JACC Vol. 22, No.
2
August 1993:58 1 -7
Captopril Potentiates the Effects of Nitroglycerin in the Coronary
Vascular Bed
IAN T . MEREDITH, MBBS, PHD,* JEFFREY F. ALISON, MBBS, FU-MIN ZHANG, MBBS,
JOHN D . HOROWITZ, MBBS, PHD,t RICHARD W . HARPER, MBBS, FACC
Clayton, Victoria and Woodville South, South Australia, Australia
Objectives . This study was designed to examine the effects of
captopril on the coronary vascular responses to nitroglycerin .
Background. The vasodilator effects of nitroglycerin are medi-
ated by sulfbydryl-dependent bioconversion and influenced by
local and systemic neural and hormonal counter-regulatory fac .
tors.
Methods . In patients with angina pectoris, the effects of 10 days
of treatment with the sulfhydryl-containing angiotensin .
converting enzyme inhibitor captopril on the coronary vasodilator
responses to lntracoronary nitroglycerin (I- to 20-peg doses) were
examined utilising a double-blind, placebo-controlled, random-
ized design . The effects of captopril on the induction of nitroglyc-
erin tolerance were also examined after a 20-h intravenot ;a
infusion of nitroglycerin .
Results. Captopril reduced mean arterial pressure at rest by
8 mm Hg compared with 3 mm Hg in the placebo group (p = NS)
and did not affect baseline coronary blood tow (168 vs .
144 ml/min in the placebo group, standard error of the differences
of means (SED) 26) or coronary vascular resistance (53 vs .
Nitroglycerin remains the cornerstone of treatment for an-
gina pectoris in patients with coronary artery disease . How-
ever, the development of tolerance to long-acting oral,
topical and intravenous preparations is well recognized (1-5)
and clinically significant.
Endeavors to understand the mechanisms of nitrate tol-
erance have provided important insights into the cellular,
local and systemic reflex mechanisms that influence the
nitrate response . At the cellular level, the action of organic
nitrates is dependent on several factors, including the avail-
ability of reduced sulfhydryl groups, which are necessary for
the bioconversion of nitroglycerin to nitric oxide or a related
nitrosothiol compound (6) . Demonstration of the link be-
tween sulfhydryl availability and responsiveness to nitro-
From the Cardiology Department, Monash Medical Centre, Clayton .
Victoria, Australia and the (Cardiology Unit, The Queen Elizabeth Hospital,
WoodviMe South, Adelaide, South Australia . Dr. Meredith is the Ralph
Reader Travelling Fellow of the National Heart Foundation of Australia .
Manuscript received September 9. 1992 ; revised manuscript received
January 27, 1993, ac :opted February 4, 199. .
Present address and address fjr coae,saQndence : Ian T . Meredith, MBBS,
PhD . Cardiovascular Division, Brigham and Women's Hospital, 75 Francis
Street, Boston, Massachusetts 02115 .
0 1993 by the American College of Cardiology
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581
PHARMACOLOGY
57 dynesss-cm -5 , SED 9) . Intraceronary nitroglycerin increased
coronary blood flow in a dose-dependent fashion in both the
captopril and placebo groups (p < 0.001) . However, captopril
potentiated the effects of all doses of nitroglycerin and shifted the
dose-response relationship to the left (p < 0 .001). At the maximal
dose of 20 fag, intracoronary nitroglycerin Increased the coronary
blood low by a further 60% In the captopril group compared with
placebo. After 20 h of intravenous nitroglycerin (24 ± 3 pglmin),
the coronary vasodilator responses to Intracoronary nitroglycerin
were attenuated (p < 0.02) in the placebo group . However, the
responses to intracoronary nitroglycerin in the captopril group,
remained similar to the responses observed before Intravenous
nitroglycerin exposure .
Conclusions . Captopril potentiates the coronary vasodilator
responses of nitroglycerin In both the absence and the presence of
nitroglycerin tolerance . The mechanisms and therapeutic impli-
cations of this Interaction require further exploration .
