation and by oxidation7. The major
pathway in man proceeds through the formation of paraxanthine (1,7-dimethylxanthine), leading to the principal urinary metabolites, l-methyl-
xanthine, 1-methyluric acid, and an acetylated uracil derivative. Minor pathways involve the formation and metabolism of theophylline and theo-
bromine8. There is no evidence that the methylxanthines are converted to uric acid or that their ingestion exacerbates gout.
There is inter-individual variation in the rate of elimination of methylxanthines due to both genetic and environmental factors, and fourfold
differences are not uncommon9. In most patients the drug obeys first-order elimination kinetics within the therapeutic range. However, at higher
concentrations zero-order kinetics becomes evident because of saturation of metabolic enzymes. This prolongs the decline of caffeine concentrations.
The disposition of methylxanthines is also influenced by the presence of other agents or of disease. For example, cigarette smoking and oral
contraceptives produce small but appreciable increases in methylxanthine clearance. The half-life of theophylline can be quite prolonged in patient
with hepatic cirrhosis, congestive heart failure, or acute pulmonary congestion and values of more than 60 hours have been observed.
Caffeine has a half-life in plasma of 3 to 7 hours; this increases by about twofold in women during the later stages of pregnancy or with long-term use
of oral contraceptive steroids. In premature infants, the rate of elimination of methylxanthines is quite slow.

Cellular Basis for the Action of Caffeine.

Three basic cellular actions of the methylxanthines have received major attention in studies to explain their diverse effects. In order of increasing
importance, they are
(1) translocations of intracellular calcium,
(2) increasing accumulation of cyclic nucleotides,
(3) blockade of receptors for adenosine.

The ability of methylxanthines to inhibit cyclic nucleotide phosphodiesterases is often cited to explain their therapeutic effects; however, there is little
compelling evidence for such a view. Plasma concentrations of caffeine that raise blood pressure seem to be below the threshold for inhibition of
phosphodiesterase10,11.12,13,14,15. This fact appears to eliminate the participation of this category of actions to the therapeutic effects of
methylxanthines.

At high concentrations (0.5 to 1 mM) caffeine interferes with the uptake and storage of Ca2+ by the sarcoplasmic reticulum in striated muscle. This
action can account for observations that such concentrations of caffeine increase the strength and duration of contractions in both skeletal and cardiac
muscle. Similar actions could enhance secretion in certain tissues. However, it is unlikely that they have an important role at therapeutic
concentrations. In vitro, it has generally been found that methylxanthines (about 0.2 mM or above) cause relaxation of vascular smooth muscle in the
presence of various stimulators of contraction (e.g., norepinephrine, angiotensin. K'). While relaxation probably results from a reduction of the
cytosolic concentration of Ca2+ it is not clear to what extent the methylxanthines alter Ca2+ binding and transport directly or influence these
functions indirectly by means of changes in cyclic nucleotide metabolism.
Dr. Carmen E. Rexach
10/14/08

This would leave the anti-adenosine action as the leading candidate16,17. Methylxanthines act as competitive antagonists at adenosine receptors at
concentrations well within the therapeutic range. The effects of exogenous adenosine are very often opposite to those of the methylxanthines, and the
removal of ambient adenosine in some experimental settings (by the addition of adenosine deaminase) will reproduce and obtund the actions of the
methylxanthines. Plasma concentrations of caffeine that raise blood pressure seem to be within the range for antagonism of adenosine receptors18.
Several other types of actions that have received relatively little attention to date that might prove to be important in certain effects of the
methylxanthines. These include their potentiation of inhibitors of prostaglandin synthesis19, and the possibility that methylxanthines reduce the uptake
and/or metabolism of catecholamines in nonneural tissues20,21.

PHARMACOLOGICAL PROPERTIES

Caffeine has a wide range of pharmacological effects and has been positively associated with stimulation of cardiovascular and central nervous
systems, glandular tissue, action on the kidney to produce diuresis, and relaxation of smooth muscles.

Cardiovascular System.

The caffeine has complex actions on the circulatory system, and the final effects largely depend upon the conditions prevailing at the time of admin-
istration, the dose used, and possibly the history of exposure to methylxanthines.
In addition to effects on the vagal and vasomotor centers in the brain stem, there is an array of more or less direct actions on vascular
and cardiac tissues in combination with indirect peripheral actions that are mediated by catecholamines and possibly by the renin-
angiotensin system. Therefore, the observation of a single function, for example, the blood pressure, is deceiving because the drugs
may act on a variety of circulatory factors in such a way that the blood pressure may remain essentially unchanged.

Blood Pressure

Placebo controlled studies have shown that caffeine decreased heart rate, increased blood pressure, and increased plasma levels of catecholamines
and free fatty acids.
The administration of 250 mg of caffeine, an amount equivalent to that in 3 cups of coffee22, has been shown, in the lab settings, to produce a
moderate rise (11-14 mm Hg) in resting systolic and diastolic pressures in normal volunteers10,11,13,23,24,25,27,28,29,30,31, in the elderly13,15, in hypertensive
subjects12, in patients with autonomic insufficiency32, and with exercise in healthy subjects26,29,30, in patients with stable coronary artery disease on
their medicines including calcium channel blockers and B-blockers33 and in a group of normotensive, healthy, caffeine naive persons, on ambulatory
BP monitoring, persisting for two days34, who have abstained from recent caffeine ingestion.

Frequent consumers of caffeine have been found to respond less to acute administration than caffeine-naive individuals11,24,35.
On the other hand, rises in BP, after caffeine consumption, have been reported, even in persons who continued their normal caffeine consuming habits
throughout study32,36.

Similarly a small but significant elevation of BP was found in habitual coffee drinkers using regular coffee compared to those who drank decaffeinated
coffee, as the subjects were followed for 6 weeks for BP measured by the subjects themselves, outside the office setting, using semiautomated,
patient activated BP device37. Caffeine and exercise seem to have additive effects on SBP, whereas caffeine's effects on DBP are weakened29.
Dr. Carmen E. Rexach
10/14/08

It has been suggested that there are individual differences in DBP response to caffeine, at rest and during exercise. Greater response may occur in
individuals with some risk factors for hypertension including parental history of hypertension, high normal resting BP (135 to 154/85 to 94 mm Hg),
high percentage of total body fat and exaggerated pressor response to exercise29.
Also tolerance to caffeine's habitual use has not been detected during exercise or at rest in various studies specially after about 12 hours of abstinence
from caffeine containing beverages. Some of the subjects with largest pressor responses to caffeine have been the ones with high caffeine
consumption >800 mg/ day29.

