From the Department of Cardiology (H.W.), KINU Medical Association
Hospital, Mitsukaido, Ibaraki, Japan; Ibaraki Prefectural University of Health
Science (M.K.), Ami, Ibaraki, Japan; and Cardiovascular Division (S.O., Y.S.),
Department of Internal Medicine, University of Tsukuba, Tsukuba, Ibaraki,
Japan.
Correspondence to Hideki Watanabe, MD, Department of Cardiology, KINU Medical Association Hospital, 13–3 Araigi-cho, Mitsukaido City, Ibaraki 303, Japan. E-mail wata-h{at}xa2.so-net.or.jp
Methods and Results—Twenty patients with congestive heart failure
were randomized to receive intravenous infusion of
nitroglycerin concomitantly with placebo (placebo
group, n=10) or intravenous ascorbate (vitamin C group,
n=10). After baseline measurements were obtained, dose titration was
started by the infusion of nitroglycerin at a rate of
0.5 µg/kg per minute (titration period). Measurements of
hemodynamic parameters and blood sampling
were performed serially at 0, 6, 12, 18, and 24 hours after the
titration period. At baseline, mean pulmonary artery pressure
(MPAP, mm Hg), mean pulmonary capillary wedge pressure
(PCWP, mm Hg), plasma vitamin E level (µmol/L), and
platelet cGMP level (pmol/109 platelets) were
comparable in the two groups (placebo group: MPAP, 48±6; PCWP, 24±4;
cGMP, 0.76±0.12; vitamin E, 18.2±1.2; vitamin C: MPAP, 49±7; PCWP,
24±4; cGMP, 0.71±0.16; vitamin E, 18.6±1.3). In both groups, at 6
hours after the titration period, MPAP and PCWP were significantly
decreased (placebo group: MPAP, 26±5; PCWP, 15±4; vitamin C: MPAP,
26±4; PCWP, 16±4), and platelet cGMP was significantly increased
(placebo group: 2.42±0.24; vitamin C: 2.26±0.26). However, at 18
hours after titration, in the placebo group, MPAP (44±5) and PCWP
(23±4) were increased, and platelet cGMP (0.85±0.20) and plasma
vitamin E levels (12.4±1.4) were significantly decreased. In contrast,
in the vitamin C group, MPAP (31±6), PCWP (17±5), platelet cGMP
(2.49±0.23), and plasma vitamin E levels (17.6±1.4) were maintained
for 18 hours after the titration period.
Conclusions—These findings indicate that ascorbate, an
antioxidant, may prevent the development of nitrate tolerance during
continuous nitrate therapy in patients with congestive heart failure.
Study Protocol
Hemodynamic Measurements
Preparation of Platelets for cGMP Assay
Platelet cGMP Assay
Measurement of Vitamin E
Statistical Analysis
Systolic blood pressure was decreased significantly in the two
groups during the titration period (vitamin C group, 143±20 to
124±18 mm Hg; placebo group, 142±20 to 120±18 mm Hg).
During prolonged infusion, systolic blood pressure was
significantly decreased 6 hours after nitroglycerin
initiation in both groups. The effect was maintained for 24 hours after
titration in the vitamin C group. However, in the placebo group,
systolic blood pressure began to increase 18 hours after
titration, and there was a significant increase in systolic
blood pressure compared with that at 0 hours after titration (18-hour
systolic blood pressure: vitamin C group, 121±20 mm Hg;
placebo group, 141±19 mm Hg) (Fig 2B
Pulmonary Artery Pressure and PCWP
Platelet cGMP Level
Plasma Vitamin E Level
Mechanisms of Nitrate Tolerance
Effect of Ascorbate on Prevention of Nitrate Tolerance
Other Studies of the Prevention of Nitrate Tolerance
Recently, the preventive effect of hydralazine on nitrate
tolerance in patients with congestive heart failure was demonstrated by
Gogia et al46 and
Elkayam.47 Münzel et
al48 showed in their study that
hydralazine could inhibit the enzyme system responsible for the
increase in superoxide anions in nitrate tolerance.