(J Am Coll Cardiol 1993;22:581-7)
glycerin and other nitrates hae been observed in isolated
vascular smooth muscle preparations (7), intact animals (8,9)
and clinical studies (4,10-12) . At the systemic level, factors
such as the prevailing level of neurohormonal activation also
influence the nitrate response . Systemic nitrate therapy is
associated with biochemical evidence of an increase in
sympathetic nervous activity, activation of the renin-
angiotensin system and plasma volume expansion (13-15) . In
combination, an increase in the forces favoring vasoconstric-
tion and an increase in plasma volume may serve to attenu-
ate systemic hemodynamic responses to nitrates (16) .
These factors form the basis of the two main theories for
the mechanism or mechanisms underlying the development
of nitrate tolerance, namely that 1) it results from depletion
of critical sulfhydryl groups in vascular smooth muscle, and
2) activation of counter-regulatory neural and hormonal
forces is responsible . As a logical extension of these theo-
ries, interest has been shown in the possible role of angio-
tensin-converting enzyme inhibitors in the prevention of
nitrate tolerance and the potentiation of nitrate effects (17-
21) .
Several mechanisms exist through which angiotensin
converting enzyme inhibitors may influence the direct vaso-
0735.1097193156.00


592 MEREDITH ET AL . JACC Vol . 22 . No. 2

CAPTOPRIL POTENTIATES INTRACORONARY NITROGLYCERIN August 1993:581-7

dilator actions of nitroglycerin . Angiotensin-converting en- Table 1 . Clinical and Morphometric Characteristics of the
zyme inhibitors block the formation of the powerful Patient Groups
vasoconstrictor angiotensin II, inhibit the degradation of the Placebo Captopril
endothelium-dependent vasodilator hradylmnin and, because of Group Group
(n=5) (n=5)
the presynaptic effects of angiotensin II, have the potential to
modulate sympathetic nervous activity (22-24) . They may also Morphometric data
influence vascular tone through effects on prostaglandin syn- Maleffemale 411 5
Age (yr) 63 .0 ± 6.6 63.6 ± 4.3
thesis (25). Furthermore, the sulfhydryl-containing angioten-
Weight (kg) 88.3 ± 12 .8 94.1 ± 5.9
sin-converti enzyme inhibitor captopril may potentiate nitro-
Body surface area (m2 ) 2 .06 ± 0,17 2 .15 ± 0.06
glycerin through donation of its sulfhydryl moiety in a fashion Clinical characteristics
sir, iler to N-acetylcysteine in vivo (4,10-12) . Duration of angina (yr) 3 ± t,5 2.1 ± 0.8
All but one in vitro study (17) that examined the interac- Positive exercise test result 4 3
tions of angiotensin-converting enzyme inhibitors and or- Previous Ml 3 2
ganic nitrates have concentrated on systemic hemodynamics Hypercholesterolemia 2 2
rather than the corn ary vasodilator effects (18-21), The Diabetes mellitus 1 0
Hypertension 3 2
purpose of the present study,, therefore, was to determine
Smoking I 2
whether the thiol-containing angiotensin-converting enzyme Medications
inhibitor captopril might oientiate the direct effects of Calcium channel blocking agents 4 3
nitroglycerin on the coronary vascular bed in humans, and Beta-adrcnergic blocking agents 2 3
prevent or impair the development of nitrate tolerance in the Long-acting nitrates* 3 3
same vascular bed after continuous intravenous exposure to Aspirin 4 4
nitroglycerin . *Either oral or topical nitrate preparations . Data arc expressed as numb,:r
of patients or mean value ± SD. Ml = myocardial infarction .

Methods
Study pates. Ten patients (nine men and one woman)
were recruited from those awaiting elective cardiac cathe-
terization for investigation of coronary artery disease . Their
ages ranged from 54 to 70 years (mean 63) . Patients previ-
ously receiving angiotensin-converting enzyme inhibitors
ware excluded from the study, as were patients with unsta-
ble angina, recent myocardial infarction (within 6 weeks),
valvular heart disease, severe hypertension or significant
disease affecting other organ systems, such as renal or liver
disease, Their clinical characteristics are described in
Table 1 . Written informed consent was obtained from all
patients in accordance with the guidelines established by the
Human Research and Ethics Advisory Committee, Monash
Medical Centre, Melbourne, Australia .
