164

Role of Adenosine in Pathogenesis of

Anginal Pain
Filippo Crea, MD, Giuseppe Pupita, MD, Alfredo R. Galassi, MD, Hassan El-Tamimi, MD,
Juan Carlos Kaski, MD, Graham Davies, FRCP, and Attilio Maseri, FRCP, FACC

The intravenous infusion of adenosine provokes anginalike chest pain. To establish its origin,
an intracoronary infusion of increasing adenosine concentrations was given in 22 patients with
stable angina pectoris. During adenosine infusion, 20 patients had chest pain without
electrocardiographic signs of ischemia. They all reported that the chest pain was similar to
their usual anginal pain. In 10 of the 22 patients adenosine was also infused into the right
atrium, but it never produced symptoms at the doses that had provoked chest pain during
intracoronary infusion. In seven other patients, the intracoronary adenosine infusion was
repeated after intravenous administration of aminophylline, an antagonist of adenosine
P1-receptors. Aminophylline decreased the severity of adenosine-induced chest pain (assessed
with a visual analog scale) from 42+±22 to 23±+17 mm (p<0.002). In the remaining five of the
22 patients, monitoring of blood oxygen saturation in the coronary sinus during intracoronary
adenosine administration showed that maximum coronary vasodilation was achieved at doses
lower than those responsible for chest pain. A single-blind, placebo-controlled, randomized
trial of the effect of aminophylline on exercise-induced chest pain was also performed in 20
other patients with stable angina. Aminophylline, compared with placebo, decreased the
severity of chest pain at peak exercise from 67±21 to 51±23 mm (p <0.02), despite the
achievement of a similar degree of ST-segment depression. Finally, the effect of intravenous
adenosine was compared in 10 patients with predominantly painful myocardial ischemia and
in 10 patients with predominantly silent ischemia. The latter tolerated a longer period of
adenosine infusion and developed significantly less severe chest pain than patients with painful
ischemia (18±3.6 vs. 14.4±3.6 minutes, p<0.05 and 26±28 vs. 63 ±23 mm, p <0.02, respec-
tively). Thus, intracoronary adenosine administration provokes chest pain similar to the
anginal pain at doses that do not produce symptoms during intra-atrial infusion. Furthermore,
aminophylline, an adenosine PI-receptor antagonist, significantly reduces the severity of both
adenosine and exercise-induced chest pain. These findings indicate that adenosine is a stimulus
adequate to produce cardiac pain and could be partially responsible for the anginal pain during
myocardial ischemia. This effect does not seem to be related to adenosine-induced coronary
dilation and appears predominantly mediated by P1-receptor stimulation. The fact that the
severity of chest pain provoked by intravenous adenosine is less in patients with silent ischemia,
although difficult to interpret because of the systemic algogenic effects of this substance, further
supports the hypothesis that adenosine may play an important role in the production of the
anginal pain. (Circulation 1990;81:164-172)

A fter the initial description of angina pectoris
by Heberden in 1772,1 many attempts have
been made to identify its mechanisms and
its relation with myocardial ischemia. Although it was
From the Cardiovascular Unit, RPMS-Hammersmith Hospital,
London, UK.
Partially supported by Grant 88/119 of the British Heart Foun-
dation. F.C. is the Maurice Wohl Foundation Lecturer.
Address for correspondence: Filippo Crea, MD, Cardiovascular
Unit, RPMS-Hammersmith Hospital, Du Cane Rd, London W12,
UK.
Received March 31, 1989; revision accepted September 13, 1989.
proposed many decades ago that stretching of the
ventricular wall2 and local release of chemical
substances3 might be the stimuli responsible for the
anginal pain, there has been no conclusive evidence
in favor of or against either of these hypotheses.
More recently, Sylven et al,4 on the basis of the
observation that the intravenous infusion of adeno-
sine provokes anginalike chest pain, have proposed
that endogenous adenosine, released in the coronary
circulation during myocardial ischemia,5 could be
responsible for the anginal pain. This hypothesis,
however, lacks objective support because 1) it is not

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known whether the chest pain produced by the
intravenous administration of adenosine originates
from the heart and 2) it is not known whether
endogenous adenosine has the same effect as exoge-
nous adenosine.
To better understand the relations between aden-
osine and the anginal pain, we performed three
different, but interrelated, studies in patients with
stable effort angina pectoris aimed at assessing 1) the
origin of the chest pain provoked by exogenous
adenosine, 2) the role of endogenous adenosine in
the production of exercise-induced anginal pain, and
3) the effect of adenosine in patients with predomi-
nantly silent and in those with predominantly painful
myocardial ischemia.