Study Limitations
Conclusions
Received September 22, 1997;
revision received October 28, 1997;
accepted November 19, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Randomized, Double-Blind, Placebo-Controlled Study of Ascorbate on the Preventive Effect of Nitrate Tolerance in Patients With Congestive Heart Failure
Abstract
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Abstract
Introduction
Methods
Results
Discussion
References
Background—Reduced cGMP
production caused by increased superoxide has been proposed as
a mechanism of nitrate tolerance during continuous nitrate therapy.
This study was designed to evaluate the effects of ascorbate, an
antioxidant, on the development of nitrate tolerance during continuous
nitrate therapy in patients with congestive heart failure.
Key Words: antioxidants • heart failure • nitroglycerin • platelets
Introduction
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Abstract
Introduction
Methods
Results
Discussion
References
Organic nitrates are
widely used in cardiovascular medicine, but their
continuous administration can result in the rapid development of
tolerance.1 2 3 The underlying mechanisms
responsible for nitrate tolerance probably are
multifactorial4 and may include neurohormonal
counterregulatory mechanisms,5 intravascular
volume expansion,6 and intrinsic abnormalities
such as desensitization of the target enzyme guanylate
cyclase7 or a decrease in
nitroglycerin biotransformation.8
Recent experimental findings have demonstrated that nitrate tolerance
is associated with increased vascular production of superoxide
anions.9 A recent study showed that tolerance was
associated with an enhanced propensity for vasoconstriction due to
increased endothelin expression within vascular smooth
muscle.10 Münzel et
al11 state that superoxide anions degrade nitric
oxide derived from nitroglycerin, whereas
autocrine-produced endothelin within vascular smooth muscle sensitizes
the vasculature to circulating neurohormones, such as
catecholamines and angiotensin II, all of which
may compromise the vasodilator potency of
nitroglycerin. Ascorbate (vitamin C) is the main
water-soluble antioxidant in human plasma.12 13
It is an effective scavenger of superoxide and other reactive oxygen
species and plays an important role in the regulation of intracellular
redox state through its interaction with
glutathione.14 The present study was
therefore designed to investigate whether ascorbate can prevent nitrate
tolerance during the continuous administration of
nitroglycerin in patients with congestive heart
failure.
Methods
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Abstract
Introduction
Methods
Results
Discussion
References
Patient Population
Twenty patients with congestive heart failure were studied after
they had given written informed consent for participation. They were
randomized to receive intravenous infusion of
nitroglycerin concomitantly with either ascorbate
(vitamin C group, n=10) or placebo (placebo group, n=10). All
vasodilators, diuretics, and inotropic agents were discontinued
at least 24 hours before the study. The clinical characteristics of the
20 patients are given in Table 1
. There
were no differences in age, sex, disease, or previous medications
between the two groups. This study was approved by the ethics
committees on human research of the University of Tsukuba and KINU
Medical Association Hospital.
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[in a new window]
Table 1. Patient Characteristics
A 7F Swan-Ganz thermodilution catheter was introduced
percutaneously through the internal jugular vein and
advanced into the pulmonary artery under fluoroscopic guidance,
and a 23-gauge polyethylene tube was inserted into the radial artery
percutaneously to measure blood pressure. A
peripheral line was inserted for infusion of
nitroglycerin and ascorbate or placebo, and a bladder
catheter was placed for urine sampling. Hemodynamic
stability (<10% variation) was ensured by two consecutive
measurements performed at 30-minute intervals. After baseline
measurements were obtained, dose titration was started by infusion of
nitroglycerin at a rate of 0.5 µg/kg per minute
(titration period). The infusion rate was doubled every 15 minutes to
achieve a 30% reduction in pulmonary capillary wedge pressure
(PCWP). After achievement of the desired hemodynamic
response, ascorbate (55 µg/kg per minute) or placebo was infused, and
the infusion rate of nitroglycerin (average, 1.5±0.5
µg/kg per minute) was maintained for 24 hours.
Hemodynamic measurements and blood sampling were
repeated 0, 6, 12, 18, and 24 hours after start of the
nitroglycerin infusion concomitant with ascorbate or
placebo. Blood samples were drawn from the right atrium for
determination of platelet cGMP and plasma vitamin E level. The
study protocol is summarized in Fig 1.
