Oral Isosorbide Dinitrate

in the Treatment of Angina Pectoris

Dose-Response Relationship and Duration
of Action During Acute Therapy
UDHO THADANI, M.B.B.S., HO-LEUNG FUNG, PH.D., ANDREW C. DARKE, PH.D.,
AND JOHN 0. PARKER, M.D.

with the statistical assistance of Margery J. Cruise, M.Sc.

SUMMARY The duration of effects of single oral doses of 15, 30 and 60 mg of isosorbide dinitrate (ISDN)
were studied in 12 patients with stable, exercise-induced angina pectoris. The effects of a 120-mg dose were
also studied in seven of these 12 patients. The average peak values for plasma ISDN concentration were 6.8,
14.3, 17.5 and 26.0 ng/ml after 15, 30, 60 and 120 mg of ISDN, respectively, and there was a 5-, 12-, 6-, and 5-
fold interindividual variation in peak plasma concentration at these doses. At rest, both the systolic and
diastolic blood pressures decreased after each dose of ISDN in both the supine (p < 0.05) and standing
(p < 0.01) positions. The reduction in systolic blood pressure was more marked in the standing position. This
effect occurred at 1 hour and persisted for 6 hours after 15 mg of ISDN and for 8 hours after other doses of
ISDN. Exercise duration to the onset of angina and to the development of moderate angina increased by a
similar degree after each dose of ISDN compared with placebo values (p < 0.001). This was apparent by 1
hour and the effects persisted for 8 hours. The maximum increase in walking time to angina occurred after 15
mg in six patients, after 30 mg in two patients, and after 60 mg in three patients. One patient did not improve
after any of the doses. The heart rate (p < 0.01) and rate-pressure product (p < 0.05) at the onset of angina
after any dose of ISDN increased compared with placebo values. However, ST-segment depression at the onset
of angina was similar after ISDN and placebo. At the onset of moderate angina, the values for rate-pressure
product after ISDN were similar to those after placebo, but ST-segment depression was less after ISDN
(p < 0.05).
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These data show that administration of single doses of ISDN from 15-120 mg increased exercise tolerance
to angina for 8 hours, but for the whole group, higher doses did not have a quantitative greater effect on exer-
cise tolerance than the lower doses.

