Vol. 282, Issue 1, H80-H86, January 2002
Alterations of endothelium-dependent and -independent
regulation of coronary blood flow during heart failure
Tomiyoshi
Saito,
Kazuhira
Maehara,
Kazuaki
Tamagawa,
Yuji
Oikawa,
Takeo
Niitsuma,
Shu-Ichi
Saitoh, and
Yukio
Maruyama
First Department of Internal Medicine, Fukushima Medical
University, Fukushima 960-1247, Japan
 |
ABSTRACT |
Conflicting data
concerning the changes in basal coronary blood flow and nitric oxide
(NO)-releasing capacity in chronic heart failure may be due to
different phases or duration of heart failure. To investigate
endothelium-dependent and -independent regulation of coronary blood
flow in different phases of heart failure, coronary pressure-flow
relationships during long diastole were obtained before and after rapid
pacing of 3 and 5 wk at 240 beats/min in 12 or 6 dogs. Neither basal
coronary blood flow nor the slope of coronary pressure-flow
relationships changed; however, zero-flow pressure increased slightly
after rapid pacing. Intracoronary injection of
NG-nitro-L-arginine methyl ester
decreased coronary blood flow at a perfusion pressure of 50 mmHg by
~20% at baseline, 55% after 3 wk of rapid pacing, and 20% after 5 wk of rapid pacing. Acetylcholine-induced increase in coronary blood
flow was maintained for 3 wk but was finally attenuated after 5 wk of
rapid pacing. In contrast, the coronary blood flow response to
adenosine gradually decreased with time. These results suggest that
basal coronary blood flow is maintained until the late stage of heart
failure, presumably by an increases in NO production during the early
stage and then by other vasodilatory substances during the late stage,
and that endothelium-dependent vasodilation via exogenously
administered acetylcholine in resistance vessels is not necessarily
impaired in the early stage despite the gradual reduction of
endothelium-independent vasodilation via adenosine in chronic heart failure.
nitric oxide; coronary circulation; microcirculation; adenosine; acetylcholine
| |
INTRODUCTION |
IT IS GENERALLY
RECOGNIZED that basal coronary blood flow is preserved until a
certain stage of heart failure by compensatory mechanisms including
systemic peripheral vasoconstriction (23, 42).
Endothelium-mediated control, particularly via production of nitric
oxide (NO), is important in the regulation of coronary circulation. A
recent clinical study (21) reported that basal release of
NO is decreased in the coronary circulation in patients with heart
failure. Other reports (18, 27), using isolated rings of
the canine epicardial coronary artery but not the small coronary vessel
from failing hearts, suggested that endothelium-dependent relaxation,
especially that mediated by increased production of NO, may serve as an
important regulatory mechanism for enhancing coronary blood flow in the
early or mild stages of heart failure. In contrast,
endothelium-dependent vasodilation is also reported to be impaired
(12, 16, 19, 34, 38). However, there are several
experimental studies (18, 27, 33) showing that agonist-induced vasodilation capacity is not necessarily impaired in
early heart failure. We (24) reported previously that
basal NO production in small coronary vessels is augmented with an
increase of coronary blood flow in dogs with pacing-induced heart
failure. However, it is unclear whether basal NO production can be
sustained until the late stages of chronic heart failure.
There is considerable evidence that coronary flow reserve,
endothelium-independent vasodilation, is diminished in chronic heart
failure (3, 23, 25, 28, 29, 36, 40-42). However, it
remains to be clarified whether the impairment of coronary flow reserve
is dependent on the severity or continuation of heart failure state.
The discrepancy in the data concerning the changes in basal coronary
blood flow and NO-releasing capacity in chronic heart failure may have
resulted from different phases or durations of heart failure.
Therefore, the purpose of this study was to investigate endothelium-dependent and -independent regulation of coronary blood
flow in different phases of heart failure using an experimental heart
failure model previously established (1, 2, 5, 18, 23, 26, 27,
30, 31, 33, 34, 38, 39).
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METHODS |
Twelve adult mongrel dogs of both sexes were used. The
experiments were carried out under the supervision of our animal
research committee in accordance with the guidelines on animal
experiments at Fukushima Medical University and the Japanese Animal
Protection and Management Law (No. 105).
Experimental preparations.