Stuffy din and protocol . A double-blind, placebo-
controlled, randomized design was employed to test whether
oral captopril therapy could potentiate the effects of intra-
coronary nitroglycerin on coronary blood flow in the ab-
sence of prior nitrate exposure and inhibit the development
of nitrate tolerance after a 24-h infusion of intravenous
nitroglycerin (Fig . 1).
After recruitment, patients were randomized to receive
either captopril (Capoten, Bristol-Myers Squibb) or placebo
(Bristol-Myers Squibb) for 10 days before their diagnostic
catheterization. The randomization, packaging and dispens-
ing of tablets was carried out by the Monash Medical Centre
Pharmacy. Patients we : instructed to begin therapy by
taking 0 .25 tablet (6.25 mg of captopril for those taking the
active preparation) three times a day on day I and 0 .5 tablet
(12.5 mg of captopril) on the subsequent 2 days . All patients
were examined on day 3 for possible adverse reactions and
to record supine and standing blood pressures . Because no
patient exhibited symptomatic postural hypotension or other
significant side effects, all patients began the maintenance
dose of one tablet three times a day (25 mg of captopril) on
day 4 . Supine and standing blood pressures were recorded
again on the day of hospital admission . The mean duration of
therapy before cardiac catheterization was 9 .5 days (range 7
to 13) . Patients were asked to refrain from using long-acting
nitrate preparations such as oral isosorbide dinitrate or
transdermal nitrate preparations i,)r 12 h before cardiac
catheterization . Calcium channel antagonists and beta-
adrenergic receptor blockers were also withheld for 12 h
before the study. Cardiac catheterization was performed in a
fasting state and all patients received standard premedita-
tion of 10 mg of oral diazepam .
Intracoronary nitrglyerin . Left heart catheterization
and coronary angiography were performed from a right
femoral artery approach in nine patients and from the right
brachial artery in one patient . Four doses of nitroglycerin
(1, 5, 10 and 20 µg) were given selectively into the left
coronary artery after exclusion of significant left main ste-
nosis or critical proximal disease of the left anterior descend-
ing artery . Nitroglycerin (5 mg/ml, Tridil, DuPont Critical
Care) was diluted in 5% dextrose and each dose was given as
a 2-ml bolus injection from a 2-ml glass Luer-Lok syringe
connected directly to the left coronary catheter by means of
a three-way stopcock . Each injection was followed by a
further 2-ml bolus injection of 5% dextrose in water to
account for the "dead space" of the catheter (previously
measured to be 2 ml) . The order of the intracoronary doses
of nitroglycerin was randomized to minimize the cumulative

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JACC Vol . 22, No . 2
August 1993 :551-7 CAPTOPRIL POTENTIAT^S INTRACORONARY NITROGLYCERIN
Figure 1 . Schematic representa-
tion of the study design illustrat-
ing the randomization phase and
the intracoronary nitroglycerin
(IC-NTG) protocol utilized be-
fore and after the overnight in-
travenous infusion of nitroglyc-
erin (1-, 5- . 10- and 20-,ug bolus
doses given in a randomized
fashion to prevent cumulative
dose effects) . Coronary sinus
blood flow responses (CSBF)
were recorded before, immedi-
ately after and 90 s after each
intracoronary dose. BP = blood
pressure ; HR = heart rate .
dose effect and time-dependent influences . An interval of
3 min elapsed between each dose of nitroglycerin . Coronary
angiography was completed after the intracoronary infusion
protocol . Left coronary artery pressure and femoral artery
pressure were monitored continuously during the procedure .
Coronary sinus flow measurements . A 7F coronary sinus
thermodiluwioo catheter (Webster Laboratories type CCS-
7U-90B) interfaced with a Webster CF-300 Flowmeter was
used to measure coronary sinus blood flow . Catheterization
of the coronary sinus was performed under fluoroscopic
control from a left subclavian venous approach . Correct
positioning of the catheter 2 to 3 cm from the coronary sinus
orifice was verified by infusion of 5 ml of nonionic contrast
medium (lopamiro, Schering) and recorded on cut film using
digital subtraction angiography . This record scrod, to guide
the positioning of the catheter for the second study 24 h
later .