SUBLINGUAL GLYCERYL TRINITRATE is the
most often used antianginal agent. Taken prophylac-
tically, it prolongs exercise tolerance in both the up-
right and supine positions.'1 However, the therapeutic
efficacy of long-acting oral nitrates in patients with
angina pectoris has been controversial. In 1975,
Aronow reported that the long-acting nitrates had lit-
tle therapeutic merit.7 Recently, however, it was
shown that isosorbide dinitrate (ISDN), given orally
in large doses, had prolonged hemodynamic effects in
patients with heart failure,8"- and improved exercise
tolerance in patients with angina pectoris during both
From the Division of Cardiology, Department of Medicine,
Queen's University, Kingston, Ontario, Canada, the Department of
Pharmaceutics, School of Pharmacy, State University of New York
at Buffalo, Buffalo, New York, and Wyeth Ltd., Downsview, On-
tario, Canada.
Supported in part by grants from the Ontario Heart Foundation
(OHF 2-5), Wyeth Ltd., and NIH grants HL 22273 and GM 20852.
Presented in part at the 28th Annual Meeting of the American
College of Cardiology, Miami, Florida, 1979.
Address for correspondence: Dr. Udho Thadani, Department of
Medicine, Cardiovascular Section, Health Sciences Center, Uni-
versity of Oklahoma at Oklahoma City, P.O. Box 26901, Room
309D, Old Main, Oklahoma City, Oklahoma 73190.
Received October 24, 1979; revision accepted February 21, 1980.
Circulation 62, No. 3, 1980.
491
acute'12-1 and long-term therapy.17' 18 However, many
of the important issues of therapeutic relevance are
unanswered. Specifically, the dose-response relation-
ship during acute and sustained therapy and the dura-
tion of action of different doses of ISDN in angina
pectoris are not well defined. Furthermore, the cor-
relation between the therapeutic effects and plasma
ISDN levels is not known. This investigation was
designed to determine the effects of acute administra-
tion of ISDN in patients with angina pectoris. The
preliminary results of this work were recently
published in abstract form."9
Methods
Thirteen male patients, ages 42-70 years (average
57 years) with stable, exercise-induced angina pec-
toris, were studied. The history of angina ranged from
6 months to 5 years (average 14 months) and was in-
duced solely and repeatedly by exercise in all patients.
None of the patients were hypertensive or had clinical
or radiologic evidence of cardiac enlargement or
failure. None was taking drugs other than sublingual
glyceryl trinitrate, and this was not required on the
days of the investigation. Four of the patients had
suffered a myocardial infarction at least 6 months
before the study. Coronary angiography was per-
formed in seven of the remaining nine patients and
 492 CI RCULATION
had shown evidence of luminal narrowing of 75% or
more of two or more coronary arteries.
The resting ECG was normal in nine patients and
showed ST-T-wave changes in the inferior leads in the
remaining four patients. During preliminary treadmill
exercise testing, all patients developed horizontal or
downsloping ST-segment depression in modified lead
V5 of 0.1 mV or more of at least 0.08 second duration.
The study was explained and informed, written con-
sent was obtained from each patient.
During preliminary studies 24-48 hours before the
definitive investigations, each patient walked on a
motor-driven treadmill using the Bruce multistage
protocol.20 The patients were instructed to indicate the
point at which definite chest pain developed (onset of
angina) and the point at which the pain became of
such severity which necessitated discontinuation of ex-
ercise (angina of moderate severity). The study group
was selected from patients who had chest pain by the
end of stage 2 or beginning of stage 3 during treadmill
exercise.
Precautions were taken to control factors that could
produce changes in exercise tolerance. The laboratory
temperature was 20-22°C, and the patient's apprehen-
sion was reduced by familiarization with the technique
and staff.
Design of Investigation
The definitive studies were performed in the morn-
ing after an overnight fast and during the days of the
investigation the patients did not smoke. The study
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was double-blind and placebo-controlled. Each patient
was studied twice a week for 3 weeks with the studies
separated by 3-day intervals. Patients taking part in
the study were randomly allocated to one of the three
groups shown in table 1. Studies were started at 0830
hours (control study), when heart rate, blood pressure,
and ECG were recorded at rest in the supine and
standing positions and during treadmill exercise.
Then, each patient took 15 mg of ISDN or placebo
and the measurements made at rest and during exer-
cise at 1, 2, 4, 6 and 8 hours after the medication.
The end point during exercise for the control study
was the development of angina of moderate severity;
after placebo or ISDN, the end point was angina of
moderate severity, fatigue or undue breathlessness. At
21/2 hours after initiation of the study, the patients ate
a light meal without coffee. Each patient was restudied
TABLE 1. Randomization of Patients to Placebo and Isosor-
bide Dinitrate
Day Day Day Day Day Day
1 4 7 10 13 16
Group 1 One patient felt lightheaded and lost consciousness
(3 patients) PL1 15 mg 30 mg 60 mg 120 mg PL2
Group 2
(4 patients) 15 mg 30 mg PLb 60 mg 120 mg PL2
Group 3
(5 patients) 15 mg 30 mg 60 mg 120 mg PL, Pbn
Abbreviations: PL1 = first placebo; PL2 = second placebo.
VOL 62, No 3, SEPTEMBER 1980
in the same manner on four other days with increasing
doses of ISDN (30, 60 and 120 mg) or placebo.
Placebo was randomly administered as shown in table
1. In addition, on the last day, each patient was
studied before and after the second placebo. The
placebo tablets and ISDN tablets were identical in
appearance.
If symptomatic hypotension developed on day 1 or
4, the patient was withdrawn from the study; if it
developed on day 7 or later, the patient remained in
the study, but the dose of ISDN was not increased and
he was restudied only after the second placebo.
Measurements and Recordings
Modified lead V, was monitored on an oscilloscope
throughout the study and records were taken on a
standard ECG at a paper speed of 25 mm/sec at 1-
minute intervals for 2 minutes in the supine and stand-