After the dogs were fasted overnight, general anesthesia was induced by
intravenous injection of 15-20 mg/kg thiopental sodium (Tanabe;
Osaka, Japan), and an endotracheal tube was inserted. With the use of a
piston-type respirator, anesthesia was maintained with a mixture of
nitrous oxide (30-40%), halothane (0.5-1.5%), and oxygen
(60-70%). The heart was exposed under sterile conditions by a
left thoracotomy in the fourth intercostal space. The proximal portion
of the left anterior descending coronary artery was dissected free, and
an ultrasonic transit time probe (type 3S, Transonic Systems; Ithaca,
NY) was inserted to measure coronary blood flow. Two screw-type
unipolar myocardial pacing leads (model 5071, Medtronic Systems;
Minneapolis, MN) were placed on the right ventricle. The pericardium
was sutured loosely. The pacing wires were embedded subcutaneously in
the back, and a permanent pacemaker equipped with DDD mode (COSMOS II,
model 284-05, Intermedics; Freeport, TX) was implanted under the skin.
Complete atrioventricular block was induced by injection of 0.1 ml
formaldehyde (37%, Wako; Osaka, Japan) into the atrioventricular node
using the method reported by Steiner et al. (32). The
heart rate was initially controlled by right ventricular pacing in the
VVI mode at 100 beats/min. The chest was closed in layers, and the
intrapleural air was evacuated. Clindamycin (600 mg, Nihon-Upjohn;
Tokyo, Japan) was given intravenously and/or intramuscularly for 3 days
after the operation. The animals were allowed to recover for at least 1 wk before the baseline study (described below) was performed.
Seven to ten days after surgery, fasted animals were placed on a
fluoroscopic table for baseline measurements. After intramuscular injection of ketamine hydrochloride (10 mg/kg), the animals were intubated and artificially ventilated as previously described. Arterial
levels of PO2 and PCO2
were kept within physiological ranges (pH 7.35-7.45;
PO2 100-150 mmHg;
PCO2 35-45 mmHg) by adjusting the volume
or frequency of respiration and administering thiopental sodium as
needed. Body temperature was kept at 37°C with a heating blanket.
Sheath introducers (8-Fr, Termo; Tokyo, Japan) were inserted into the
left carotid artery and external jugular vein for monitoring arterial
and central venous pressures, respectively (AP-641G, Nihon Koden;
Tokyo, Japan). After insertion of the introducers, a bolus of 100 IU/kg
heparin was injected, followed by 50 IU/kg hourly throughout the
experiment to prevent blood coagulation. Coronary blood flow was
monitored with a Transonic flowmeter (Transonic Systems). Left
ventricular peak systolic pressure (in mmHg) and left ventricular
end-diastolic pressure (in mmHg) were measured (AP-641G and ED-601G,
Nihon Koden) using a transducer-tipped pressure-monitoring catheter
(4-Fr, Camino; San Diego, CA) inserted from the left carotid artery
into the left ventricle. Cardiac output (in l/min) was measured by the
thermodilution technique using a Swan-Ganz catheter (model 93-121A,
7-Fr, American Edwards Laboratories; Santa Ana, CA). Right atrial
pressure (RAP, in mmHg) was also measured with the Swan-Ganz catheter.
The electrocardiograms obtained from leads II or aVF were monitored continuously.
Fluoroscopic images were obtained with a Toshiba X-ray system (model
KXO-15D). Left coronary angiography was performed in a right lateral
projection by manually injecting 2 ml of contrast medium (Hexabrix 320, Tanabe) through a 5-Fr hand-crafted right Judkins-type catheter, which
was inserted through the sheath introducer through the left carotid
artery with the help of a fluoroscopic image.
Experimental protocol.
After the pacing (100 beats/min) was stopped transiently, measurements
of diastolic coronary pressure-flow relationships were performed under
the following conditions: 1) in the control state before
drug administration, 2) after 30 min of continuous
intracoronary infusion of
NG-nitro-L-arginine methyl ester
(L-NAME; 1 mg/kg), 3) after intracoronary injection of adenosine (0.015 mg/kg) for 30 s to assess
endothelium-independent vasodilation, and 4) after
intracoronary injection of acetylcholine (0.01, 0.1, and 1.0 µg/kg)
for 30 s to assess endothelium-dependent vasodilation. The
injection was made by hand, but the injection speed was controlled
constant for administering each total dose during the time period of
30 s as precisely as possible. As a result, coronary blood flow
reached plateau within 10-15 s and was kept constant during the
remaining injection time. The dose of L-NAME was the same
as that used in our previous study (24) and depressed the
coronary blood flow responses to acetylcholine to <15% both in the
baseline and failing state.
After the cessation of pacing, a prolonged diastole (5-8 s)
occurred. Perfusion pressure and coronary blood flow were measured at
intervals corresponding to each 5-mmHg reduction after the dicrotic
notch of the arterial pressure curve. Coronary blood flows at perfusion
pressures of 40, 50, and 60 mmHg were also measured. Because atrial
contraction continued after ventricular pacing was stopped, the
influence of atrial contraction on coronary blood flow was always
observed, as shown in our previous reports (24, 26). When
the flow curve was slightly but significantly interfered by atrial
contraction, the curve was extrapolated as without atrial contraction,
because an atrial contraction-induced small flow decrease was always
followed by a small flow increase of a similar magnitude. The
arterial pressure at the time when coronary blood flow reached zero was
defined as the zero-flow pressure.