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Figure 1. Study protocol.
PCWP and pulmonary arterial pressure were
determined with the Swan-Ganz catheter connected to a pressure
transducer (BSM-8301, AP-800P; Nihon Kohden). Systolic and
diastolic arterial pressures were determined
with the 23-gauge polyethylene tube connected to the pressure
transducer. The zero pressure reference level was taken at midchest
level. Cardiac output was determined in triplicate by the
thermodilution technique. Heart rate was continuously monitored on lead
II of the ECG. All measurements were performed with the patient at the
supine position.
Blood samples were drawn into syringes containing 5
mmol/L EDTA and a cGMP phosphodiesterase inhibitor
(10-3 mol/L
2-O-propoxyphenyl-8-azapurin-6-one dissolved in 1%
triethanolamine). Platelet-rich and platelet-poor plasma were
prepared immediately after blood sampling by
centrifugation at 200g for 20 minutes.
Platelet-rich plasma was centrifuged further at
2500g for 10 minutes, and the supernatant was discarded. The
pellet was suspended in modified Tyrode's solution (containing 0.35%
bovine serum albumin and 5 mmol/L HEPES, pH 7.35) to
obtain a final platelet count of 2 to 3x106
platelets/µL. The samples were stored frozen at -70°C until
analysis.15
Trichloroacetic acid (0.5 mL at a final concentration of 6%)
was added to 1 mL of the platelet preparation. After
centrifugation at 2500g for 20 minutes,
trichloroacetic acid was extracted four times from the supernatant with
water-saturated ether. The aqueous phase then was assayed for cGMP
using a commercially available radioimmunoassay kit (Yamasa
Shoyu).16 The results are expressed in picomoles
per 109 platelets. The coefficients of
variation averaged 3.4% for intra-assay error and 11.9% for
interassay error.
Vitamin E (
-tocopherol) content in plasma was
estimated using the high-performance liquid
chromatography method of Thompson and
Hatina.17
Results are expressed as mean±SD for
hemodynamic parameters and mean±SEM for
platelet cGMP and vitamin E levels. Differences among the test days
were analyzed by repeated-measures ANOVA with Bonferroni's
test, and differences between the two groups were analyzed with
the Student's t test. Findings of P<.05 were
considered statistically significant.
Results
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Abstract
Introduction
Methods
Results
Discussion
References
Heart Rate and Blood Pressure
Heart rate did not change during the study in either group, and
there was no difference in heart rate between the two groups (Fig 2A).
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Figure 2. Changes in heart rate (A) and systolic
blood pressure (B). 
, Vitamin C group values. 
, Placebo group
values. Values are mean±SD. *P<.05 vs. 0 hour in the
prolonged infusion. §P<.05 vs. 0 minute in the
titration period.
).
Mean pulmonary artery pressure (MPAP: vitamin C group:
45±8 to 24±7 mm Hg, placebo group: 46±6 to 25±5 mm Hg)
and mean PCWP (vitamin C group: 23±5 to 17±6 mm Hg, placebo
group: 24±5 to 16±4 mm Hg) were significantly decreased during
the titration period in both groups. These effects were maintained for
12 hours after the titration period in the two groups. However, at 18
hours after the titration period, MPAP and PCWP began to increase in
the placebo group, whereas the levels in the vitamin C group were
maintained for 24 hours after titration (MPAP: vitamin C group:
31±6 mm Hg, placebo group: 44±5 mm Hg; PCWP: vitamin C
group: 17±5 mm Hg, placebo group: 23±4 mm Hg) (Fig 3).
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Figure 3. Changes in mean pulmonary artery pressure
(A) and mean pulmonary capillary wedge pressure (B). ,
Vitamin C group values. , Placebo group values. Values are mean±SD.
*P<.01 vs. 0 hour in the prolonged infusion.
P<.01 vs. vitamin C group. §P<.05
vs. 0 minute in the titration period.