Coronary sinus blood flow was determined using rapid
infusions of room temperature 5% dextrose in water until
equilibrium was reached (26) . A minimum of three baseline
flow measurements were recorded after selective left coro-
nary catheterization and before the intracoronary injections
of nitroglycerin. Coronary sinus blood flow responses to
intracoronary nitroglycerin were recorded immediately be-
fore injection for 30 s after the injected dose and again 90 s
after each dose . Each flow was recorded on a multichannel
chart recorder (Nihon Kohden, model WS-180G) and labeled
with an alphabetic code to minimize bias in analyzing flow
responses . Chart records were analyzed subsequently by an
independent observer unaware of the dose given or the
patient's exposure to intravenous nitroglycerin . Effects of
nitroglycerin are expressed as the change in coronary sinus
flow 30 s after intracoronary nitroglycerin injection .
Intravenous nitroglycerin . On completion of the initial
intracoronary protocol, diagnostic coronary angiography
was performed and the patient was transferred to the coro-
nary care unit for approximately 24 h of intravenous nitro-
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MEREDITH ET AL . 583
29Y9
m
20M
a
.
0 ~
a
t i
CsBF
BP IHR
glycerin therapy and hemodynamic monitoring . Intravenous
nitroglycerin (100 pg/ml solution in 5% dextrose in water in
a glass bottle) was delivered by an infusion pump (1VAC 591
Star Flow volumetric pump) to a peripheral vein under
continuous arterial pressure and electrocardiographic moni-
toring. ':tie infusion was initiated at 5 jig/min and increased
by 5 tg/min every 5 min until an infusion rate of 25 µg/min
was achieved . This was subsequently titrated against arterial
blood pressure to a maintenance infusion rate that produced
either a decrease in systolic blood pressure of approximately
25% of the initial supine level or a systolic pressure of
95 mm Hg . After baseline intraarterial measurements and
initial stabilization of the intravenous infusion, heart rate and
arterial blood pressure were recorded hourly, as was the
average nitroglycerin infusion rate .
To minimize compounding effects of oral captopril and
intravenous nitroglycerin on blood pressure (which could
have potentially limited the dose of nitroglycerin received by
the patients taking active captopril), each scheduled dose of
the trial medication was given as two half-doses separated by
I h during the period of nitroglycerin infusion . All patients
returned to the cardiac catheterization laboratory for a
repeat intracoronary nitroglycerin study after 20 ± 2 .5 h
(mean ± SD) of intravenous nitroglycerin infusion . Intrave-
nous nitroglycerin was discontinued 30 min before the
second intraeoronary study .
Data analysis and statistical methods. Statistical analysis
of the data was performed by an independent consultant
statistician . Analyses were achieved using the statistical
package Genstat 5, version 2 .1 (Payne, 1987) on a Vax VMS
mainframe computer . The between-group comparison (cap-
topril vs . placebo) for hemodynamics at rest, coronary sinus
blood flow and coronary vascular resistance were performed
using a one-way analysis of variance (ANOVA) . Similarly, the
between-group comparison of the duration of intravenous
nitroglycerin, total dose of intravenous nitroglycerin received
and average effect on blood pressure were analyzed by one-


584 MEREDITH ET AL . JACC Vol . 22, No. 2

CAPrOPRIL POTENTIATES INTi ACORONARY NITROGLYCERIN August 1993 :581-7

way analysis of variance . Results were expressed as mean Table 2. Captopril Effects on Sedentary Blood Pressure and
value ± standard error of the differences of means (SED) . Heart Rate
The effects of captopril on intracoronary nitroglycerin- Placebo Captopril
induced changes in coronary blood flow and coronary Group Group SED
vascular resistance (within-patient, between-dose effects) Baseline
before and after exposure to intravenous nitroglycerin (be- SBP (mm Hg) 138 157 11
tween-day effects) were examined by nested analyses of DBP (nun Hg) 73 84 5
MAP (mm Hg) 95 l08 6
variance . Because absolute coronary sinus flow increased in
HR (bratsimin) 68 f6 3
a time-dependent fashion during the course of the intracor-
Day 3 (dose titration)
onary infusion protocol and varied between group and day, SBP (mm Hg) 132 152 8
responses to intracoronary nitroglycerin were expressed as a DBP (mm Hg) 72 78 5
percent change from baseline flow measurement recorded MAP (mm Hg) 92 103 4
immediately before each dose . The percent change in flow HR (beats/min) 65 66 3
and coronary vascular resistance was analyzed using a Day 10 treatment
SBP (mm Hg) 136 145 7
nested analysis of variance . The null hypothesis was rejected
DBP (mm Hg) 70 75 3
at p < 0 .05 .