Methods
Patients
Sixty-two patients with chronic stable angina pec-
toris (symptom duration ranging from 6 months to 12
years; mean, 3.8 years), positive exercise test for
myocardial ischemia (horizontal or down-sloping ST-
segment depression >1.5 mm), and documented
coronary artery disease (internal diameter reduction
>70% of at least one major branch) participated in
this study. Nineteen patients had suffered a previous
myocardial infarction more than 3 months before the
study.
All patients were normotensive, in sinus rhythm,
and without evidence of heart failure, cardiomyopa-
thy, or valvular disease. No patient had evidence of
left ventricular hypertrophy or conduction defects on
the electrocardiogram that could interfere with the
interpretation of ST-segment changes, and no patient
was taking digitalis. Patients were requested to abstain
from xanthine-containing food and drinks for at least
12 hours before study. Nitrate preparations, other
than sublingual nitroglycerin and calcium entry-
blocking agents, were withdrawn 2 days before the
study; /3-blocking agents were withdrawn 4 days
before. Only sublingual nitroglycerin was used during
the latter period, and a minimum of 6 hours was
allowed to elapse before testing was begun if this
drug was used.
All patients gave written informed consent for
participation in the study.
Adenosine Preparation
Adenosine (adenosine base, Fluorochem, Derby,
UK) was dissolved in 0.9% NaCl and prepared for
intravenous human use by the Pharmacy, Hammer-
smith Hospital, London, England, in a concentra-
tion of 5 mg/ml.
Assessment of Chest Pain
At the beginning of each test, patients were
informed that they could develop chest pain or other
unpleasant symptoms. They were instructed to
promptly report the onset of chest pain or of any
other discomfort. The severity of chest pain was
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Crea et al Adenosine and Anginal Pain 165
assessed by use of a visual analog scale, a well-
accepted method for the assessment of pain.6 The
10-cm scale was marked from no symptoms to severe
symptoms. The scale was measured from 0 to the
subject's mark in millimeters. Patients were also
asked to report the distribution, radiation, and type
of chest pain and the presence of any other symptom.
Intracoronary Adenosine Administration
Twenty-two patients were studied (20 men and two
women, aged 45-68 years; mean, 58 years). During
exercise testing, all patients developed chest pain.
ST-segment depression at the onset of chest pain was
0.9+0.3 mm (ranging from 0.6 to 1.5 mm). Coronary
angiography showed one-vessel disease in 10 patients,
two-vessel disease in 11 patients, and three-vessel
disease in one patient. After routine diagnostic cor-
onary angiography (Judkins technique), a 7F catheter
was advanced through an 8F femoral sheath to the
left coronary ostium. Adenosine was then infused at
a rate of 1 ml/min into the left coronary ostium at
increasing concentrations of 10-8, 10-7, 10-6, 10-5,
10-4, 10-3 , 2.5 x 10-3, and 4x 10`3 M for periods of 2
minutes each. Two electrocardiographic leads (V5
and aVF) and arterial pressure (obtained through
the side port of the femoral sheath) were continu-
ously monitored and recorded on paper and on
magnetic tape throughout the whole study. The infu-
sion was stopped in the presence of 1) intolerable
symptoms, 2) increase in heart rate greater than 30
beats/min, and 3) ST-segment depression greater
than 1.5 mm.
These 22 patients were also submitted, during the
same cardiac catheterization, to one of the following
three protocols: 1) In 10 patients, adenosine was also
infused through a 7F catheter positioned into the
right atrium. The same protocol as that for the
intracoronary infusion was used, but doses of aden-
osine were 20 times greater. 2) In seven other
patients, the intracoronary adenosine infusion with
the same doses given during the first intracoronary
infusion, was repeated after the intravenous admin-
istration of aminophylline (7 mg/kg over a period of
10 minutes). 3) In the remaining five patients, a 5F
fiberoptic catheter was advanced through the left
subclavian vein and into the great cardiac vein before
intracoronary adenosine infusion. The proximal end
of the catheter was coupled to a reflectometer (mod-
el IVH3, Schwarzer) to obtain a continuous in vivo
measurement of oxygen blood saturation in the great
cardiac vein by applying the reflection spectropho-
tometry principle.7 The second infusion of adenosine
was always stopped at the onset of chest pain.