Future studies will be required to describe relevant underlying hemodynamic relationships of above risk factors [parental history of hypertension, high
normal resting BP (135 to 154/85 to 94 mm Hg), high percentage of total body fat and exaggerated pressor response to exercise] and caffeine's
effects.

The persistence of caffeine's pressor effects during exercise may have implications for physicians who supervise exercise programs. The view that
"caffeine induces dilation of peripheral vasculature during exercise...an obvious advantage during exercise" appears premature for persons susceptible
to caffeine's pressor effects29.
However, pressor response may disappear with heavy exercise, eg work loads greater than 600 kg X m/min30.

In combination with psychological stress, caffeine has been shown to produce an additive increase in systolic an diastolic pressure27,28, for example, in
male college students during performance of a challenging arithmetic task25, or during heightened work stress27. Caffeine in moderate amounts,
administered to male mice during exposure to population crowding and frequent confrontations in cramped tunnels to reach food and water produced
additive increases in plasma renin, systolic blood pressure, adrenal weight, and levels of plasma corticosterone and blood urea nitrogen (Henry and
Stephens, 1980).

Human studies of caffeine's effects on stress reactivity have focused on cardiovascular reactivity elicited by acute laboratory stressors25,28,38,39,40.
Caffeine has had consistent effects on blood pressure (BP) in these placebo-controlled studies of healthy, normal subjects, elevating resting BP levels
and adding significantly (5-10 mm Hg) to the level of BP reached during exposure to the stressor. As a general rule, the studies suggest that caffeine
raises BP during stress by elevating the resting baseline from which the response is measured and not by potentiating the acute BP stress response.
Potentiation of cardiovascular reactivity is apparent in other variables however. Caffeine potentiated stress-related increases in cardiac output in one
study28and forearm blood flow38,39 and forearm vasodilation39 in others. Taken together, the studies suggest that caffeine can indeed influence
cardiovascular stress reactivity, either by adding to the level reached during stress or by potentiating the stress response itself.

Some of the observers have failed to find any significant changes in HR, BP and urine catecholamine excretion, in subjects even on high dose
12mg/kg/day of caffeine, on regularly repeated dosing for 3 to 4 days, or significant interactions between cigarette smoking and such caffeine dosing
on above CV parameters41.

Epidemiological studies have found either no positive association between coffee consumption and BP42,43 or have failed to confirm it after controlling
for smoking43,44,45, or suggested a small contribution to elevation in SBP and DBP within three hours after caffeine consumption independent of the
overall average daily consumption46 or variation in SBP levels in some population subgroups as well as treated hypertensives47. Some studies have
suggested an additive effect for SBP between coffee consumption and tobacco consumption and a significant association between DBP and coffee
consumption, that might be masked by negative correlation of DBP with tobacco consumption47. On the other hand, some have observed a significant
Dr. Carmen E. Rexach
10/14/08

inverse relationship between caffeine and blood pressure, with increasing caffeine consumption being associated with a progressively lower blood
pressure48.

The exact duration of the caffeine free period required to make an individual once again vulnerable to the pressor effects of caffeine is unknown34.
Regular consumers of moderate amounts of caffeine need not be concerned about it's effect on blood pressure. Infrequent consumption may cause a
small but significant transient increase in blood pressure which is unlikely to be harmful to an individual but might influence the diagnosis of
hypertension in a patient with borderline elevated BP34. The hypertensive effect on SBP persisted for 180 min after acute administration of caffeine in
borderline hypertensives, even though only it remained significant for 90 min after caffeine ingestion only12.

Heart Rate

Although after acute caffeine ingestion, an increase in heart rate49,50, or no change12,13,25,35 has been reported, the commoner response may be slight
decrease in heart rate, in laboratory settings10,14,15,23,27,29,30,51,52,53, lasting approximately 75 min after caffeine ingestion in borderline hypertensives12,
and also on ambulatory monitoring34, presumably due to direct vagal stimulation23, baroreceptor reflex33, or effect on the sinoatrial node34. Not
surprisingly, inconsistent effect has been reported in patients with autonomic failure, who have diminished baroreflexes, in response to caffeine32. It
has been suggested that Caffeine probably has a direct cardioacceleratory effect and elicits a vagally mediated bradycardia by baroreflex activation
consequent to it's pressor effect (Bock J, Buchholtz J. Uber das Minutenvolum des Herzens beim Hunde und uber den Einfluss des Coffeins auf die
Grosse des Minutenvolums. Arch Exp Pathol 1920; 88:192-215) Heart rate was slowed in a dose related manner, started at 30 min and lasted till 3
hours. The mean decrease was 10 bpm in group receiving 8.8 mg/kg at 30 min. Bradycardia was the only parameter that correlated with time course
of plasma caffeine levels. There was no consistent correlation between heart rate and BP, thus bradycardia is not due to baroreflex, but possibly due
to direct central vagal stimulation23. Thus the administration of 250 to 350 mg of caffeine may produce small decreases in heart rate and modest
increases in both systolic and diastolic blood pressure. Such doses may have no effect on these parameters in those who consume caffeine regularly.

ARRHYTHMIAS

At higher concentrations (>10 mg/kg/day) caffeine produces definite tachycardia54; sensitive individuals may experience other arrhythmias55,56, such
as premature ventricular contractions. Arrhythmias may also be encountered in persons who use caffeine-containing beverages to excess. However, it
appears that the risk of inducing cardiac arrhythmias in normal subjects is quite low11, and that patients with ischaemic heart disease or pre-existing
ventricular ectopy can usually tolerate moderate amounts of caffeine without provoking an appreciable increase in the frequency of arrhythmias. No
significant arrhythmias were observed during maximal exercise stress test in old individuals with stable angina on medical therapy33.