MAP (mm Hg) 91 too 4
HR (beats/min) 70 66 3
Difference'
Results
A SBP (mm Hg) -2 -9 3
Patients were sufficiently well randomized to the capto- A DBP (mm Hg) -3 -7 2
pril and placebo treatment groups for there to be no signifi- A MAP (mm Hg) -3 -8 3
cant differences between groups in age, weight, body surface A HR (beats/min) -2 0 1
area, duration of symptoms, history of previous myocardial "Absolute difference (A) between baseline and day 10 of treatment . p =
infarction, burden of coronary artery disease (by qualitative NS for aft variables. DBP - diastolic blood pressure ; HR = hear rate ;
coronary angiographic appearance) and type and number of MAP = mean arterial pressure ; SBP = systolic blood pressure ; SED =
standard error of the differences of mean values .
antianginal medications taken (Table 1) . Although baseline
blood pressure at rest appeared to be higher in the group
randomized to receive captopril, the differences did not
reach statistical significance (systolic blood pressure 157 vs . intracoronary nitroglycerin was greater in the captoptil
138 mm Hg in the placebo group, SED 11 mm Hg ; diastolic group (p < 0 .005). At the 20-Mg dose, coronary vascular
pressure 84 vs . 73 mm Hg, SED 5 mm Hg captopril vs . resistance was reduced by 27 .6% compared with 18% in the
placebo, respectively) (Table 2). placebo group (SED 3 .2%, p < 0.005) .
After 10 days of treatment, blood pressure at rest was Nitroglycerin infused intravenously (mean Late 25 and
23 4ntin, respectively, SED 3 ftg/min) after the initial
9/7 mm Hg lower in the captopril group compared with
intracoronary study resulted in virtually identical arterial
2/3 mm Hg lower in the placebo group (SED 3/2 min Hg, p =
NS) (Table 3) . At the initial cardiac catheterization, there pressures in both groups but a greater average decrease in
were no significant between-group differences in mean arte- mean arterial pressure during the course of the infusion in
rial pressure, heart rate or left ventricular end-diastolic the captopril group (mean difference 28 v3 . 19 mm Hg in the
pressure (Table 3). Captopril treatment did not affect coro- placebo group, SED 3 min Hg, p < 0 .02) (Table 4) . How-
nary blood flow at rest (168 vs . 144 mUmin in the placebo ever, at repeat cardiac catheterization, 30 min after discon-
group, SED 26 ml/min) or coronary vascular resistance (57 tinuation of intravenous nitroglycerin, blood pressure was
vs . 53 dynes•s-cm° s , SED 9 dynes-s-cm -1 ) .
Elects of captwll on intracoronary nitreglycedn . To the
Table 3. Captopril Effects on Hemodynamics at Rest During
absence of prior nitrate exposure, intracoronary nitroglyc-
Initial Cardiac Catheterization
erin (1 to 20 pg) increased coronary blood flow in a dose-
dependent fashion, with a threshold effect at or below I µg in Placebo Captopril
Group Group SED
both the captopril and placebo groups (p < 0 .001) (Fig . 2).