Aminophylline and Exercise-Induced Chest Pain
Twenty men (aged 48-67 years; mean, 58 years)
who consistently had anginal pain during at least two
consecutive exercise tests were studied. Coronary
angiography showed one-vessel disease in four
patients, two-vessel disease in 10 patients, and three-
vessel disease in six patients.
166 Circulation Vol 81, No 1, January 1990
% 100
80-
60 -
40-
20-
O- C pi
Chest pain Typical Abdominal
chest pain pain
Fourteen of these 20 patients underwent a single-
blind, placebo-controlled, randomized study. They
were randomized into two groups of seven patients
each. One group underwent treadmill exercise test-
ing 2 minutes after the intravenous administration of
aminophylline (7 mg/kg over a period of 20 minutes)
on day 1 and after placebo on day 2. The other group
received placebo on day 1 and aminophylline on day
2. Tests were performed on two consecutive days
between 9:00 AM and 12:00 noon. The laboratory
temperature was kept at 20-24° C. The modified
Bruce protocol was used with 1.5 mm ST segment
depression as the end point. A 12-lead electrocardio-
gram and blood pressure (cuff sphygmomanometer)
were obtained before drug treatment, immediately
after treatment, at 1-minute intervals during the
exercise, and at 5 and 10 minutes after exercise.
Three electrocardiographic leads were continuously
monitored before, during, and after exercise. The
level of the ST segment, 60 msec after the J point,
was calculated after signal averaging by a computer-
assisted system (CASE Marquette 12) in all 12 leads.
The calculated values were printed out, along with
the heart rate, against time in trend format. This
provided measurements of the ST segment level with
an accuracy of 0.1 mm. The lead showing the greatest
ST-segment depression was selected for analysis.
In the remaining six patients, the same single-
blind, placebo-controlled, randomized trial was
repeated, but a lower dose of aminophylline (1.2
mg/kg over a period of 10 minutes) was used.
Adenosine in Patients With Silent and
Painful Ischemia
Ten patients with predominantly silent ischemia
(group 1) and 10 patients with predominantly painful
ischemia (group 2) were enrolled for this study.
Group 1 consisted of 10 men (eight English and
two Irish, aged 44-68 years; mean, 62 years). Coro-
nary angiography showed one-vessel disease in two
patients, two-vessel disease in four patients, and
three-vessel disease in four patients. Criteria for
inclusion in this group were 1) development of ST-
segment depression of 2 mm or more (to avoid
borderline cases) during exercise without occurrence
of chest pain and 2) absence of angina for the last 3
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FIGURE 1. Bar graph of symptoms caused by
intracoronary (open bars) and intra-atrial (crossed
bars) adenosine infusion. Chest pain was caused by
adenosine in 13 of 15 patients during intracoronary
infusion and in all 10 patients in whom this sub-
stance was infused into the right atrium. Chest pain
was similar to the spontaneous anginal pain in all
patients during intracoronary administration, but
only in five during intra-atrial infusion. Furthermore,
patients frequently complained of other symptoms
Other like abdominal pain, facial flushing, or anxiety
symptoms during intra-atrial infusion, but never during intra-
coronary administration.
months before study despite evidence of episodes of
transient ST-segment depression during 24-hour
Holter monitoring (number of episodes ranging from
1 to 6; mean, 2.6±2.2). No patient, however, was
totally asymptomatic; all patients reported some,
although rare, episodes of typical angina.
Group 2 consisted of 10 men (eight English, one
Indian, and one Portuguese, aged 45-68 years; mean,
61 years). Coronary angiography showed one-vessel
disease in one patient, two-vessel disease in five
patients, and three-vessel disease in four patients.
Criteria for inclusion were 1) development of chest
pain at ST segment depression less than 1.5 mm
during exercise testing and 2) at least one episode of
angina per week for the last 3 months before study.
A single-blind, placebo-controlled, randomized
design was used. Adenosine was infused through an
antecubital vein with a constant infusion pump begin-
ning at 50 ug/kg/min and increasing to 100, 150, 200,
250, and 300 ,ug/kg/min at 4-minute intervals. The
infusion was stopped in the presence of 1) increase in
heart rate greater than 30 beats/min, 2) intolerable
symptoms, and 3) ST-segment depression greater than
1.5 mm. Three electrocardiographic leads were mon-
itored throughout the test; 12-lead electrocardiogram
and arterial blood pressure (cuff) were taken during
the control period at 2-minute intervals during the
infusion and at 5 and 10 minutes during recovery.
Statistical Analysis
Continuous variables were compared by t test for
paired and unpaired data, as appropriate. A value of
p<0.05 was considered statistically significant. Data
are reported as mean+1 SD.