MYOCARDIUM

Substantial increases in circulating epinephrine (+207%), NE (+75%), and plasma renin activity (+57%) have been documented after a 250 mg dose
in normal subjects10. Thus it might be expected that caffeine would potentiate exercise induced increases in myocardial oxygen consumption by a net
increase in peak systolic pressure or peak heart rate, or both. An increase in myocardial oxygen demand at any given workload would be expected to
reduce exercise duration in patients with coronary artery disease. Both angina and marked elevation in left heart filling pressure, with secondary
pulmonary congestion, would be potential consequences33. Caffeine might also be expected to produce abnormal diastolic relaxation33. In study by
Paulus57 the observed increases in left ventricular end diastolic pressure during pacing induced ischemia persisted more than three times as long after
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10/14/08

caffeine pretreatment than with myocardial ischaemia alone. Tolerance to caffeine has been documented in some studies11, an individual's previous
use of caffeine may be a determinant of the pharmacodynamics of caffeine.
In dogs with coronary stenoses, large doses of intravenous caffeine potentiate impaired left ventricular diastolic relaxation, resulting in marked
elevation of left ventricular diastolic pressure57. In isolated heart muscle, caffeine and other methylxanthines prolong the time course of ventricular
relaxation by reducing the rate of intracellular calcium sequestration during diastole by sarcoplasmic reticulum33,58,59.
There is controversy as to whether circulating catecholamines or plasma renin activity is increased significantly in caffeine-naive subjects; however,
it is generally agreed that little change occurs in chronic users.
While some studies have shown elevated cardiac output and stroke volume49, in other studies caffeine has not been shown to have significant effects
on LV ejection fraction and cardiac index, in young healthy men, at rest, or during exercise30.
Selected patients with history of stable angina pectoris had no significant change in total exercise duration, time to onset of angina and time to onset
of 0.1 mV of ST depression. Rate pressure product at onset of angina and onset of 0.1 mV of ST depression were not significantly different after
caffeine ingestion. In response to exercise, echocardiographic measures of LVSF and LVDF were similar in both groups, in all but two patients who
showed worsening of diastolic function at rest and further worsening with exercise after caffeine. There was no significant increase in frequency or
severity of atrial or ventricular arrhythmias33.
A similar lack of effect of caffeine on exercise duration, time to 0.1 mV ST depression , and heart rate blood pressure product was demonstrated by
Piters in patients in whom medications were withheld on the day of the testing. However a significant increase in exercise duration before the onset of
angina was noted60. Caffeine has been shown to increase circulating free fatty acids and glycerol during exercise in normal subjects, with associated
improvements in exercise duration61,62, maximum oxygen consumption50, resting metabolic rate63, or perceived exertion64. Some authors have not
observed these changes65. Enhanced peripheral lipolysis may not be noted at lower workloads achieved in patients with ischaemic heart disease,
especially in presence of B-blockers66.

HUMORAL EFFECTS/ MECHANISMS

Humoral or sympathetically mediated vasoconstriction has been suggested11,14 as the major effect at dose of 250 mg. Increases in circulating
epinephrine (+207%), NE (+75%), and plasma renin activity (+57%) have been documented after a 250 mg dose in normal subjects, at rest10.
Additive increases in epinephrine with exercise have been noted30. Some studies found a stronger relationship between caffeine and NE rather than
caffeine and Epinephrine67,68. Others have been unable to demonstrate these elevations in normotensives11,69, and in borderline hypertensives12.
Activation of renin angiotensin system has been presented as the predominant physiologic effect10,11. Though some have noted no change in plasma
renin activity after acute caffeine administration12, in normotensives13, and in borderline hypertensives12, and in patients with autinimic insufficiency32
or a fall in PRA14.

Many observers have not been able to link catecholamine or PRA responses to the pressor effects12,13,14,30,32. No study, to our knowledge, has
demonstrated an association between caffeine induced changes in renin and blood pressure elevations. Alternatively caffeine's adenosine antagonistic
actions16 have been suggested89 to cause elevated systemic vascular resistance31,90,91. The vasodilator and the depressor effects of adenosine and the
effect of increasing plasma norepinephrine and PRA, can be blocked by relatively low dose of caffeine, in young, healthy human subjects31.
Theophylline enhances the production of endogenous adenosine in the heart as well as antagonizes the capacity of this autacoid to dilate coronary
arteries (see Berne et al., in Symposium. 1987b). Vasodilating effects of adenosine seem to be mediated by a subclass of adenosinergic (A2-
receptors), which are related to stimulation of cAMP formation92.

Most effects of therapeutic doses of caffeine, on regional and peripheral blood flow and vascular resistance, are variable and depend upon the locale of
the vascular bed and the experimental conditions employed. Conflicting patterns of haemodynamic effects have been observed.
Dr. Carmen E. Rexach
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In study by Smits, coffee did not increase FBF in their subjects. Also FVR did not fall whereas DBP rose. This might suggest increased SVR. This is in
concordance with studies showing increased peripheral vascular resistance in normal regular caffeine consumers, at rest30,29 and during exercise30,
and in contrast to other studies where a fall in SVR has been reported49,93. However, it has been shown that drug related elevation in SVR might get
less pronounced during heavier exercise29,30. The xanthines can increase coronary blood flow in man. However, it has been repeatedly demonstrated
that methylxanthines cause a marked increase in cerebrovascular resistance with an accompanying decrease in cerebral blood flow and oxygen
tension. This apparently reflects the anti-adenosine action of the xanthines, and prominent role of adenosine in cerebrovascular autoregulation.

Several studies confirm that caffeine's pressor response at rest may be attributed to heightened systemic vascular resistance26,28,30. In contrast,
during work on challenging mental tasks, caffeine elevates BP by potentiating the cardiac stimulatory properties of the task29,28. This suggests that the
methylxanthines have little direct action on the major resistance vessels. It is more likely that any change in peripheral vascular resistance results
from interplay of the effects on the brain stem and the heart, with modification or reinforcement by autonomic reflexes, changes in the concen-
trations of circulating catecholamines and interaction with autoregulatory local hormones.

Relation to Myocardial Infarction.

For the past 20 year coffee consumption has been implicated as a risk factor for the development of ischemic heart disease but there has been
controversy over a possible deleterious effect of caffeine in the etiology of acute myocardial infarction. Coffee consumption has been associated an
increased risk of myocardial infarction94,95,96,97,98,99. On the other hand, the results of a number of studies indicate that coffee drinking is
associated with little, if any, increased incidence of coronary heart disease82. Several epidemiologic surveys have failed to confirm, in particular after
controlling for cigarette smoking43,44,45, the suggestion by the Boston Collaborative Drug Surveillance Program79,80 that an association exists
between coffee consumption and coronary heart disease100,81,101.

There is also an association between coffee consumption and raised cholesterol concentrations, reported in people who drink boiled coffee83,85, and
also in populations where boiled coffe is rarely consumed88,84. Some of these studies have suggested that the risk of coronary heart disease
increases disproportionately with increasing levels of coffee consumption96,98,88.