ing positions and at I-minute intervals during exercise.
Further records were taken at the onset of angina and
when angina became of moderate severity. The
average values for heart rate and ST-segment depres-
sion during 10 consecutive beats were measured from
the ECG. Blood pressure was measured using
sphygmomanometry at 1-minute intervals at rest and
during exercise. The rate-pressure product was cal-
culated as the product of heart rate multiplied by
systolic blood pressure and was expressed in mm
Hg.min-> X 10-2.
Venous blood (8 ml) was collected at rest before
each exercise period for determination of plasma
ISDN concentration. Blood was collected in tubes
containing EDTA, spun in a refrigerated centrifuge at
3000 rpm at 3°C within 5 minutes of sampling, and
the plasma stored at -20°C. Plasma ISDN levels
were measured by a gas chromatographic method,2'
which is a modification of the method described for
determining plasma nitroglycerin concentration.22 In
our laboratory, the variation in plasma ISDN concen-
tration with replicate measurements with this method
is less than 10%. With the plasma sample of 0.2 ml,
this method is sensitive to plasma concentration of 0. 1
ng/ml or greater.
Conventional statistical methods were used
throughout. Significance of changes were studied by
analysis of variance and the significance of results
determined using a multiple range test.23 As five of the
12 patients did not receive a 120-mg dose, separate
analysis was performed with 12 patients for placebo
and the 15-, 30- and 60-mg doses and with seven
patients for placebo and the 15-, 30-, 60- and 120-mg
doses.
Results
transiently 1 hour after the first oral dose of 15 mg of
ISDN. His systolic blood pressure dropped from 120
mm Hg to 60 mm Hg in the standing position, but in-
creased to 80 mm Hg in the supine position. The ECG
showed sinus bradycardia but was otherwise normal.
This patient was not given further doses of ISDN and
 ISDN FOR ANGINA/Thadani et al.
has been excluded from the study. Of the remaining 12
patients, all were studied after placebo and 15, 30 and
60 mg of ISDN, and seven of the 12 patients were also
studied after 120 mg of ISDN. Five patients did not
receive a 120-mg dose because they experienced
lightheadedness at the 60-mg dose. The study was
completed in these 12 patients without serious com-
plications.
Plasma ISDN Concentration
The time course of plasma ISDN concentration for
the whole group after each dose of ISDN is shown in
figure 1. The mean plasma peak concentrations were
observed at 1 hour, 30 minutes, 2 hours and 2 hours
after 15-, 30-, 60- and 120-mg ISDN doses, respec-
tively. The average peak values were 6.8, 14.3, 17.5,
and 26.0 ng/ml after 15, 30, 60, and 120 mg of ISDN,
with a 5-, 12-, 6-, and 5-fold interindividual variation
in peak plasma concentrations at these doses. Further-
more, plasma concentration peaked at different times
in different patients after similar doses of ISDN.
Plasma concentration peaked at 30 minutes in five, at
50 r
30
20
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10t-
CY
E
z
r_
0 patients did not develop AP2 until exercised 4 hours
0::
XI
z time to fatigue was substituted for AP2. Thus, after
W
z creased significantly compared with the values after
0
1.0o
U')
cJ
e-
z
C,)
0.1L
0 2 4 6 8 duration to API and AP2 observed during the control
HOURS AFTER ORAL DOSE
FIGURE 1. Time course of plasma isosorbide dinitrate
(ISDN) concentrations after single oral doses of 15, 30, and
60 mg in 12 patients and after 120 mg ISDN in seven
patients with angina pectoris. Data are mean ± SEm.
493
1 hour in five and at 2 hours in two patients after both
15 and 30 mg of ISDN, at 30 minutes in three, 1 hour
in one patient and at 2 hours in eight patients after 60
mg of ISDN, and at 30 minutes in one patient, at 1
hour in two, at 2 hours in two, and at 4 hours in two
patients after 120 mg ISDN.
Adverse Effects
None of the patients had angina at rest and none
required glyceryl trinitrate tablets for angina
precipitated during exercise.
Eight patients experienced transient lighthead-
edness after ISDN; in five this occurred after the 60-
mg dose and in three, it developed after 120 mg. These
symptoms occurred 2-4 hours after oral ingestion of
the drug and disappeared on assumption of the supine
position. One of these eight patients had presyncope 3
hours after 60 mg ISDN, but this was reversed on
assumption of the supine posture.
Exercise Tolerance (tables 2 and 3, figs. 2 and 3)
Exercise was discontinued because of moderately
severe angina during the control studies and the series
of exercise tests after placebo 1 and placebo 2. After
placebo 1 and 2, exercise duration to the onset of
angina pectoris (AP1) and to the development of
angina pectoris of moderate severity (AP2) did not
change significantly from the respective pre-placebo
control values (fig. 2).
After ISDN, exercise duration to AP1 and AP2 was
prolonged in 11 of the 12 patients after the 15-mg
dose, in 10 of the 12 patients after 30 mg, in eight of
the 12 patients after the 60-mg dose, and in six of the
seven patients after the 120-mg dose. All patients
developed AP1 after each dose of ISDN, but two
after ISDN 30 and 60 mg. In these patients, exercise
was discontinued because of fatigue and the exercise
each dose of ISDN, walking time to AP, and AP2 in-
placebo (p < 0.001) (fig. 2). This improvement in ex-
ercise tolerance was apparent within 1 hour and per-
sisted for 8 hours after 15, 30, 60 and 120 mg of ISDN
compared with the corresponding placebo values
(p < 0.01) (fig. 2). Exercise duration to AP1 and AP2,
4 hours after placebo or ISDN was consistently less
than the duration of exercise at 2 or 6 hours (fig. 2).
This was presumably because the patients were fed 2½/2
hours after ingestion of placebo or drug. The average
data (fig. 2 and table 2) show that after 60 and 120 mg
of ISDN, patients exercised longer than after 15-mg
doses. However, when daily variations in exercise
studies were taken into consideration, we found that
the increase in average walking time to AP1 and AP2
after 15, 30, 60 and 120 mg were similar.
In any given patient, walking time to angina during
the control studies varied from one day to another, so
the data were normalized by calculating the percent-
 494 CIRCULATION VOL 62, No 3, SEPTEMBER 1980