Results
Intracoronary Adenosine Administration
Intracoronary adenosine administration produced
chest pain, without electrocardiographic signs of myo-
cardial ischemia, in 20 of 22 patients (Figure 1). All
patients tolerated the highest dose of adenosine. No
patient developed electrocardiographic signs of myo-
cardial ischemia. Four patients reported chest pain
at a concentration of 10`3 M; 13 patients, at a
concentration of 2.5 x 10`3 M; and three patients, at a

0
CD
._c
00
00C
CDC
c c
so
t.g 0
E
E the minimum intra-atrial adenosine dose that caused
2 3 4 5 6 7 8 9
Patients
concentration of 4 x 10-3 M. All patients experienced
chest pain with character, location, and radiation
similar to their usual anginal pain. Both spontaneous
and adenosine-induced chest pain were retrosternal
without radiation in 14 patients, with radiation to the
left arm in four patients, and with radiation to the
neck in one patient. In the remaining patient, aden-
osine produced chest pain without radiation at a dose
of 2.5 x10-3 M and chest pain with radiation to the
left arm at the higher dose. This pattern was similar
to that of spontaneous angina. Indeed, this patient
reported that his angina was retrosternal only when it
was of short duration or when it was promptly
relieved by nitrates; more prolonged angina radiated
to his left arm.
Intra-atrial infusion of adenosine provoked chest
pain in all 10 patients in whom it was given at a
concentration of 5x10`2 M. No patient developed
electrocardiographic signs of myocardial ischemia. In
eight of these 10 patients who also had chest pain
during intracoronary administration of adenosine,
the ratio between the intravenous and intracoronary
adenosine dose producing chest pain was 12.5 in one
patient, 20 in six patients, and 50 in one patient
(Figure 2). During intra-atrial adenosine administra-
tion, chest pain was similar to the usual anginal pain
in only five patients. It was retrosternal without
radiation in eight patients; two patients experienced
radiation to both arms. Three patients had abdomi-
nal pain. Six patients experienced facial flushing. Five
patients complained of difficulty in breathing accom-
panied by a feeling of anxiety (Figure 1).
Aminophylline decreased the severity of chest pain
provoked by intracoronary adenosine in all seven
patients who underwent this protocol. Before ami-
nophylline, adenosine administration provoked chest
pain at a concentration of 10-3 M in two patients,
2.5x10`- M in four patients, and 4x10-3 M in one
patient. The severity of chest pain provoked by
adenosine administration was 42+22 mm before ami-
nophylline. After aminophylline, the severity of chest
pain, at the same doses of adenosine, was signifi-
cantly less (23+ 17 mm,p<c0.c002) (Figure 3). Further-
more, after aminophylline, two patients were able to
tolerate a higher dose (one level higher) of adenosine
before the onset of chest pain than they were able to
tolerate before aminophylline.
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Crea et al Adenosine and Anginal Pain 167
FIGURE 2. Bar graph of the minimum molar
concentration of adenosine (infusion rate, 1 ml/min)
able to provoke chest pain in 10 patients in whom
both intracoronary (open bars) and intra-atrial
(crossed bars) infusion was given. Two patients only
(indicated by the asterisk) did not have any chest
pain during intracoronary administration up to a
dose of 4x10- M In the remaining eight patients,
chest pain was from 12.5 to 50 times higher than the
10 minimum dose thatproduced
during intra-
coronary administration.
In all five patients in whom blood oxygen satura-
tion was monitored in the great cardiac vein, it
progressively increased during increasing doses of
intracoronary adenosine. The maximum value of
oxygen saturation (80+9%, ranging from 68% to
93%) was achieved at a concentration of 10-3 M in
one patient, 2.5 x 10-3 M in three patients, and 4 x 10-3
M in the remaining patient. All five patients had
chest pain. Oxygen saturation at the adenosine dose
immediately before the development of chest pain
was already 74±7%, ranging from 63% to 87%
(Figure 4).
During intracoronary adenosine infusion, blood
pressure and heart rate did not change for doses that
did not produce symptoms. At doses that provoked
chest pain, a modest, but significant, increase of
systolic blood pressure was noted (8 6 mm Hg,
p<0.05); diastolic blood pressure and heart rate did
not change significantly. During intra-atrial adeno-
sine infusion, a significant increase of heart rate
(23+9 beats/min,p<0.001) was observed. Blood pres-
sure, on the average, did not change. However, an
increase was observed in six patients; a reduction was
observed in five patients; and a reduction followed by
an increase occurred in three patients.