MECHANISMS OF CAFFEINE TOLERANCE:

Caffeine and other methylxanthines competitively inhibit the binding of adenosine receptor ligands in brain tissue (Snyder 81). This action has been
proposed as the mechanism of well documented behavioral stimulant effects of caffeine81, 84 . Chronic daily administration of caffeine leads to the
development of tolerance to many effects of drug on the behavior 82,83,88. It has also been associated with an increase in the number of adenosine
binding sites in the brain 83,85,86,88, suggesting that upregulation of adenosine receptors is the cellular basis of caffeine tolerance (Marangos 85; Snyder
85
). Chronic treatment with caffeine may not uniformly affect all subtypes of adenosine receptors or adenosine binding sites in different regions and
upregulation of adenosine receptors is not the mechanism of tolerance to caffeine. Other effects of caffeine (inhibition of phosphodiesterase and
release of stored calcium) may become important with continuous administration of caffeine (Holtzman 91).
Dr. Carmen E. Rexach
10/14/08

DISCUSSION

Caffeine has a wide range of pharmacological effects and has been positively associated with stimulation of cardiovascular and central nervous
systems, glandular tissue, action on the kidney to produce diuresis, and relaxation of smooth muscles. Caffeine has physiological effects similar to
those observed in association with psychological or psychosocial stress25. In addition to its many other stimulant effects, the dietary consumption of
caffeine can intensify the physiological responses elicited by psychological stressors in the laboratory and possibly in everyday life and potentially
increase the pathogenic consequences that have been attributed to exaggerated stress reactivity (Lane 90). Because caffeine consumption and stress
are both common features of contemporary life, a caffeine related potentiation of these harmful effects of stress could have especially important
implications for the development of cardiovascular disease25. Human studies of caffeine's effects on stress reactivity have focused on cardiovascular
reactivity elicited by acute laboratory stressors25,38,39,28,40. Taken together, the studies suggest that caffeine can indeed influence cardiovascular stress
reactivity, either by adding to the level reached during stress or by potentiating the stress response itself70.

The habitual consumption of caffeine leads to the development of tolerance to the drug's cardiovascular and neuroendocrine effects. The extent of any
potential pathogenic consequences of caffeine/stress interactions should be directly related to caffeine and stress exposure, but if daily consumption
of the drug leads to tolerance to its effects, the negative effects on health attributable to caffeine should be minimal. The most frequently cited
studies11,12,13,41,52,34,71 offer evidence that the effects of an acute caffeine dose on resting levels of blood pressure, catecholamines, and plasma renin
activity may disappear after several days of chronic administration of high caffeine doses e.g. 750 mg/day12. However, other studies have shown
significant caffeine effects on cardiovascular and neuroendocrine stress reactivity, similar in magnitude, in habitual caffeine consumers39,30,40,72 and in
individuals described as "caffeine-naive" 25,70.

A pressor response to caffeine taken in the morning can still be seen in the regular coffee drinkers, particularly those with lower morning
concentrations of caffeine52,11. No relationship was seen between maximum SBP changes with caffeine or placebo and subject's (elderly healthy men
and women) mean daily consumption of caffeine68. The comparisons of habitual moderate caffeine consumers and light consumers failed to find even
non-significant trends linking level of habitual caffeine consumption to reduced caffeine effects70. The habitual group consumed more caffeine than
expected on average (6.6 mg/kg), close to levels estimated for the highest 10% of adults73. If even at these higher daily doses, habitual consumption
plays such a small role in modulating caffeine effects, it might be reasonable to conclude that tolerance is not present70. It has been suggested that a
person's daily caffeine intake (within a broad range of 0-1000 mg/ day is probably not meaningfully related to the magnitude of caffeine's effects70.

On long term use, compared with placebo, caffeine persistently produced a 5/8 mm Hg rise in blood pressure at 30 min, though a much smaller rise
at 30 min., and much weakening of response after one hour. Although BP fell after the meal, post prandial BP remained significantly higher after
caffeine vs placebo (p<0.05 for SBP and DBP)32. In many epidemiological studies, coffee drinkers had higher SBP and DBP. Also among treated
hypertensives who were excluded from calculations, S and DBP were higher among coffee drinkers47.

The presence of significant caffeine effects might depend on 12 to 24 hours of abstinence26,23,38,27,30. In most of the studies, acute CV reactivity to
caffeine was apparent, and no influence of regular caffeine use on physiological responses was seen e.g, after about 12 hours of abstinence, when
tested comparing healthy students below (50-190 mg/d; M=11 5 mg/d + 10 SEM) vs above (199-1,582 mg/d; M=407 mg/d + 141 SEM) the median
for average daily caffeine consumption27; after 17 hrs of abstinence tolerance was apparently lost completely14; BP elevations were similar in the
caffeine naive subjects and in habitual consumers post 12 hours of abstinence25; S.B.P. and D.B.P. in young, healthy, male volunteers, 1-6 cups per
day regular coffee drinkers, after 36 hours of abstinence, were elevated 3 to 6 mm Hg, and elevation persisted for 4 hours of observation23. Denaro
9167 suggested that on average dosing of caffeine for 5 days produced persistent activation of the sympathetic nervous system, an effect especially
pronounced with high dose (12 mg/kg/day) caffeine; however, development of tolerance was suggested during the day67. Probably overnight
Dr. Carmen E. Rexach
10/14/08

abstinence allowed tolerance to abate somewhat so that the individuals became sensitive to the catecholamine-releasing effect of caffeine by the next
morning67. The overnight period of abstinence is consistent with normal patterns of caffeine consumption in habitual consumers. If caffeine tolerance
is lost overnight, an equal loss of tolerance would be expected to occur every night in habitual consumers.

A pressor response to morning caffeine doses can particularly be seen in the regular coffee drinkers with lower morning concentrations of caffeine52,11.
Overnight period of abstinence produced pre-drug caffeine levels below 1 µg/ml in most studies. The low initial level may be important. In (Robertson
81 11
) 250 mg caffeine raised the BP of regular coffee drinkers by 4.2 mm Hg only if initial plasma level was below 1 µg/ml. A negative correlation
between the initial level of caffeine in plasma and magnitude of BP response to an acute caffeine dose has been reported52. Smits has shown that
hemodynamic effects of caffeine may be influenced by the residual plasma caffeine concentration, which in turn is a function of individual clearance
rates52. A report of tolerance to acute caffeine dose after several days of chronic administration11 may be due to a high dose (750 mg/day), coupled
with subjects' unusually slow rate of caffeine elimination (t1/2= 10 hrs vs normal 3-5 hrs), which might have maintained significant caffeine levels
and effects throughout the study. There might be a relatively flat dose response curve for these caffeine effects. Thus acute caffeine effects may be
detected only if the initial caffeine levels are below some threshold probably 1 µg/ml.