Platelet cGMP level was significantly increased during
the titration period in both groups (vitamin C group: 0.74±0.15 to
2.13±0.22 pmol/109platelets; placebo group:
0.78±0.13 to 2.24±0.20 pmol/109platelets,
mean±SEM). The elevated platelet cGMP level was maintained for 12
hours after the titration period in both groups. However, in the
placebo group, platelet cGMP level was decreased 18 hours after the
titration period, whereas platelet cGMP level in the vitamin C
group was maintained for 24 hours after the titration period (vitamin C
group: 2.49±0.23; placebo group: 0.85±0.20) (Fig 4).
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Figure 4. Changes in platelet cGMP level. , Vitamin C
group values. , Placebo group values. Values are mean±SEM.
*P<.01 vs. 0 hour in the prolonged infusion.
P<.01 vs vitamin C group. §P<.05 vs.
0 minute in the titration period.
There was no difference in plasma vitamin E level between the two
groups at baseline (vitamin C group: 18.2±1.2 µmol/L; placebo
group: 18.6±1.3 µmol/L, mean±SEM). During the titration
period, plasma vitamin E level was not changed in either group. At 6 or
12 hours after the titration period, plasma vitamin E levels were not
changed in either group, and there was no difference in plasma vitamin
E level between the two groups. At 18 hours after the titration period,
plasma vitamin E level in the vitamin C group was not changed, but the
value in the placebo group was significantly decreased (vitamin C
group: 17.6±1.4 µmol/L; placebo group: 12.4±1.4 µmol/L)
(Fig 5).
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Figure 5. Changes in plasma vitamin E
( -tocopherol) level. , Vitamin C group values. ,
Placebo group values. Values are mean±SEM. *P<.01 vs.
0 hour in the prolonged infusion. P<.01 vs. vitamin C
group.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This placebo-controlled, double-blind study demonstrated that
ascorbate, a water-soluble antioxidant, maintained vasodilation and
intracellular production of cGMP during prolonged infusion of
nitroglycerin in patients with congestive heart
failure. These findings suggest that ascorbate may prevent the
development of nitrate tolerance during continuous nitrate
tolerance.
Although the phenomenon of nitrate tolerance was first described
during the early part of this century,18 it was
not considered clinically important19 until later
research demonstrated that nitrate tolerance limited the efficacy of
nitrates in patients with ischemic heart disease and congestive
heart failure.11 20 21 The mechanisms of nitrate
tolerance remain poorly defined and are likely
multifactorial.4 21 22 Several mechanisms of this
phenomenon have been proposed. Nitrate tolerance is thought to be due
to the inability of vascular tissue to respond to
nitroglycerin.23 Many previous
studies have proposed four possible mechanisms of nitrate tolerance:
(1) desensitization of the target enzyme guanylate
cyclase,7 (2) increase in phosphodiesterase
activity,24 (3) intracellular sulf- hydryl
group depletion,25 and (4) impaired
nitroglycerin
biotransformation.26 Rajagopalan and
coworkers27 recently demonstrated that enhanced
angiotensin II activity resulted in increased
production of oxygen-derived free radicals, which inhibit the
vasodilation effect of nitroglycerin-derived nitric
oxide.