Aminophylline and Exercise-Induced Chest Pain
All patients had exercise-induced chest pain after
both aminophylline and placebo. However, after the
higher dose of aminophylline (7 mg/kg), the severity
80 - p < 0.002
0 60-
a)
0)
E 40-
t'
20 -
0-
Control Aminophylline
FIGURE 3. Plot of effect of aminophylline on the severity of
the chest pain caused by intracoronary administration of
adenosine. The severity of chest pain (assessed by a visual
analog scale) provoked by adenosine administration before
aminophylline was significantly less than that produced by the
same doses of adenosine after aminophylline.
168 Circulation Vol 81, No 1, January 1990
0 nary molar concentrations of adenosine (infusion
L-
m
._,
U)
Adenosine (molar concentrations)
of chest pain, compared with placebo, decreased
both at its onset (from 29±20 to 18± 16 mm,p<0.02)
(Figure 5) and at peak exercise (from 67±21 to
51±23 mm, p <0.02) (Figure 6). Aminophylline did
not delay the onset of chest pain; the interval between
onset of pain and onset of myocardial ischemia was
similar to that after placebo (0.5±1.2 vs. 0.6±1.6
minutes,p=NS). Peak ST-segment depression after
aminophylline infusion was similar to that after pla-
cebo (1.6±0.1 vs. 1.5 ±0.1 mm,p=NS) (Figure 6). In
each patient the difference of ST-segment depression
between the two tests never exceeded 0.2 mm. Ami-
nophylline administration at this higher dose, how-
ever, did increase both exercise duration (from
8.3±3.2 to 10.7±2 minutes,p<0.001) and peak heart
rate-blood pressure product (from 175 ± 37 to 206 ±46
beats/min-mm Hg-10-2,p<0.001).
The administration of the lower dose of aminophyl-
line (1.2 mg/kg), compared with placebo, decreased
the maximum severity of chest pain (from 64±28 to
43 ±27 mm,p<0.05), but it did not delay the onset of
chest pain (time to chest pain, 6+2.6 vs. 6.7±3.4
minutes, p=NS). Peak ST segment depression after
aminophylline infusion was similar to that after pla-
cebo (1.6±0.1 vs. 1.6±0.1 mm, p=NS); in each
patient the difference of ST-segment depression
between the two tests never exceeded 0.2 mm. Ami-
Angina severity ST depression
(mm) (mm)
p<0.02 p NS
50- 0.5 - 100-
40- 0.4 -
T T
30 -
T 0.3 - 60 -
20 - 0.2 -
10 - 0.1 - 20 -
0- 0-
P A P A
FIGURE 5. Bargraphs ofeffect ofaminophylline on exercise-
induced chest pain. The severity of chest pain at its onset was
less after aminophylline (A) administration (7 mg/kg) than
afterplacebo (P) administration, despite a comparable degree
of ST-segment depression.
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FIGURE 4. Plot of effects of increasing intracoro-
rate, 1 ml/min) on blood oxygen saturation in the
great cardiac vein. Massive coronary dilation, as
indicated by marked increases of oxygen blood
saturation, can be observed at doses that do not
produce any chest pain. These findings suggest that
adenosine-induced chestpain is unlikely to be caused
by stretching ofpetiarterial sensory nerve endings.
nophylline administration at this lower dose, com-
pared with placebo, did not affect the exercise dura-
tion (8.4±1.9 vs. 8.3±3.1 minutes, p-NS) nor the
peak heart rate-blood pressure product (163±37 vs.
154±28 beats/min-mm Hg.10-2, p=NS).
Adenosine in Patients With Painful and Silent
Myocardial Ischemia
Placebo administration did not produce symptoms
in any of the patients. Adenosine infusion produced
chest pain in 19 of the 20 patients. Only one patient
in group 1 (who had a history of asymptomatic
myocardial infarction) did not develop any pain; in
this patient, the test was interrupted after 14.3 min-
utes because of nausea. Time to onset of chest pain
was greater in group 1 than in group 2 (13.3±5.9 vs.
9.5±2.2 minutes), although this difference did not
achieve statistical significance (p=0.07) (Figure 7).