TABLE 2. Clinical, Electrocardiographic and Circulatory Data During Exercise

Hours After Oral Dose
TWT (seconds) ST-segment depression (mm)
0 1 2 4 6 8 0 1 2 4 6 8
AP,
Placebo, 255 293 293 258 275 287 2.4 2.3 2.2 2.3 2.2 2.4
*25 *29 -27 -23 -27 *30 *0.4 *0.5 -0.4 *0.3 0.4 *0.4
Placebo2 274 304 306 274 287 307 2.2 2.4 2.2 2.3 2.3 2.3
22 *21 *26 23 *25 *26 *0.4 -0.4 *0.3 *0.4 *0.4 -0.4
ISDN
15 mg 218 404t 397t 315t 334t 343t 2.2 1.9 1.9 2.3 2.1 2.6
*21 -34 *43 *34 *42 437 -0.3 Q0.4 *0.4 *0.4 *0.3 0.4
30 mg 225 425t 424t 370t 402t 406t 2.0 1.7 2.4 2.0 2.3 2.5
-22 -34 *37 *45 *34 *30 -0.4 *0.4 *0.8 0.3 0.4 0.4
60 mg 263 420t 455t 359t 4101 406t 2.1 1.6 1.6 2.0 2.0 2.1
*21 *39 *33 *37 *33 *37 *0.4 *0.3 *0.3 0.3 *0.4 Q0.4
120 mg 297 465t 466t 420t 418t 420t 2.4 2.1 2.0 2.4 2.2 2.8
*36 *31 *28 *37 *55 *49 *0.4 *0.4 *0.5 *0.4 *0.4 -0.4
AP2
Placebo, 331 384 390 354 365 387 2.7 2.9 2.9 3.0 3.0 2.9
*28 *31 *31 *32 *32 *34 *0.4 *0.4 *0.4 *0.4 *0.4 *0.5
Placebo2 384 408 403 366 391 402 2.9 2.9 2.9 3.0 3.0 2.7
25 *30 *31 *30 *30 *29 *0.4 0.4 *0.4 *0.4 *0.4 *0.4
ISDN
15 mg 334 456t 443t 401t 410t 415t 2.8 2.1t 2.1t 2.3t 2.5 2.8
*31 *34 *36 =31 *36 *31 0.3 *0.4 0.4 *0.3 *0.3 *0.4
30 mg 364 475t 484t 439t 458t 4551 2.7 2.0t 2.1t 2.5t 2.7 2.7
*29 *33 *33 *32 *0.4 *0.4 *0.4 0.4
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30 *29 *0.4 *7
60 mg 365 489t 4811 441t 466t 463t 2.6 1.8t 1.7t 2.2t 2.3t 2.3t
*25 *30 *33 *29 *30 *32 *0.4 *0.3 *0.4 0.3 *0.4 *0.4
120 mg 393 503t 490t 459t 474t 488t 3.0 2.4t 2.1t 2.7* 2.4t 3.1
*47 *32 *40 *41 *42 *57 *0.3 *0.4 *0.4 *0.4 0.4 0.4
Data are mean * SEM.
Abbreviations: AP, = onset of anginal pain; TWT = treadmill walking time; HR = heart rate; SBP = systolic blood pressure;
ISDN = isosorbide dinitrate; AP2 = onset of moderately severe chest pain.
p values in comparison to placebo values. * = < 0.05; t = < 0.01.

age changes in walking time after drug or placebo on
any given day by the following formula:
walking time to angina after drug -
walking time to angina before drug
X 100
walking time to angina before drug
The average percentage increase in walking time to
AP1 after ISDN 15, 30, 60, and 120 mg were similar.
Similar calculations were also made for AP2 and the
percentage increase in walking time to AP2 after
ISDN 15, 30, 60 and 120 mg were also similar.
To take the placebo effects into account, the per-
centage change in walking time to AP1 at any given
hour after placebo was subtracted from the percentage
changes in walking time to AP, after drug at the iden-
tical hour to obtain the net percentage change in walk-
ing time to AP1 after the drug. The individual values
for the maximum percentage increase in walking time
to AP1, irrespective of time after the ingestion of the
drug, are shown in figure 3. Improvement in net walk-
ing time to AP1 by 25% or more after 15, 30, and 60
mg ISDN was observed in 1 1, 11 and nine patients,
respectively. The maximum increase in walking time
to AP1 occurred after 15 mg in six patients, after 30
mg in two patients, and after 60 mg in three patients.
Three patients improved less after the 60-mg dose
than after the 15- or 30-mg dose. Of the seven patients
who also received 120-mg doses, exercise tolerance
improved by 25% or more in six, but four of these six
patients had less improvement in walking time after
this dose than that after the 15- or 30-mg dose.
The individual data was also analyzed for AP2.
Eleven, nine and eight patients had improvement in
walking time to AP2 by 25% or more after 15, 30, and
60 mg of ISDN, respectively. The maximum increase
in walking time to AP2 occurred after 15 mg in seven
patients, after 30 mg in two patients, and after 60 mg
in two patients. Three patients improved less after the
60-mg dose than after the 15- or 30-mg dose. Of the
 ISDN FOR ANGINA/Thadani et al. 495

TABLE 2. (Continued)
Hours After Oral Dose
HR (beats/min) SBP (mm Hg)
0 1 2 4 6 8 0 1 2 4 6 8
AP1
119 116 114 120 116 122 180 174 173 175 174 176
---5 =1=6 =t=5 =1=44 4-5 -6 =1-7 =7 -7 -17 -4-6 =1=8
112 113 116 118 115 119 171 170 172 171 169 167
1=5 =5 -1-5 =1=5 =416 =1=7 ---7 i6 =i=7 -7 ---7 -1=8

120 138t 136t 133 129 133 180 174 171 170 173 170
1=5 -17 -17 --5 7 =+17 =1=7 =1=8 =1=9 =9 =1=8 1=9
116 134t 134t 134t 135t 133 175 167 166 171 172 172
-4-5 -+=7 =1=7 =4-7 =4-7 =1=8 =1=8 =1=10 ==9 =18 8 -7
112 133t 137t 133t 129t 132t 176 160* 163* 162* 168 169
=1-5 =1=7 -7 ---6 -7 =4-7 ---7 =1=9 110 =--9 =8 9
119 136t 133t 131t 129t 135t 187 187 179 181 177 183
9 =110 =10 8 11 =11 8 =11 =11 =11 =9 =10
AP2
125 125 125 128 127 131 184 181 179 179 179 180
=1=5 -16 := 7 =1=6 -16 -17 =8 -18 =i17 -8 == 7 8
124 123 125 127 123 128 176 176 174 175 175 172
-16 =1=6 =-=6 -1-6 -1-6 -1=7 -17 =1=8 ---7 =1-7 =1=8 1-7