Regular caffeine users who are physically active respond to an acute caffeine challenge by increasing plasma epinephrine and fat oxidation. Even on
increasing caffeine consumption by 500 mg/day for 6 weeks caffeine challenge still increased fat oxidation, though epinephrine response was less71.
This might suggest that even if tolerance develops, it might not be complete tolerance to all the effects74. Support for the notion that tolerance to
caffeine may be incomplete comes from several different types of research. The pressor effects of caffeine persist after 7 days of dosing in patients
with autonomic failure32. A pressor response to caffeine taken in the morning was in the regular coffee drinkers, particularly those with lower morning
concentrations of caffeine52,11.

All the CV and biochemical effects are variable at individual level in most of the studies23,27. Individual responses to caffeine even after 5 days of use
varied, at least one third of the study population (3/9) still had elevations of SBP, DBP, FFA and NE, and only 1/9 subject showed some tolerance67.
Individual variation in the extent of development of tolerance to effects of caffeine may underlie individual differences to adverse effects of caffeine on
health67. Similar interindividual variation should be expected in studies by Robertson11. Their (Robertson's) subjects continued to show a trend
towards higher levels of SBP and DBP and lower HR while on caffeine67. Robertson did not look to determine if complete tolerance developed67. They
measured catecholamines for only four hours after the dose and subjects in their placebo group were different from caffeine group67. The
administration of 3.5 mg/kg of caffeine resulted in a wide range of observed plasma caffeine levels in the experimental subjects70. Given that most
studies correlations are based on observations of independent subjects, they may also reflect individual differences in the overall response to the
drug70.

Caffeine metabolism has been shown to be dose dependent under multiple dosing conditions; also the primary metabolites of caffeine, the
dimethylxanthines, which may also have pharmacological actions, are subject to dose dependent metabolism as well75. With high levels of
consumption of caffeine, possibly related in part to saturable metabolism of caffeine and other dimethylxanthines, tolerance may not fully compensate
for some of the pharmacological effects of caffeine and its metabolites67.

Most of the studies have examined effects of single dose of caffeine, or of the doses given at regular intervals, whereby significant effects of caffeine
dosed in an irregular manner throughout the day, or only part of the day, can not be excluded41. This pattern with the heaviest consumption in the
morning and decreasing consumption throughout the day, may be a more common pattern among general population41. It has been shown in animal
studies that temporal spacing of caffeine dosing, rather than magnitude of dose, is important. Whereas continuous administration (caffeine added to
Dr. Carmen E. Rexach
10/14/08

the only accessible drinking water) may lead to tolerance, intermittent administration (every 48 to 72 hours) sensitizes the animals to stimulatory
effects of caffeine76.

Caffeine can influence cardiovascular stress reactivity. Caffeine raises BP during stress by elevating the resting baseline from which the response is
measured70. Caffeine consumption may add to the blood pressure elevations seen in medical students, fluctuating their peak SBP into borderline
hypertensive range (140-159)27 or telephone marketing workers77 during periods of occupational stress. Potentiation of stress reactivity is apparent
in other variables also e.g. stress-related increases in cardiac output28, forearm blood flow38,39, forearm vasodilation39 and neuroendocrine reactivity.
The observed interactions of caffeine and stress may be present even in individuals who habitually consume moderate amounts of caffeine70.
Significance of caffeine stress interactions in laboratory to cardiovascular and neuroendocrine reactivity in everyday psychosocial environment remains
to be demonstrated, however, it might be reasonable to assume that it may raise BP during more natural stressors as well70. Caffeine use might
increase potential health consequences from prolonged exposure to occupational stress27.

Acute elevation of BP after caffeine administration alone, or during psychologic stress, could be clinically significant/relevant in management of BP25,
particularly in subgroups of patients with cardiovascular disease, and people with impaired excretion of methylxanthines e.g. cirrhotics and users of
oral contraceptives25. Similar elevations could potentially eliminate or reverse the therapeutic effects of a number of the antihypertensive medications
currently in use. Time sequence & duration of caffeine induced changes are important factors in assessing potential health effects.
Coffee drinking has been implicated as an independent risk factor for coronary heart disease78,79,80,81,43. Possible mechanisms include increased blood
pressure36,13,47,26, glucose intolerance82 and elevated cholesterol83,84,85,88 and exaggerated cardiovascular86 and neuroendocrine stress reactivity,
through effects on lipid metabolism87. Thus caffeine could possibly accelerate cardiovascular disease development. Given the prevalence in everyday
life of caffeine consumption and stress, opportunities of caffeine and stress interaction are common and their detrimental effects on health may be
widespread

If potentially harmful combined effects of the very common features of contemporary life are confirmed by future research, the awareness could lead
to significant improvements in prevention of cardiovascular effects25. The discrepancies regarding tolerance can be resolved only with further studies.
Almost all the studies have been short term studies, on a very small sample of a highly selected population, revealing great interindividual and
interstudy variation. These limitations complicate extrapolation of experimental data, in lab, to general population of coffee drinkers. Caffeine dose of
3.5 mg/kg equals 250 mg for a 160 lbs subject, and is found in 10-15 oz of brewed coffee. Thus effects of significant magnitude could be expected to
occur from dietary caffeine intake of majority of adults in US, given average daily intake of 3-4 mg/kg. Certain population subgroups e.g. elderly13,
pregnant females, cirrhotics, persons with higher BMI, high normal resting BP and parental history of hypertension29 may be particularly susceptible to
the effects of caffeine. Stratification of epidemiologic data on caffeine consumption may help to resolve this question. Ubiquitous consumption of
caffeine coupled with it's significant effects on human body suggest that time sequence and duration of caffeine induced changes, effects of habitual
caffeine use, caffeine/stress interactions and other potential health effects deserve further investigation.

REFERENCES

1. Gilbert R. M. Caffeine as a drug of abuse. In: Gibbins R. J., Israel Y., Kalant H., Popham R. E., Schmidt W., Smart R. G. eds. Research advances in
alcohol and drug problems. vol. 3. New York: John Wiley & Sons; 1976.

2. Bonham G. S., Leaverton P. E. Use habts among adults of cigarettes, coffee, aspirin and sleeping pills. Vital and health statistics (DHEW Publication
No.PHS, 80-1559). Washington, D. C., US Government Printing Office, 1979.
Dr. Carmen E. Rexach
10/14/08

3. Gilbert R. M. Caffeine consumption. In Spiller G. A. (ed) The methylxanthine beverages and food: Chemistry, consumption, and health effects. Liss,
New York, pp 185-213, 1984.