The severity of chest pain, both at the onset and at
peak, was significantly less in group 1 than in group 2
(10±9 vs. 24±12 mm, p<0.02 and 26±28 vs. 63±23
mm,p<0.02, respectively) (Figure 8). No patient had
ST-segment depression at the onset of chest pain;
however, seven patients in each group subsequently
developed ST-segment depression greater than 1 mm
during the test. Only three patients in group 1 and
five in group 2 reported that adenosine-induced chest
Angina severity ST depression
(mm) (mm)
2-
p< 0.02 p NS
80- 1.6-
1.2-
40 - 0.8 -
0.4 -
0 - 0 -
P A P A
FIGURE 6. Bargraphs ofeffect ofaminophylline on exercise-
induced chest pain. The severity of chest pain at peak exercise
was less after aminophylline (A) administration (7 mg/kg)
than after placebo (P) administration, despite a comparable
degree ofpeak ST-segment depression.
 Crea et al Adenosine and Anginal Pain 169

Time to pain Total duration

(min) (min)
24 24 <0.05 5-
cn
p = 0.07 4-
20- 20- a)
CL
._
3-
16 -16 0 2-
0
12- 12-
z
0 - ,1
-
1 . - L
8 8 50 100 150 200 250 300
Adenosine (Qglkg/min)
4 4
FIGURE 9. Bar graph of effect of intravenous administration
0 0
of increasing doses of adenosine in patients with silent (open
S P S P bars) andpainful (closed bars) myocardial ischemia. Seven of
FIGURE 7. Bar graphs of effect of intravenous administra- 10 patients with silent ischemia, but only two of 10 patients
tion of increasing doses of adenosine in patients with silent (S) with painful ischemia, tolerated doses of adenosine that were
and painful (P) myocardial ischemia. Time to pain and total 250 gg/kg/min or more.
duration of the test were longer in patients with silent ischemia.
only two in group 2 tolerated a dose of 250 gg/
pain was similar in character and location to their kg/min or more (Figure 9). The test was interrupted
angina pain; six of these patients developed ST because of chest pain in one patient in group 1 and in
segment depression greater than 1 mm during the four in group 2, because of ST-segment depression in
test (three in group 1 and three in group 2). The pain three patients in each group, because of tachycardia
was located in the center of the chest without radia- or frequent ventricular extrasystoles in four patients
tion in five patients in group 1 and in four patients in in group 1 and in three patients in group 2, and
group 2; in the remaining patients, it radiated to because of nausea in one patient in group 1. In the
either the jaws (two in group 1 and four in group 2) remaining patient in group 1, the maximum dose of
or to the arms (two in group 1 and one in group 2). adenosine was achieved.
Eight patients (three in group 1 and five in group 2) Placebo administration did not produce hemody-
experienced facial flush. Six patients (three in each namic changes in any of the patients. The hemody-
group) complained of difficulty in breathing accom- namic response to adenosine administration was
panied by a feeling of anxiety. Two patients (one in similar in the two groups. Heart rate increased by
each group) had severe nausea. 21 ± 16 beats/min (p<0.001) in group 1 and by 20±12
The total duration of the test was greater in group beats/min (p<0.001) in group 2. Blood pressure did
1 than in group 2 (18±3.6 vs. 14.4+3.6 minutes, not change significantly in either group.
p<0.05) (Figure 7). Seven patients in group 1 but
Discussion
1 00 -
o Silent ischemia
p < 0.02 Origin of Adenosine-Induced Chest Pain
* Painful ischemia 0 Our study shows that in patients with stable angina
80- 0 pectoris, the intracoronary administration of adeno-
o
sine causes chest pain without electrocardiographic
signs of myocardial ischemia. The character, location,
60-
0
0 and radiation of adenosine-induced chest pain are
E
p < 0.02 0 remarkably similar to those of the anginal pain
= 40 *0 experienced by the patients during their daily life.
E 0 Because the half-life of adenosine in blood is 10
I seconds8 and the transit time in the coronary circu-
20 - 0
0 lation is about 6-8 seconds,9 the amount of adeno-
o

t 000
0
0 sine reaching the right atrium during intracoronary
0-
000
f~~~~~~~~~~~~~~~~~~
0
0 0 0

0
a However, even though it was assumed that no sub-
Pain onset
FIGURE 8. Plot of effect of intravenous administration of
increasing doses of adenosine in patients with silent and
painful myocardial ischemia. The severity of chest pain at its
onset and at the time the test was terminated was significantly
less in patients with silent ischemia. It is worth noting that,
despite a statistically significant difference between patients
with silent and those with painful ischemia, the overlapping of
results between the two groups is considerable.
administration was considerably less than that infused.