Captopril, however, potentiated the effects of intracoronary SBP (mm Hg) 138 151 19
nitroglycerin and shifted the dose-response relationship up- DBP (mm Hg) 74 87 9
ward and to the left (p < 0 .001, SED 5% for the within-dose, MAP (mm Hg) 100 108 12
HR (beatslmin) 68 66 4
between-group comparison) . At the maximal dose of intia
LVEDP (mm Hg) 13 16 4
coronary nitroglycerin tested (20 µg), captopril increased the Coronary sinus blood Now (ml/min) 144 168 40
coronary blood flow response by 60% compared with pla- Coronary vascular resistance 57 53 9
cebo (34.6% vs. 21% increase in flow, SED 5%) . In accor- (dynes'scm 5 )
dance with the coronary blood flow responses, the percent p = NS for all variables . LVEDP = left ventricular end-diastolic pressure ;
reduction in coronary vascular resistance for a given dose of other abbreviations as in Table 2 .

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JACC Vol. 22, No. 2
August 1993 :581-7
0 5 10 15 20
Dose of IC-NM (ug)
Figure 2 . Dose-response curves showing the effects of captopril
treatment (squares) and placebo (circles) on the coronary blood flow
responses (percent change from baseline flow) to I-, 5-, 10- and
20-µg bolus doses of nitroglycerin given directly into the left main
coronary artery (IC-NTG) . SED = standard error of the difference
for the within-group, between-dose comparisons .
similar in the captupril and placebo groups (142176 vs .
140173 mm Fig, SED 2019 mm Hg) . The 9111 mm Hg decrease
in blood pressure between days in the captopril group did not
reach significance (SED 615 mm Hg for the within-group,
between-day comparison).
Effects of captopril on nitroglycerin toleu-ance . Coronary
blood flow at rest (187 mUmin in the captopril group vs .
180 mUmin in the placebo group, SED 30 ml/min) and
coronary vascular resistance (42 vs . 45 dynes-s-cm' -S , SED
12 dynes-s-cm 5 ) after intravenous nitroglycerin were similar
in the captopril and placebo groups . However, coronary
blood flow responses to intracoronary nitroglycerin were
attenuated in the placebo group after exposure to intrave-
nous nitroglycerin . The increases in coronary flow observed
with the 1-, 5-, 10- and 20-µg doses of intracoronary nitro-
glycerin were reduced by 46%, 22%, 39% and 35%, respec-
tively, in the placebo group (Fig . 3). Although the attenua-
tion was sizable, only the differences in the coronary blood
flow response to the 10- and 20-µg doses of intracoronary
Table 4. Between-Group Comparison of Infusion Rate, Duration
and Effect of Intravenous Nitroglycerin
Placebo Captopril
Group Group
Total duration (hr) 19.6
Mean infusion rate (E:glmin) 23
Total NTG dose (mg) 29.7
Average blood pressure during infusion period
UP (nun FIB) 110 112
D111' (nun Fig) 66
MAP (nun Hg) 81
19
Average decrease in MAP from baseline
(mm Hg)*
Average increase in HR (beats/min) 10
*p = 0 .02; p = NS for all other variables. NTG = nitroglycerin ; other
abbreviations as in Table 2 .
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MEREDITH ET AL. 585
CAFTOPRIL POTENTIATES INTRACORONARY NITROGLYCERIN
SED
Captopril
36 Z
a
30
I
® s
24
6a V*
0 ®. g
d
Placebo
0
0 5 10 15 20
Dose of IC-NTG (ug)
Figure 3. Dose-response curves showing coronary blood flow re-
sponses (percent change from baseline flow) to the four doses of
intracoronary nitroglycerin (lC-NTG) in the captopril group
(squares) and placebo group (circles) before (closed symbols) and
after (open symbols) 24 h of intravenous nitroglycerin exposure .
SED = standard error of the difference for the within-group,
between-day comparisons of dose effects .
nitroglycerin reached significance (17% vs . 10% and 22% vs .
14% for the day 1 vs . day 2 comparison of the 10- and 20-µg
doses, respectively, SED 3%, p < 0 .02) . In the captopril
group, coronary blood flow responses to the graded doses of
intracoronary nitroglycerin did not differ from those ob-
served before intravenous nitroglycerin exposure . With re-
spect to the maximal dose of intracoronary nitroglycerin
tested, coronary blood t#ow increased by 34 .6% before and
31% after the intravenous nitroglyc°rin infusion (SED 7 .5%
for the within-group, between-day comparison) . The poten-
tiating effect of captopril was therefore maintained after
intravenous nitroglycerin .