132 141t 139t 142t 136* 141 184 176 173 179 178 176
---5 =--7 ---6 =1=6 =1=7 i1=7 ---8 -8 =1-9 =-18 =1=8 =10
128 138t 139t 141t 138t 141t 181 174 170 176 176 174
=1=7 =1-7 =1-8 =--6 =1=7 -18
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=1-9 =19 =1=9 =1=8 =1=8 =-=8

123 136t 139t 136t 135t 138t 170 166 164 168 174 172
=1i6 =4-7 =--7 ---6 =17 =17 =1=8 =9 =l=10 =i8 =1=8 =1=9
128 139t 136t 134t 134t 141* 191 190 180 186 183 183
=l111
==10 =1=12 =ig9 =12 =13 =1=8 =1=10 =i=10 8 =i=9 =1=10

seven patients who also received 120 mg of ISDN, ex-
ercise tolerance improved by 25% or more in five, but
four of these five patients experienced less improve-
ment in walking time after this dose than after the 15-
or 30-mg dose.
Electrocardiographic ST-segment Changes (tables 2 and 3)
During exercise in the six control studies and after
placebo 1 and 2, 11 of the 12 patients developed ST-
segment depression of 1 mm or more at the onset of
angina, and this became more pronounced at AP2.
During each exercise period, ST depression at AP1
and AP2 after placebo 1 and 2 was similar to the con-
trol exercise period (table 2). ST-segment depression
at AP1 was similar after placebo and any given dose of
ISDN. However, when ST segments were assessed
after ISDN at the same duration of exercise when
angina had occurred during the placebo studies, there
was significantly less ST-segment depression after
each dose of ISDN for up to 4 hours (p < 0.05). At
AP2, ST-segment depression was less pronounced
after any given dose of ISDN compared with the
placebo values (p < 0.05). The reduction in ST-
segment depression at AP2 after ISDN was apparent
for 4 hours after 15- and 30-mg doses and for 6 hours
after 60- and 120-mg doses.
Examination of individual values showed that ST-
segment depression was less pronounced both at AP1
and AP2 after any given dose of ISDN in nine of the
12 patients.
Circulatory Changes at Rest (tables 2 and 3, figs. 4 and 5)
Resting blood pressure in the supine and standing
positions was not altered after placebo 1 and 2 (figs. 4
and 5). However, after each dose of ISDN, systolic
blood pressure decreased significantly compared with
the placebo values (p < 0.001) (figs. 4 and 5). At 1
hour the reduction in systolic blood pressure was more
marked in the standing position, and this effect per-
sisted for 8 hours (fig. 5). The reduction in standing
systolic blood pressure at 4, 6, and 8 hours after ISDN
60 and 120 mg was greater than that after ISDN 15
mg (p < 0.05) (fig. 5). Similarly, reduction in systolic
blood pressure at 4 and 6 hours after 60 and 120 mg
was greater than after the 30-mg dose (p < 0.05).
 496 CIRCULATION VOL 62, No 3, SEPTEMBER 1980

TABLE 3. Analysis of Variance

Lying
DF With Without
With Without 120 120
Variable Source Error 120 120 F p F p
HR (beats/min) D D)I 4,24 3,33 1.6 NS 3.9 0.035
T IT 4,24 4,44 11.6 0.001 20.0 0.001
DT DIT 16,96 12,132 1.0 NS 1.1 NS
SBP (mm Hg) D DI 4,24 3,33 29.3 0.001 65.2 0.001
T IT 4,24 4,44 2.7 NS 4.1 0.05
DT DIT 16,96 12.132 1.2 NS 1.8 0.05
DBP (mm Hg) D DI 4,24 3,33 3.7 0.05 13.6 0.001
T IT 4,24 4,44 3.4 0.05 6.1 0.01
DT DIT 16,96 12,132 1.4 NS 1.5 NS
RPP D DI 4,24 3,33
T IT 4,24 4,44
DT DIT 16,96 12,132
Time for angina D DI 4,24 3,33
T IT 4,24 4,44
DT DIT 16,96 12,132
STI D DI 4,24 3,33
T IT 4,24 4,44
DT DIT 16,96 12,132
Abbreviations: DF degrees of freedom; AP1 time to the onset of angina; AP2 = time to the development of moderate
angina; With 120 = data in seveni patients who received 13-, 30-, 60- and 120-mg doses; Without 120 = data in 12 patients who
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received 15-, 30- and 60-mg doses; F = F ratio; I) dose; T = time; I = individual, DI, IT, DT, I)IT = interactions between
dose, time and individual; HR = heart rate; SBP systolic blood pressure; DBP diastolic blood pressure; RPP = product
of heart rate and systolic blood pressure; STI = ST-segment depression.