4. Graham D. M. Caffeine-Its identity, dietary sources, intake and biological effects. Nutr. Rev. 36:97-102;1978.

5. Shirlow M. J. Patterns of caffeine consumption. Human nutrition: Appl. Nutrition 1983;37:307-313.

6. Conway T. L., Vickers R. R., Ward H. W., & Rahe R. H. Occupational stress and variation in cigarette, coffee and alcohol consumption (Report No.
79-32). Bureau of Medicine and Surgery, Department of the Navy, Research Work Unit, ZF51.524.002-5020.

7. Arnaud MJ. The pharmacology of caffeine. Prog Drug Res 1987;31:273-313.

8. Rowe DJF, Watson ID, Williams J and Berry DJ. The clinical use and measurement of theophylline. Ann Clin Biochem 1988;25:4-23.

9. Symposium. Update on theophylline. Grant JA and Ellis EF, eds. J Allergy Clin Immunol 1986a;78:669-824.

10. Robertson D., Frolich J. C., Carr R. K., Watson J. T., Hollifield J. W., Shand D. G., Oates J. A. Effects of caffeine on plasma renin activity,
catecholamines and blood pressure. N Eng J Med. 1978;298:181-6.

11. Robertson D., Wade D., Workman R., Woosley R. L. Tolerance to the humoral and hemodynamic effects of caffeine in man. J. Clin. Invest.
67:1111-1117; 1981.

12. Robertson D., Hollister A. S., Kincaid D., Workman R., Goldberg M. R., Tung C., Smith B. Caffeine and hypertension. Am J Med 77:54-60;1984.

13. Izzo J. L., Ghosal A., Kwong T., Freeman R. B., Jaenike J. R. Age and prior caffeine use alter the cardiovascular and adrenomedullary responses to
oral caffeine. Am. J. Cardiol. 52:769-773;1983.

14. Smits P., M.D., Hoffman H., M.Sc., Thien T., M.D., Houben H., M.D. and van't Laar A., M.D. Hemodynamic and humoral effects of coffee after 1-
selective and nonselective -blockade. Clin. Pharmacol. and Ther. 1983;34:153-158.

15. Conrad K. A., Blanchard J. Cardiovascular effects of caffeine in elderly men. Am J Ger Soc 1982;30:267-72.

16. Fredholm B. B. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980;1:129-132.

17. Burns R. F., Daly J. W., Snyder S. H. Adenosine receptors in brain membranes binding of N6-cyclohexyl[3H]adenosine and 1,3-diethyl-8-
[3H]phenylxanthine. Proc Natl Acad Sci USA 1980;77:5547.

18. Berne R. M., Knutt R. M., Ely S.W.,et al. Adenosine in the local regulation of blood flow: a brief overview. Fed Proc 1983;42:3136.

19. Vinegar RE, Eriksson JF, Selph JL, Welch RM, White HL. Potentiation of the anti-inflammatory and analgesic activity of aspirin by caffeine in the
rat.Proc Soc Exp Biol Med 1976;151:556-560.
Dr. Carmen E. Rexach
10/14/08

20. Kalsner S. Mechanism of potentiation of contractor response to catecholamines by methylxanthines in aortic strips. Br J Pharmacol 1971;43:379-
388.

21. Kalsner S, Frew RD, Smith GM. Mechanism of methylxanthine sensitization of norepinephrine responses in a coronary artery. Am J Physiol
1975;228:1702-1707.
22. Clinton W. P. The chemistry of coffee. In McMahon B., Sugimura T., eds. Coffee and Health. Cold spring harbor laboratory, 1984:1-10.

23. Whitsett T. L., Manion C. V., Christensen H. D. Cardiovascular effects of coffee and caffeine. Am J Cardiol 1984;53:918-22.

24. Ammon HPT, Bieck PR, Mandalaz D, Verspohl EJ. Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers. Br J Clin
Pharmacol 1983;15:701-706.

25. Lane J. D.: Caffeine and cardiovascular responses to stress. Psychosomatic Med 45:447-451;1983.

26. Pincomb G. A., Lovallo W. R., Passey R. B., Whitsett T. L., Silverstein S. M., Wilson M. F. Effects of caffeine on vascular resistance, cardiac output
and myocardial contractility in young men. Am. J. Cardiol. 56:119-122;1985.

27. Pincomb G. A., Lovallo W. R., Passey R. B., Brackett D., Wilson M. F. Caffeine enhances the physiological response to occupational stress in
medical students. Health Psychol 6:101-112;1987.

28. Pincomb G. A., Lovallo W. R., Passey R. B., Wilson M. F. Effect of behavior state on caffeine's ability to alter blood pressure. Am J Cardiol 61:798-
802;1988.

29. Pincomb G. A., Wilson M. F., Sung B. H., Passey R. B., Lovallo W. R. Effects of caffeine on pressor regulation during rest and exercise in men at
risk for hypertension. Am Heart J 1991;122:1107-1115.

30. Sung B. H., Lovallo W. R., Pincomb G. A., Passey R. B., Brackett D. J., Wilson M. F. Effects of caffeine on blood pressure response during exercise
in normotensive young men. Am J Cardiol 1990;65:909-913.

31. Smits P., Schouten J., Thien T. Cardiovascular effects of two xanthines and the relation to adenosine antagonism. Clin Pharmacol Ther
1989;45:593-599.

32. Onrot J, Goldberg MR, Biaggioni I, Hollister AS, Kincaid D, Robertson D. Hemodynamic and humoral effects of caffeine in autonomic failure. N Eng
J Med 1985;313:549-54.

33. Hirsch AT, Gervino EV, Nakao S, Come PC, Silverman KJ, Grossman W. The effect of caffeine on exercise tolerance and left ventricular function in
patients with coronary artery disease. Ann Int Med 1989;110:593-598.

34. Myers M. G., Reeves R. A. The effect of caffeine on daytime ambulatory blood pressure. Am J Hypertens 1991;4:427-431.
Dr. Carmen E. Rexach
10/14/08

35. Charney D. S., Galloway M. P., Heninger G. R. The effects of caffeine on MHPG, subjective anxiety, autonomic symptoms and blood pressure in
healthy humans. Life Sci 1984;35:135-144.

36. Freestone S., Ramsay L. E. Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic treated hypertensive patients.
Am J Med. 73:348-353;1982.

37. van Dusseldorp M., Smits P., Thien T., Katan M. B. Effects of decaffeinated versus regular coffee on blood pressure. Hypertension 1989;14:563-
569.

38. Lane J. D., Williams R. B. Caffeine affects cardiovascular responses to stress. Psychophysiology 22:648-655; 1985.

39. Lane J. D., Williams R. B. Cardiovascular effects of caffeine and stress in regular coffee drinkers Psychophysiology 24:157-164;1987.
40. Greenberg W., Shapiro D. The effects of caffeine and stress on blood pressure in individuals with a family history of hypertension.
Psychophysiology 24:151-156;1987.