Discussion
In this study, we examined the capacity of oral captopril
therapy to influence the effects of intracoronary nitroglyc-
erin both in the absence and in the presence of previous
nitrate exposure. Captopril was chosen because many of the
factors known to potentiate the action of or prevent toler-
ance to organic nitrates, including the availability of reduced
suffhydryl groups, could potentially be influenced by a
thiol-containing angiotensin-converting enzyme inhibitor .
SED The dire : coronary vasodilator effects of nitroglycerin were
21 1 .6 examined because previous studies on nitrate potentiation
25 3 and tolerance have generally concentrated on the systemic
26.4 2 .9 hemodynamic effects of nitrates . In part, this emphasis has
resulted from the belief that the predominant mechanism by
7
which nitrates relieve myocardial ischemia is dilation of the
65 5
systemic veins and, to a lesser extent, arteries, with attend-
81 3
28 3
ing reduction in ventricular preload and afterload .
The ischemia-relieving mechanism of nitrate depends,
2 4 however, on the clinical situation, the extent of coronary
atherosclerosis and the dose and route of nitrate administra-
tion (27,28) . In addition to diminishing myocardial oxygen

MEREDITH ET AL .
586
CAPTOPRIL POTENTIATES INTRACORONARY NITROGLYCERIN
demand through alterations in preload and afterload, nitro-
glycerin is capable of enhancing myocardial oxygen supply
by directly dilating smooth and stenotic coronary arteries
and by increasing subendocardial and collateral blood flow
(29-31) . Investigation of an agent thought to potentiate the
action of nitrates or inhibit nitrate tolerance in the setting of
coronary artery disease should therefore include examina-
tion of its influence directly on the coronary vascular bed .
Captopril and nitroglycerin potentiatlon . We observed
that captopril did not influence either resting coronary sinus
blood flow or resting vascular resistance . This finding is
consistent with results of previous investigations (32) in
patients with angina pectoris and presumably reflects the
interaction between ventricular unloading and the direct
reduction in coronary vasomotor tone . However, captopril
therapy did potentiate the acute coronary vasodilator effects
of intracoronary nitroglycerin in the absence of previous
nitrate exposure . This potentiation was preserved after
exposure to intravenous nitroglycerin (24 ± 3 aglmin)-an
infusion rate sufficient to induce partial tolerance to the
effects of intracoronary nitroglycerin in patients receiving
placebo therapy .
A factor of considerable importance was the choice of
dosing regimen for intracoronary nitroglycerin, which in-
cluded the steep region of the dose-response curve, as
previously shown by Vekshtein et al . (33) in large human
epicardial coronary arteries . This permitted the detection of
relatively small shifts in sensitivity to nitroglycerin, which
might have been more difficult had larger doses been used, as
in some previous studies (4,11) .
Nitroglycerin tolerance. One important aspect of the re-
sults was the induction of nitroglycerin tolerance itself . A
shift approaching one order of magnitude in the dose-
response curve for intracoronary nitroglycerin was produced
by infusion of 23 ± 4 pglmin for 20 h in the placebo group .
This finding is consistent with the results of previous inves-
tigators (4,5,34) who, in general, utilized somewhat higher
infusion rates of nitroglycerin for tolerance induction,
whether detected by means of systemic or coronary hemo-
dynamic effects . The choice of a relatively low infusion rate
for the induction of nitroglycerin tolerance partially reflected
concern that greater rates of infusion might have induced
significant hypotension in patients in whom captopril was
coadministered . At the intravenous nitroglycerin infusion
rate chosen, them was in fact a slightly greater decrease in
blood pressure in the captopril group. Our demonstration of
tolerance development at the level of the coronary circula-
tion with infusion rates of nitroglycerin commonly used to
made unstable angina pectoris (35) reinforces previous
suggestions that maintenance of the therapeutic effects of
continuously administered nitroglycerin may require use of
low infusion rates or the concomitant administration of other
agents to circumvent tolerance development .