Compared with placebo, diastolic blood pressure
decreased after each dose of ISDN both in the supine
(p < 0.05) and standing (p < 0.01) positions (figs. 4
and 5). Resting heart rate in the supine position did
not change significantly after any of the doses of
ISDN, but was higher in the standing position com-
pared with the placebo values (p < 0.001) (fig. 5).
Circulatory Data During Exercise (tables 2 and 3; fig. 6)
Group data for heart rate and systolic blood
pressure during exercise are shown in table 2. Com-
pared with placebo, patients exercised to a higher
heart rate after any given dose of ISDN (p < 0.001),
but the values for systolic blood pressure at the onset
of AP1 or the development of AP2 did not change
significantly after any given dose of ISDN. Compared
with placebo, the rate-pressure product at AP1 in-
creased significantly after ISDN (p < 0.05), but the
values for this parameter at AP2 were similar after
placebo and ISDN.
At AP1, the rate-pressure product increased at 1
and 2 hours after the ISDN 15-mg dose, at 1, 2, 4, 6
and 8 hours after the ISDN 30- and 60-mg doses and
at l and 2 hours after ISDN 120-mg dose (fig. 6).
Discussion
Our results show that ISDN administered orally
was rapidly absorbed from the gastrointestinal tract
and exerted sustained hemodynamic and antianginal
effects. The drug produced a dose-related reduction in
resting systolic blood pressure. This effect was more
marked in the standing than the recumbent position.
The effects of the drug on treadmill walking time to
angina were, however, not dose- or plasma-
concentration-related; a single dose of 15 mg pro-
duced an improvement in exercise performance
similar to that seen after single doses of 30, 60 and 120
mg. Before these results can be put into their proper
perspective, it is necessary to examine the methods in
the present study. Patients were carefully selected and
all had stable angina pectoris. Such a selection may
impose limitations in applying the results to a broader
clinical population, but is necessary for meaningful
comparison of drug effects in such a complex clinical
syndrome as angina pectoris.
The studies involved repeated exercise testing over 3
weeks, which could have influenced the exercise per-
formance of patients owing to a training effect. This
fact was taken into account in designing the study and
during the 3-week period, each patient was studied
after placebo twice; the first placebo was administered
randomly and the second was given on the last day of
the study. The drug effects were considered significant
only if these were different from the values after both
the first and second placebos.
 ISDN FOR ANGINA/Thadani et al. 497
TABLE 3. (Continued)
Standing ATAP1 ATAP2
With Without With Without With Without
120 120 120 120 120 120
F p F p F p F p F p F p
10.7 0.001 13.1 0.001 4.7 0.01 12.5 0.001 2.9 0.0O ; 9.4 0.001
8.1 0.001 13.7 0.001 1.0 NS 1.5 NS 0.9 NM 3 1.2 NS
2.7 0.01 3.6 0.001 1.7 NS 2.0 0.05 1.6 NS3 1.8 0.05
35.4 0.001 79.9 0.001 0.2 NS 2.7 NS 1.8 NS 2.9 0.05
7.6 0.001 12.5 0.001 0.2 NS 1.6 NS 1.7 NS 4.8 0.05
1.8 0.05 4.3 0.001 1.1 NS 1.5 NS 1.1 NS 1.5 NS
6.4 0.01 18.9 0.001 2.6 NS 9.6 0.001 4.6 0.01 8.0 0.001
3.1 0.05 6.6 0.001 1.2 NS 2.4 NS 0.4 NS 0.9 NS
0.7 NS 2.6 0.01 1.2 NS 2.0 0.05 0.7 NS 0.4 NS
2.2 NS 3.8 0.05 0.4 NS 1.7 NS
0.5 NS 0.1 NS 0.7 NS 1.3 NS
1.3 NS 1.4 NS 1.4 NS 1.1 NS
11.0 0.001 13.7 0.001 7.9 0.001 9.7 0.001
8.3 0.001 11.7 0.001 8.9 0.001 12.0 0.001
0.8 NS 1.3 NS 0.7 NS 0.8 NS
0.3 NS 1.3 NS 3.6 0.05 5.9 0.01
5.1 0.01 6.2 0.001 4.8 0.01 7.6 0.001
1.4 NS 1.6 NS 1.9 0.05 2.4 0.01
A PI AP2
Downloaded from http://ahajournals.org by on February 24, 2021

500 r 500

0
a)
C,)

E 400 400
E
-5

300
30 300
C>~~~~~~~~~0 -0 15 mg

-4~~~~~30
mg1
O I
r--x cxc] 60mg ISDN

0. 120rmg
200; A
PLACEBO;1200
PLACEBO 2

0 2 46 8 0 2 4 6 8
HOURS AFTER ORAL DOSE
FIGURE 2. Duration of action of single oral doses of 15, 30 and 60 mg of isosorbide dinitrate (ISDN) in 12
patients and 120 mg in seven patients with angina pectoris. Data are mean + SEM. Compared to placebo,
walking time to the onset ofangina pectoris (AP1) and to the development of moderately severe angina pec-
toris (AP2) increased significantly after each dose (p < 0.001). This effect was apparent by 1 hour
(p < 0.001) and persisted for 8 hours (p < 0.01) after each dose. The increase in walking time to AP1 and
AP2 was similar after each dose.
 ~ ~ ~ ~X10
498 CIRCUL-ATION Voi 62, No 3. SEPTEMBER 1980
+ 250
(L)
E
+ 200
fJ~
c D
01

v
O

+150
_ E
E a-o
c) Q)
C)
Lc: +Io00
_c

Q) _O)
(n

a)
W..
Q
1 50F
,(I)
z

E-
1(a
oF[
C: 4-

50j
15 30 60 120
SDN mg
DOSE
FIGURE 3. Individual data in 12 patients after single oral doses of 15, 30, and 60 mg of isosorbide dinitrate
(!SDN) and in seven patients with angina pectoris after single doses of 120 mg ISDN. The percent change in
walking time to angina (AP1) after ISDN was calculated av.
time to AP1 after ISDN- time to AP1 before ISDN
time to AP1 before ISDN
time to AlP after placebo r__ time to AlP, before placebo
X.1.00

time to AlP1 before placebo

Maximum improvement in exercise tolerance occurred after 15 mg in six patients, after 30 mg in two and
Downloaded from http://ahajournals.org by on February 24, 2021

after 60 mg in three patients.