Ascorbate (vitamin C) is the main water-soluble antioxidant in
human plasma.12 13 It effectively scavenges
superoxide and other reactive oxygen species, and it plays an important
role in the regulation of intracellular redox state through its
interaction with glutathione.14 Several large
epidemiological studies have suggested that dietary intake of vitamin C
and plasma vitamin C concentration is inversely associated with the
risk of ischemic heart disease.28 29 30
Recently, ascorbate has been reported to reverse
endothelial vasomotor dysfunction in the brachial
circulation of patients with coronary artery
disease31 and to improve
endothelial dysfunction in chronic
smokers.32 In an experimental animal study,
Bassenge and Fink33 demonstrated that ascorbate
prevented nitrate tolerance in the dilatation of coronary
arteries and production of platelet cGMP. We recently
reported effects of ascorbate on the prevention of nitrate tolerance in
normal volunteers.34 The present study
provides the first evidence that the development of nitrate tolerance
in patients with congestive heart failure may be prevented by
supplementation with an antioxidant, ascorbate. We demonstrate that
ascorbate prevented the attenuation of hemodynamic
effect and reduced production of cGMP during the continuous
administration of nitroglycerin in patients with
congestive heart failure. These findings strongly support the theory
that increased the production and activity of oxygen-derived
free radicals contribute to the development of nitrate
tolerance in patients who receive long-term therapy with organic
nitrates. Igarashi and coworkers35 studied the
effect of vitamin C on plasma vitamin E levels and found a
statistically significant increase in plasma vitamin E level with the
use of a vitamin E and vitamin C diet for 6 weeks. Our study also
demonstrated that plasma vitamin E (-tocopherol) level
was decreased during continuous nitrate therapy in the placebo group
and that plasma -tocopherol level in the vitamin C group
did not change during continuous nitrate therapy. Thus,
-tocopherol may be regenerated by ascorbate not only
from -tocopheroxyl radical but also from 8a-hydropheroxy
-tocopherones.36 Furthermore,
enzymatic regeneration of -tocopherol has been
reported.37 These findings suggest that the
concomitant administration of ascorbate may be effective in prevention
of nitrate tolerance in patients with congestive heart failure during
continuous nitrate therapy.
Because nitrate tolerance has the potential to limit the
therapeutic efficacy of nitrates in patients with congestive heart
failure, there has been an extensive effort to develop effective
strategies to prevent this phenomenon. Some studies have found that the
concomitant administration of ACE inhibitors and
nitroglycerin reversed or prevented nitrate
tolerance,38 39 40 41 42 but other studies have failed to
confirm these findings.43 44 Although it is
difficult to explain the differences in the efficacy of ACE
inhibitors between these studies, the use of higher doses
of ACE inhibitors may be required to inhibit
angiotensin II formation. Münzel and
Bassenge45 reported that high-dose enalapril
reversed nitrate tolerance in vivo. However, they did not evaluate the
intracellular production of cGMP. Therefore, more information
is needed to determine the clinical usefulness of ACE
inhibitors and diuretics in the prevention of
nitrate tolerance.
There are some limitations in the present study. First, we
measured platelet cGMP level to evaluate the intracellular
production of cGMP. The in vivo effects of
nitroglycerin on the intracellular production
of cGMP in vascular smooth muscle cells can be evaluated only through
biopsy. Nitroglycerin activates soluble
guanylate cyclase in platelets, and the increased level
of platelet cGMP inhibits platelet
adhesion.49 50 Platelets contain
predominantly the soluble guanylate
cyclase.51 52 Therefore, platelets are an
appropriate material for the clinical measurement of intracellular
cGMP. In a previous study, we demonstrated that platelet cGMP level
can be used as an indicator of the effects of
nitroglycerin and the development of nitrate
tolerance.15 Second, we did not investigate the
effects of other antioxidants, such as vitamin E and ß-carotene.
Vitamin E and ß-carotene may both favorably influence
cardiovascular risk, but there are several important
differences between these naturally occurring antioxidants. Vitamin C
is water soluble and present in most body fluids; vitamin E and
ß-carotene are both lipid soluble, and the concentrations of these
compounds in plasma and specific cellular compartments differ. The
primary mechanisms of these antioxidants also are distinct. Thus, the
beneficial effects observed in this study cannot necessarily be assumed
to be obtainable with other antioxidants. More recently, we reported
the preventive effect of vitamin E on nitrate tolerance in healthy
volunteers and patients with ischemic heart
disease.53 Further studies are needed to evaluate
the effect of other antioxidants on nitrate tolerance in patients with
congestive heart failure.
Our findings suggest that continuous nitrate therapy results
in a lack of hemodynamic effect and that combination
therapy with ascorbate is potentially useful for the prevention of
nitrate tolerance during continuous nitrate therapy in patients with
congestive heart failure. Further studies are required to clarify the
possible beneficial effects of antioxidants on the development of
nitrate tolerance during continuous nitrate therapy.
Footnotes
Presented in part at the 46th Annual Scientific Session of the American College of Cardiology, Anaheim, Calif, March 16–19, 1997, and published in abstract form (J Am Coll Cardiol. 1997;29:170A).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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