Peak stantial degradation occurred due to the decreased
transit time caused by adenosine-induced coronary
dilation,5 the recirculating adenosine was inadequate
to produce pain because the dose that caused chest
pain during intra-atrial infusion was, in the majority
of patients, 20 times greater than the dose causing
symptoms during intracoronary administration. It is
reasonable to assume, therefore, that the chest pain
provoked by intracoronary adenosine infusion was

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170 Circulation Vol 81, No 1, January 1990
entirely cardiac in origin. It is worth noting that the
intracoronary infusion of substance P, a substance
known to be involved in nociception, does not pro-
voke chest pain, even with concentrations high enough
to give systemic effects.10
Because the fraction of the cardiac output to the
left coronary artery is about 2-3%,11 because the
transit time from right atrium to left coronary artery
is about 8-10 seconds,12 and because the half-life of
adenosine in blood is about 10 seconds,8 the fact that
the amount of adenosine causing chest pain during
intracoronary adenosine administration was 5% of
that during intra-atrial administration would be com-
patible with a cardiac origin of the pain. However, in
about half of our patients the chest pain experienced
was different from the usual anginal pain, and anxi-
ety, difficulty in breathing, abdominal pain, and facial
flushing were often the predominant symptoms; these
facts strongly suggest that, in these cases, the symp-
toms did not entirely originate from the heart. This is
in agreement with experimental results showing that
adenosine stimulates afferent nerves in various tis-
sues such as chemoreceptors,13 renal pelvis,14 and
lung15 and with the observation in humans that the
intrabrachial infusion of adenosine causes pain in the
forearm.'6
This study not only proves that the chest pain
caused by adenosine originates from the heart, but it
also sheds some light on its possible mechanisms.
Indeed, the fact that aminophylline, a potent antag-
onist of adenosine P,-receptors,'7-1' significantly
decreases the severity of chest pain provoked by the
intracoronary administration of adenosine appears to
suggest that P1-receptors can play a key role in
mediating this algogenic effect. This is in agreement
with the observation that in healthy volunteers ami-
nophylline reduces the severity of systemic symptoms
caused by intravenous adenosine administration.4 On
the other hand, our data appear to rule out that chest
pain was due to mechanical distortion and stretching
of sensory cardiac nerves located in the myocardial
interstitium and in the vascular adventitia.20 In fact, a
massive increase of blood oxygen saturation in the
great cardiac vein, indicative of massive coronary
resistive vessel dilation, was observed at doses of
adenosine lower than the minimum dose able to
provoke chest pain. Although Sylven et al,2' in a
previous study, found that both chest pain and coro-
nary dilation occurred at the same intravenous bolus
dose of adenosine, the presence of systemic effects
and the lack of an appropriate dose-escalating
approach are likely to account for the inability of
their study to clearly separate the algogenic and the
vasoactive effects of this substance.
In theory, the intracoronary administration of aden-
osine can cause myocardial ischemia.22 However, it is
unlikely that myocardial ischemia was the cause of
chest pain in our patients. Indeed, no patient devel-
oped electrocardiographic signs of myocardial isch-
emia during adenosine infusion, although, during the
exercise test, all patients had already developed
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obvious ST-segment depression before reporting chest
pain. Also unlikely is the possibility that chest pain
was due to a nonspecific effect of the intracoronary
infusion of saline (the vehicle used to dissolve aden-
osine). Indeed, to minimize the risk of untoward
effects from the vehicle, the increasing doses of
adenosine were always given at the same infusion
volume rate (1 ml/min). The fact that the chest pain
never occurred at adenosine concentrations lower
than i0` M confirms that saline was not responsible.
Endogenous Adenosine and Chest Pain
The demonstration that the pain provoked by
exogenous adenosine originates from the heart sug-
gests, but does not prove, that endogenous adenosine
released during myocardial ischemia could have the
potential to cause exercise-induced angina. To test
this hypothesis we assessed the effect of aminophyl-
line on exercise-induced chest pain in patients with
stable angina pectoris. In our study, aminophylline,
compared with placebo, significantly reduced the
severity of exercise-induced chest pain despite the
fact that patients achieved a degree of ST segment
depression similar to that achieved after placebo.
This was observed not only at the higher dose of
aminophylline, which markedly improves exercise
capacity,23,24 but also at the lower dose of this drug,
which does not affect exercise capacity. It would
appear, therefore, that the effect of this drug on the
anginal pain is independent of the effect on exercise
capacity.