The study can be criticized in that the different
doses of ISDN were not administered in a random
order. Such an approach would be ideal, but in view of
the hypotensive effects of the drug, we elected, for
patient safety, to double the doses of ISDN only if no
symptomatic hypotension developed.
A truly double-blind trial in an investigation like
this, in which the active drug had effects on resting
blood pressure, which were different from the placebo,
is difficult. To minimize the bias, the investigator was
not aware of the dose sequence of ISDN admin-
istered in a given patient and the first placebo was ad-
ministered in a random order. Despite these limita-
tions, the results have important implications.
In the present study, oral ISDN was rapidly ab-
sorbed and the plasma levels increased in proportion
to the amount of the oral dose. Although the present
results cannot quantitate the extent of ISDN first-pass
metabolism, oral ISDN was not completely bio-
transformed by the liver during its passage through
the hepatic circulation. These findings are in agree-
ment with a recent report in which plasma levels
peaked at 30 minutes after a single oral dose of 5 mg
of ISDN.24
At rest, the hypotensive effects of ISDN were more
marked in the standing than in the supine position and
were greater at higher doses. These findings are in
agreement with a previous report in which the effects
of low doses (5-10 mg) and high doses (20 mg) were
studied in six patients.13 In the present study, the
hypotensive effects of oral ISDN were present at 1
hour and the effects persisted for 8 hours after any
given dose. The reduction in systolic blood pressure
was associated with a consistent increase in heart rate
only in the standing position. These findings and those
reported in previous studies13' 14 are in contrast to the
reports by Needleman and colleagues,25 who found
that nitrates administered orally or into the hepatic
vein of rats had no pharmacologic effects and
suggested that the nitrates were rapidly inactivated by
the liver enzymes of these animals.25 Our studies
suggest that in man, ISDN is rapidly absorbed after
oral administration, does not undergo complete first-
pass transformation, and exerts significant phar-
macologic effects.
Although sublingual glyceryl trinitrate prolongs ex-
ercise tolerance in patients with angina pectoris,1 the
usefulness of long-acting nitrates, including ISDN in
angina pectoris, was until recently seriously ques-
tioned.7 In one study, 10 mg of sublingual ISDN pro-
longed exercise tolerance after 10 minutes but had no
effect after 1 hour, and the drug was considered to be
no more effective than sublingual nitroglycerin.26
Many other studies showed that small doses of ISDN
 ISDN FOR ANGINA/Thadani et al. 499

140 140

15mg 1
o. 30mg S
X-_ 60mg 9SDN
I 120
x-*

......c 120 mg]

120 oa o~z PLACEBOI
PLACEBO2
m
0
c
0.
In
E to
o
In 100 _ .100 (D
0)
- c:
(P

(D
0)
a:
0 80 _ ,-,1 .80 to
ci)
I T 11..dcS,
a

.... Y,
:.=y
601 60
DIASTOLIC

P/
I I l I

0 2 48 0 6 2 4 6 8
Hours After Oral Dose
FIGURE 4. Duration of action ofsingle oral doses of 15, 30 and 60 mg of isosorbide dinitrate (ISDN) in 12
patients and 120 mg in seven patients on heart rate and blood pressure in the supine position. Data are
Downloaded from http://ahajournals.org by on February 24, 2021

mean ± SEM. Systolic (p < 0.01) and diastolic (p < 0.05) blood pressure decreased after each dose of ISDN
compared with placebo. The reduction in systolic blood pressure persisted for 8 hours after each dose. No
significant changes in heart rate occurred.

(5-10 mg) administered sublingually or orally were no
better than placebo.7 27-29 In recent studies, however,
after the oral administration of large doses of ISDN,
its pharmacologic effects on hemodynamics in patients
with heart failure persisted for 3-7 hours.81-, 30 These
reports stimulated interest in long-acting nitrates as
antianginal agents and in four recent reports, single
oral doses of 20-50 mg of ISDN were shown to
prolong exercise tolerance for 2-5 hours in patients
with stable angina pectoris.'3-18 However, in none of
these studies were the effects of different doses of
ISDN on exercise tolerance evaluated in the same in-
dividuals. In the present study, improved exercise
tolerance of 25% or more was observed in 11 patients
after a dose of 15 mg, in 1 1 patients after a dose of 30
mg, and in nine patients -after a dose of 60 mg oc-
curred. Of the seven patients who also received 120-
mg doses, exercise tolerance improved in six of seven
patients. One patient did not improve after any of the
doses. The improvement in exercise tolerance was
present at 1 hour after the oral dose, and the beneficial
effects persisted for 8 hours after each dose in the pres-
ent study. More important, near-maximum improve-
ment occurred after a single dose of 15 or 30 mg of
ISDN in the majority of patients, and little further
was gained by increasing the doses to 60 or 120 mg.
For the group, the increase in exercise tolerance seen
after the high doses of 60 and 120 mg ISDN was
similar to the increase in exercise tolerance after the
smaller doses of 15 and 30 mg. However, only seven
patients were studied after the 120-mg dose. Our data
do not provide an explanation as to why higher doses
of ISDN do not have quantitatively greater effects on
improving exercise tolerance than lower doses.
Possibly, with the doses given in the present study, one
was observing a plateau of response. Had we given
doses lower than 15 mg, we might have been able to
demonstrate the standard type of S-shaped dose-
response curve.
The improved exercise tolerance was associated
with a significant reduction in ST-segment depression
in nine of the 12 patients, a finding in agreement with
previous reports.13-16
In the present study, patients could exercise to
higher heart rates after each dose of ISDN, and these
findings are in agreement with earlier reports with this
agent in patients with angina pectoris.18318 In previous
reports, the effects of ISDN on the rate-pressure
product during exercise have been conflicting.'4
Some workers have reported higher rate-pressure
 500 CIRCULATION VOL 62, No 3, SEPTEMBER 1980