41. Brown C. R., Benowitz N. L. Caffeine and cigarette smoking: Behavioral, cardiovascular and metabolic interactions. Pharmacol Biochem Behav
34(3) 565-570, 1989.

42. Bertrand CA, Pomper I, Hillman G, Duffy J C, Michell I. No relation between coffee and blood pressure. N Eng J Med 1974;291:871-874.

43. Dawber TR, Kannel WB, Gordon T. Coffee and cardiovascular disease. Observations from the Framingham study. N Eng J Med 1974;291:871-874.

44. Willemsen L, Tibblin G, Elmfeldt D, Wedel H, Werko L. Coffee consumption and coronary heart disease in middle aged Swedish men. Acta Med
Scand 1977;201:547-552.

45. Yano K, Rhoads GG, Kagan A. Coffee, alcohol and risk of coronary heart disease among men living in Hawaii. N Eng J Med 1977;297:405-409.

46. Shirlow M. J., Berry G., Stokes G. Caffeine consumption and blood pressure: An epidemiologic study. International J of Epidemiol 1988;17:90-97.

47. Lang T., M.D., Degoulet P, M.D., et al. Relation between coffee drinking and blood pressure: Analysis of 6,321 subjects in Paris Region. Am J
Cardiol 1983;52:1238-1242.

48. Periti M., Salvaggio A., Quaglia G, et al: Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 1981;67:1111-1117.

49. Gould L, Venkataraman K, Goswani M, Gomprecht RF: The cardiac effects of coffee. Angiology 24:455-463, 1973.

50. Toner M. M., Kirkendall D. T., Dello D. J., Chase J. M., Clearly P. A., Fox E. L. Metabolic and cardiovascular responses to exercise with caffeine.
Ergonomics 1982;25:1175-1183.

51. Harris L., Myers M. G., Leenan F. H. H., Grant D. M. The cardiovascular effects of caffeine post myocardial infarction. [Abstract] Circulation
1985;72:116.
Dr. Carmen E. Rexach
10/14/08

52. Smits P., Thien T., Laar A. Circulatory effects of coffee in relation to the pharmacokinetics of caffeine. Am. J. Cardiol. 56:958-963;1985.

53. Colton T., Gosselin R. E., Smith R. P. The tolerance of coffee drinkers to caffeine. Clin Pharmacol Ther 1968;9:31-39.

54. MacCornack F. A. The effects of coffee drinking on the cardiovascular system: experimental and epidemiologic research. Prev Med 1977;G:104-
119.

55. Dobomyer D. J., Stine R. A., Leier C. V., Greenberg R., Schaal S. F. The arrhythmogenic effects of caffeine in human beings. N Eng J Med
1983;308:814-816.

56. Sutherland D. J., McPherson D. D., Renton K. W., Spencer C. A., Montague T. J. The effect of caffeine on cardiac rate, rhythm and ventricular
repolarization. Chest 87:319-324;1985.

57. Paulus W. J., Serizawa T., Grossman W. Altered left ventricular diastolic properties during pacing induced ischemia in dogs with coronary stenosis.
Potentiation by caffeine. Circ Res 1982;50:18-27.

58. Blinks J. R., Olson C. B., Jewell B. R., Braveny P. Influence of caffeine and other methylxanthines on mechanical properties of isolated mammalian
heart muscle. Evidence for a dual mechanism of action. Circ Res 1972;30:367-92.

59. Henderson A. H., Brutsaert D. I., Forman R., Sonnenblick E. H. Influence of caffeine on force development and force frequency relations in cat and
rat heart muscle. Cardiovasc Res 1974;8:162-172.

60. Piters KM, Colombo A, Olson HG, Butman SM. The effect of coffee on exercise induced angina pectoris due to coronary artery disease in habitual
coffee drinkers. Am J Cardiol 1985;55:277-80.

61. Costill DL, Dalsky GP, Fink WJ. Effect of caffeine ingestion on metabolism and exercise performance. Med Sci Sports 1978;10:155-158.

62. Berglund B, Hemmingsson P. Effects of caffeine ingestion on exercise performance at low and high altitudes in cross country skiers. Int J Sports
Med 1982;3:234-236.

63. LeBlanc J, Jobhin M, Cote J, Samson P, Labrie A. Enhanced metabolic response to caffeine in exercise trained human subjects. J Appl Physiol
1985;59:832-837.

64. Casal DC, LeonAS. Failure of caffeine to affect substrate utilization during prolonged running. Med Sci Sports Exerc 1985;17:174-179.

65. Powers SK, Byrd RJ, Tully R, Callender T. Effects of caffeine ingestion on metabolism and performance during graded exercise. Eur J Appl Physiol
1983;50:301-307.

66. Ople LH. Effect of beta adrenergic blockade on biochemical and metabolic response to exercise. Am J Cardiol 1985;55:95D-100D.
Dr. Carmen E. Rexach
10/14/08

67. Denaro C. P., Jacob III B. P., Benowitz N. L. Effects of caffeine with repeated dosing. Eur J Clin Pharmacol (1991) 40:273-278.

68. Heseltine D, Dakkak M, Woodhouse K, Macdonald A, Potter JF. The effect of caffeine on postprandial hypotension in the elderly. J Am Geriat Soc
1991;39:160-164.

69. Jung R. T., Shetty P. S., James W. P. T., Bernard M. A., Callingham B. A. Caffeine: It's effect on catecholamines and metabolism in lean and obese
humans. Clin Sci 1981;60:527-535.

70. Lane J. D., Adcock A., Williams R. B., Kuhn C. M. Caffeine effec on Cardiovascular and Neuroendocrine responses to acute psychosocial stress and
their relationship to level of habitual caffeine consumption. Psychosomatic medicine 52:320-336;1990.

71. Bangsbo J., Jacobsen K., Nordberg N., Christensen J. and Graham T. Acute and habitual caffeine ingestion and metabolic responses to steady
state exercise. J Appl. Physiol. 72(4):1297-1303;1992.

72. Greenstadt L., Yang L., Shapiro D. Caffeine, Mental stress, and risk for hypertension: a cross-cultural replication. Psychosom Med 50:15-22;1988.

73. Barone J. J., Roberts H. Human consumption of caffeine. In Dews P. B. (ed), Caffeine. New York, Springer-Verlag, 1984, pp 59-76.