After intravenous administration of nitroglycerin, there was
no significant decrease in the response to intracoronary nitro-
glycerin in the captopril-treated patients (that is, there was no
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JACC Vol . 22, No. 2
August 1993:581-7
attenuation of captopril potentiation in the presence of nitrate
tolerance) . It is possible that this may represent a type II error
resulting from small numbers of patients or the relatively small
shift in the nitroglycerin dose-response curve induced by prior
exposure to nitroglycerin, or both. Conversely, it is not certain
from previous studies (9-11,34) whether the phenomenon of
potentiation of nitroglycerin responses by sulfhydryl-
containing drugs such as N-acetylcysteine exhibits any speci-
ficity for induction of nitroglycerin tolerance .
Possible mechanisms of the captopril-nitroglycerin inter-
action. The mechanism of interaction between captopril and
nitroglycerin was not explored in this study. Previous inves-
tigations in isolated coronary vasculature (17) have sug-
gested that the interaction between captopril and nitrates is
mediated by changes in the sulfhydryl availability ; however,
studies in normal volunteers (21) have suggested that both
captopril and the nonsulfhydryl angiotensin-converting en-
zyme inhibitor enalapril limit tolerance to nitroglycerin .
Furthermore, captopril appears to be ineffective in limiting
the attenuation of the systemic hemodynamic effects of
nitroglycerin in patients with congestive heart failure (18,19) .
Angiotensin-converting enzyme inhibitors have the po-
tential to influence a variety of factors that may in turn
influence the response to nitroglycerin . Apart from their well
documented influences on the renin-angiotensin system and
sympathetic nervous system, evidence (23,24) now indicates
that angiotensin-converting enzyme inhibitors also influence
endothelium-dependent relaxation, in part by preventing the
degradation of bradykinin . Angiotensin-converting enzyme
inhibitors have been reported (25) to stimulate vascular
prostacyclin synthesis and to interfere with the lipooxygen-
ase pathway . Further investigations are therefore required
to delineate the various possible biochemical and neuro-
humoral factors that may be involved .
The two theoretic "sulthydryl-specified" mechanisms
whereby captopril might interact with nitroglycerin involve
1) potentiation of nitroglycerin bioconversion to nitric oxide
by means of a sulfhydryl-dependent initial denitration step
(36), which appears to be the major site of development of
tolerance to nitroglycerin (37), or 2) formation of a potent
vasodilator S-nitrosothiol ("SNOCAP") from nitric oxide
and captopril (38), or both. Similar mechanisms appear to
be responsible for the interaction between nitrates and
N-acetyicysteine (8), which by virtue of its lack of intrinsic
vasodilator effects can be administered in considerably
greater doses than captopril (4,15,37) . Although there is no
evidence to suggest that the incremental activation of soluble
guanylate cyclase by either N-acetylcysteine or captopril in
humans is proportional to their respective sulfhydryl con-
tent, this hypothesis might be effectively explored utilizing
an isomer of captopril devoid of angiotensin-converting
enzyme inhibitor effects (for example, SQ 14,534) . This type
of investigation as well as substitution of captopril with a
nonsulfhydryl angiotensin-converting enzyme inhibitor
would facilitate the evaluation of the possible mechanisms
underlying the effects of angiotensin-converting enzyme

JACC Vol . 22, No . 2
August 1993:581-7 CAPTOPRIL POTENTIATES INTRACOR©NARY NITROGLYCERIN
inhibition on the responses to nitroglycerin within the coro-
nary vascular bed . The latter issue was raised by the recent
findings of Dupuis et al . (16,19) related to activation of
neurohumoral mechanisms during induction of nitrate toler-
ance in patients with congestive heart failure .
Conclusions . The results of this study may be of consid-
erable clinical significance . Potentiation of the coronary
vasodilator effects of nitroglycerin by captopril, an effect
previously demonstrated with N-acetylcysteine (4,11), may
lead to beneficial anti-ischemic effects in patients with un-
stable angina, particularly if there is simultaneous augmen-
tation of the antiaggregatory effects of nitroglycerin on
platelets (39) . The potential utility of the coadministration of
nitroglycerin and captopril in patients with unstable angina
therefore merits clinical investigation.
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