140r 140
15mg 1
*- -0
60mg -ISDN
120mg
-A PLACEBO
. PLACEBO 2 120
120 1
a)

c 0
0
0
(n
0 100 F m00
c(n)
-D (I)
Lii
rn
a:
801 -80 3
a: I
CD
I

60F 60
DIASTOLIC

L 1

0 2 4 6 8 0 2 4 6 8
HOURS AFTER ORAL DOSE
FIGURE 5. Duration of action of single oral doses of15, 30 and 60 mg of isosorbide dinitrate (ISDN) in 12
Downloaded from http://ahajournals.org by on February 24, 2021

patients and of 120 mg ISDN in seven patients on heart rate and blood pressure in the standing position.
Data are mean ± SEM. Both systolic and diastolic blood pressure decreased (p < 0.001) and heart rate
increased (p < 0.01) after each dose of ISDN compared with placebo. Reduction in systolic blood pressure
was significant for 6 hours after the 15-mg dose and for 8 hours after the remaining doses.

products,14' 16 while others have reported no change in
this parameter after ISDN compared with placebo."'
In the present study, the rate-pressure product at the
onset of angina increased significantly after ISDN
compared with the values after placebo. On the other
hand, the values of rate-pressure product at the onset
of moderate angina were similar after either ISDN or
placebo.
Heart rate and systolic blood pressure are impor-
tant determinants of myocardial oxygen requirements,
but these two variables do not take into account
the influence of ventricular volume and myocardial
contractility, which are important determinants of
myocardial oxygen requirements. Nitrates have been
shown to reduce ventricular end-diastolic volume and
dimensions in the upright position both in normal
subjects and in patients with angina pectoris.3' How-
ever, Goldstein and co-workers3' have shown that sub-
lingual glyceryl trinitrate-induced decrease in end-
diastolic dimensions diminished substantially during
exercise. In their six patients with angina pectoris,
ventricular end-diastolic dimensions during exercise
decreased substantially in two patients and by less
than 4% in the remaining four. It has also been shown
that nitrates improve systolic function in hypokinetic
segments during supine exercise32 and reduce left ven-
tricular end-diastolic pressure.33 Glyceryl trinitrate-
induced reduction in left ventricular end-diastolic
pressure may improve subendocardial perfusion and
augment collateral blood flow to the ischemic areas.3'
In the present study, and in previous studies in
patients with angina pectoris,'3- ' the effects of ISDN
on ventricular volumes, contractility or filling pressure
were not measured. Therefore, we cannot comment on
the overall effects of different doses of ISDN on the
myocardial oxygen supply-and-demand equation in
the patients studied.
Our results show that the majority of patients with
stable angina pectoris showed maximum improvement
in exercise tolerance after single oral doses of 15 and
30 mg of ISDN. Furthermore, prolonged antianginal
effects persisted for at least 8 hours after single doses
of 15, 30, 60 and 120 mg of ISDN, but a dose-response
relationship did not exist. However, in view of the
development of tolerance to the circulatory effects
during chronic therapy with nitrates,35-'2 caution
should be exercised in extending these results to
sustained therapy.
 ISDN FOR ANGINA/Thadani et al. 501

N
0

c
E
is
2501-
API

I
E
E
c-
m 200 -
U)

I 1 1 -L 0-o----0
o 15mg1
X
'9- _ -- 30mg -ISDN
0 x- --x 60mg
0 Q....C 120mgJ
-0 *- *PLACEBO
a-
L..
150j n aPLACEBO 2
I l
0 2 4 6 8 0 2 4 6 8
Hours After Oral Dose
FIGURE 6. Duration of action ofsingle oral doses of 15, 30 and 60 mg isosorbide dinitrate (ISDN) in 12
patients and of 120 mg in seven patients with angina pectoris. Data are mean + SEm. The rate-pressure
product at the onset of angina pectoris (A PJ increased at 1 and 2 hours after 15 mg, at 1, 2, 4, 6 and 8 hours
after 30 and 60 mg and at 1 and 2 hours after 120 mg compared with placebo (p < 0.01). No significant
Downloaded from http://ahajournals.org by on February 24, 2021

changes in this parameter were observed at the onset of moderately severe angina pectoris (AlP2) after any
dose.
Acknowledgment
We are grateful to Wyeth Ltd., Downsview, for the supply of
identical tablets for the different doses of ISDN and placebo and to
the nursing staff of the Cardio-Pulmonary Laboratory for their
cooperation throughout the study. We thank Ronald Ruggirello for
his excellent technical assistance in the measurement of plasma
ISDN concentrations. The help of G. Whiteside for typing the
manuscript is gratefully acknowledged.
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