It is worth noting that aminophylline did not delay
the onset of angina, although it did decrease the
severity of chest pain not only at peak exercise but
also at its onset. These findings are not in contrast
with the hypothesis that adenosine is responsible for
the anginal pain, although they do indicate that other
mechanisms are also important. The nature of these
mechanisms can only be speculative. Interestingly,
ATP, which is released in the coronary circulation by
the ischemic cells25 and acts through the stimulation
of P2-receptors, which are not blocked by aminoph-
ylline,26 27 has the potential to stimulate sensory
nerve endings.28
Adenosine and Silent Ischemia
If adenosine is, at least partially, responsible for
the anginal pain, it would be logical to expect a
different response to adenosine in patients with
painful and silent myocardial ischemia.
In our study, patients with predominantly silent
ischemia had significantly less chest pain during
intravenous infusion of adenosine and tolerated sig-
nificantly higher doses of this substance than those
with predominantly painful ischemia. Seven patients
with silent ischemia but only two with painful isch-
emia tolerated infusion rates of 250 ug/kg/min or
greater. The doses of adenosine tolerated by patients
with silent ischemia were much higher than the
maximum dose tolerated by healthy volunteers in
previous studies in which constant rate infusions

were used.29,30 The doses tolerated by our patients
with painful ischemia are comparable with those
reported by Fuller et a129 in healthy volunteers, but
they are higher than those reported by Conradson et
al.30 The subjects enrolled in the latter study, how-
ever, had characteristics different from our patients:
they had a younger age (ranging from 23 to 40 years),
and there was a higher incidence of women (three
out of eight).
In our study, seven patients with silent and seven
patients with painful ischemia developed electrocar-
diographic signs of myocardial ischemia during aden-
osine infusion that could interfere with the interpre-
tation of chest pain. However, because myocardial
ischemia always occurred at doses higher than that
causing chest pain, its severity at the onset of isch-
emia, which was less in patients with silent than in
those with painful ischemia, was probably entirely
related to the direct algogenic effect of adenosine.
Patients with silent ischemia did have chest pain
during adenosine infusion in the absence of electro-
cardiographic signs of myocardial ischemia but not
during episodes of transient severe myocardial isch-
emia. These findings confirm that the pain provoked
by the intravenous administration of adenosine is
unlikely to be entirely cardiac in origin. Therefore,
the lesser severity of adenosine-induced chest pain in
patients with silent ischemia than in those with
painful ischemia probably reflects a generalized, rather
than a local, reduced sensitivity to the algogenic
effects of adenosine. Our study confirms and expands
the hypothesis that in some patients a generalized
defective perception of painful stimuli can play a key
role in determining silent ischemia, already proposed
in previous studies on the basis of the results obtained
by using various painful stimuli like cold pressor,
forearm ischemia, and skin or dental pulp electric
stimulation.31-34 It is worth noting that in this, as in
the previous studies, despite a statistically significant
difference between patients with silent and those
with painful ischemia, the overlapping of results
between the two groups was considerable. It would
appear, therefore, that although a generalized defec-
tive perception of painful stimuli may account for
silent ischemia in those patients with a low sensitivity
to adenosine, other mechanisms have to be invoked
to explain silent ischemia in those patients who have
a response to adenosine similar to that observed in
patients with painful ischemia.
Although the interpretation of the different results
observed in patients with silent and painful ischemia
is limited by the systemic effects of adenosine, they
appear to lend support to the hypothesis that aden-
osine plays an important role in the production of the
anginal pain, or at least, they do not contradict it.
Indeed, had we found that the algogenic effects of
adenosine were similar in the two populations of
patients, a serious shadow would have been cast on
our working hypothesis.
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Crea et al Adenosine and Anginal Pain 171
Conclusions
In conclusion, intracoronary adenosine administra-
tion provokes chest pain with character, location, and
radiation similar to the anginal pain at doses that do
not produce symptoms during intra-atrial infusion.
Furthermore, aminophylline, a potent antagonist of
adenosine P1-receptors, reduces both adenosine and
exercise-induced chest pain. These findings suggest
that the stimulation of P1-receptors by adenosine
could be partially responsible for the anginal pain
during myocardial ischemia. The fact that the sever-
ity of chest pain provoked by intravenous adenosine
is milder in patients with silent ischemia than in those
with painful ischemia, although difficult to interpret
because of the systemic effects of adenosine, is in
agreement with this working hypothesis.
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KEY WORDS * aminophylline * adenosine * angina a
myocardial ischemia
 Role of adenosine in pathogenesis of anginal pain.
F Crea, G Pupita, A R Galassi, H el-Tamimi, J C Kaski, G Davies and A Maseri

Circulation. 1990;81:164-172
doi: 10.1161/01.CIR.81.1.164
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1990 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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