74. Evans S. M., Griffiths R. Caffeine tolerance and choice in humans. Psychopharmacology 108:51-59;1992.

75. Denaro C. P., Brown C. R., Wilson M., Jacob P., Benowitz N. L. Dose dependency of caffeine metabolism. Clin Pharmacol Ther 48:277-285;1990.

76. Meliska C. J., Landrum R. E.,Landrum T. A. Tolerance and sensitization to chronic and subchronic oral caffeine: Effects on wheelrunning in rats.
Pharmacol Biochem Behav 35(2):477-479;1990.

77. France C., Ditto B. Cardiovascular responses to occupational stress and caffeine telemarketing employees. Psychosom Med 51:145-151;1989.

78. Hennekens C. H., Drolette M. E., Jesse M. J., Davies J. E., Hutchison G. B. Coffee drinking and death due to coronary heart disease. N Eng J Me
294:633-636;1976.

79. Coffee drinking and acute myocardial infarction: Report fromthe Boston Collaborative Drug Surveillance Program. Lancet 1972;2:1278-1281.

80. Jick H, Miettinen OS, Neff RK, Shapiro S, Heinonen OP, Slone D. Coffee and myocardial infarction. N Eng J Med 1973;289:63-67.

81. Klatsky AL, Friedman EG, Siegelaub AB. Coffee drinking prior to myocardial infarction: Results from Kaiser-Permanente epidemiological study of
myocardial infarction. JAMA 1973;226:540-543.

82. Curatolo P. W. The health consequences of caffeine. Ann. Intern. Med. 98:641-653;1983.

83. Thelle D. S., Arnesen E., Forde H. The Tromso heart study: does coffee raise serum cholesterol? N Eng J Med 308:1454-1457;1983.
Dr. Carmen E. Rexach
10/14/08

84. Davis B. R., Curb J. D., Borhani N. O., Prineas R. J., Molteni A. Coffee consumption and serum cholesterol in the hypertension detection and follow
up program. Am J Epidemiol 128:124-136;1988.

85. Bak A. A. A., Grobbee D. E. The effect on serum cholesterol levels of coffee brewed by filtering or boiling. N Eng J Med 321:1432-1437;1989.

86. Schneiderman N. Psychophysiologic factors in atherogenesis and coronary artery disease. Circulation 76(Suppl):1-41;1987.

87. Dimsdale J. E., Herd J. A. Variability in plasma lipids in response to emotional arousal. Psychosom Med 44:413-430;1982.

88. Williams P. T., Wood P. D., Vranzian K. M., Albers J. J., Garay S. C., Taylor C. B. Coffee intake and elevated cholesterol and apolipoprotein B levels
in men. JAMA 253:1407-1411;1985.

89. von Borstel R. W., Wurtman R. J., Conlay L. A. Chronic caffeine consumption potentiates the hypotensive action of circulating adenosine. Life Sci
1983;32:1151-1158.

90. Fredholm B. B. On the mechanism of action of theophylline and caffeine. Acta Med Scand 1985;217:149-153.

91. Smits P., Boekema P., Abreu R. D., Thien T., van't Laar A. Evidence for an antagonism between caffeine and adenosine in the human
cardiovascular system. J Cardiovasc Pharmacol 1987;10:136-143.

92. Fredholm B., Sollevi A. Cardiovascular effects of adenosine. Clin Physiol 1986;6:1-21.

93. Starr I, Gamble CF, Margolies A, Donal JS, Joseph N, Eagle E: A clinical study of the action of 10 commonly used drugs on cardiac output, work,
and size: On respiration, on metabolic rate, and on electrocardiogram. J Clin Invest 16:799-823, 1937.

94. Kahn H. A., Philips R. L., Snowdon D. A., Choi W. Association between reported diet and all cause mortality; Twenty year follow up on 27,530
Seventh-Day Adventists. Am J Epidemiol. 119:774-787;1987.

95. LaCroix A. Z., Mead L. A., Liang K. Y., Thomas C. B., Pearson T. A. Coffee consumptio and the incidence of coronary heart disease. N Eng J Med.
315:977;1986.

96. LeGrady D., Dyer A. R., Shekelle R. B., Stamler J., Liu K., Paul O., Lepper M., Shyrock A. M. Coffee consumption and mortality in the Chicago
Western Electric Company Study. Am J Epidemiol. 126:803-812;1987.

97. Vandenbroucke J. P., Kok F. J., Van 'T Bosch G., Van Den Dungen P. J., Van Der Heide-Wessel C., Van Der Heide R. M. Coffee drinking and
mortality in a 25 year follow up. Am J. Epidemiol. 123:359-361;1986.

98. Rosenberg L., Werler M. M., Kaufman D. W., Shapiro S. Coffee drinking and myocardial infarction in young women: an update. Am J Epidemiol
126:147-149;1987.
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99. Rosenberg L., Palmer J. R., Kelly P., Kaufman D. W., Shapiro S. Coffee drinking and nonfatal myocardial infarction in men under 55 years of age.
Am J Epidemiol 128:570-578;1988.

100. Heyden S, Tyroler HA, Heiss G, Hames CG, Bartel A. Coffee consumption and mortality. Arch Intern Med 1978;138:1472-1475.

101. Murray SS, Bjelke E, Gibson RW, Shuman LM. Coffee consumption and mortality from ischemic heart disease and other causes: results from the
Lutheran brotherhood study, 1966-1978 Am J Epidemiol 1981;113:661-667.

And now a word on “vagal Inhibition”. If you attempt to find out what this term means by searching on the internet, you will find that it has
several different meanings, which can be very confusing! This excerpt from a blog on http://www.bio.net/bionet/mm/neur-sci/1999-
April/037752.html
was written by Dr. Frank Le Fevre in response to a question about vagal inhibition.

The vagus nerve sends projections to much of the body visceral organs It originates in the brain stem and
is very important in the control of Heart rate, gastric motility, digestive, and metabolic activities.
When the vagus sends messages to the heart, the heart rate slows. When the vagus sends messages to
salivary glands, they secrete saliva. Vagal stimulation of the pupil causes the aperature to close
(mydriasis.)

One common term used in conjunction with vagal function is vagal tone. Increased vagal tone results in a
slower heart rate, salivary secretions,and pupillary constriction. Decreased vagal tone has the opposite
effects. It is possible to inhibit the actions of the vagus which would decrease vagal tone, but that is
probably not what is implied by vagal inhibition.

You see vagal inhibition a potentially sloppy phrase. Vagal inhibition of the heart slows the heart rate.
Inhibition of the vagus accelerates the heart rate.

What did you observe when you tapped the intestines of the frog? Think about your options as stated above, and decide how you
would explain this phenomenon.