After the baseline study was completed, the pacing rate was increased
from 100 to 240 beats/min by changing the pacing mode from VVI to DDD,
and the animals were allowed to recover from anesthesia. After 3 and 5 wk of ventricular pacing at 240 beats/min, measurements were made
20-30 min after the pacing rate was reset to 100 beats/min to
avoid the direct effects of tachycardia on coronary blood flow
mechanics and to allow for a comparison with baseline data obtained at
the same rate.
Before euthanization, the same catheter used for drug administration
was advanced just distal to the flow probe, and Evans blue (10 mg/ml,
Wako) was injected through the catheter to measure the left anterior
descending coronary artery perfusion area. After euthanization, the wet
weight of the myocardium in the perfusion area was determined, and the
coronary blood flow was normalized to the flow per 100 g of left
ventricular mass. The corresponding weight of the perfusion area before
pacing or after 3 wk of rapid pacing was estimated from the following
equation using the left ventriculogram: left ventricular mass = 
/6(L'D'2 
LD2)CF3, where L is the
longest length of the long axis of the ventricular chamber,
D is the longest length of the short axis of the ventricular chamber, L' is the longest length of the long axis of the
pericardial silhouette, D' is the longest length of the
short axis of the pericardial silhouette, and CF3 is the
volume correction factor proposed by Kennedy et al. (17). Therefore, the left ventricular mass before or after 3 wk of rapid pacing = the left ventricular mass measured after death × [(L'D'2 LD2) before or after 3 wk of rapid pacing 
(L'D'2 LD2) after 5 wk of rapid pacing]. Six animals
died between 3 and 5 wk of rapid pacing. At that time, the heart was
excised as soon as possible, and the wet weight of the myocardium was
measured after the perfusion area was determined as described above.
Arterial blood was drawn to measure norepinephrine and atrial
natriuretic peptide concentrations before the hemodynamic measurements in the baseline state and ~20 min after changing the pacing rate from
240 to 100 beats/min in the posttachycardiac failure state after 3 and
5 wk of rapid pacing. The blood was collected into tubes
containing EDTA and placed on ice immediately. After centrifugation for
15 min at 3,000 rpm at 4°C, the plasma was separated and stored at
20°C. Plasma norepinephrine levels were determined by high performance liquid chromatography, and, after extraction, atrial natriuretic peptide (35) levels were determined by radioimmunoassay.
Statistical analysis.
Data are expressed as means ± SE. Complete data were collected
with 6 of 12 animals throughout 5 wk of rapid pacing; with the
remaining 6 animals, data were collected for 3 wk. Multiple comparisons
were performed using ANOVA, followed by Fisher's post hoc comparison
test. For comparison of paired data, Student's t-test was
used. A probability of P < 0.05 was considered
statistically significant.
| |
RESULTS |
Changes in hemodynamic and neurohumoral parameters.
Table 1 shows the hemodynamic data
obtained before (baseline) and after 3 and 5 wk of rapid ventricular
pacing (heart failure). Mean RAP and left ventricular end-diastolic
pressure increased significantly, and mean carotid arterial pressure
and cardiac output decreased significantly. After 3 and 5 wk of rapid
pacing, plasma norepinephrine and atrial natriuretic peptide levels
increased significantly, indicating ventricular dysfunction. Thus these data suggest that the chronic heart failure state persists from 3 to 5 wk and may even have deteriorated slightly.
Diastolic coronary pressure-flow relationships before and after
rapid pacing.
Figure 1 shows a comparison of the
coronary perfusion pressure-flow relationships and zero-flow pressures
during long diastole under control conditions obtained at baseline and
after 3 and 5 wk of rapid pacing at mean perfusion pressures of 40, 50, and 60 mmHg. Table 2 summarizes the mean
values of the zero-flow pressures and slopes of the diastolic coronary
pressure-flow relationships. The zero-flow pressure increased slightly
in the heart failure state, but the slope of the coronary perfusion
pressure-flow relationships did not change throughout the 5 wk of rapid
pacing.
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Fig. 1.
Diastolic coronary pressure-flow relationships. Zero-flow
pressures and coronary blood flows (means ± SE) at perfusion
pressures of 40, 50, and 60 mmHg under control conditions are shown at
the baseline state (n = 12), after 3 wk of rapid pacing
(n = 12), and after 5 wk of rapid pacing
(n = 6). Coronary blood flows were corrected for
myocardial weight of the left anterior descending coronary artery
perfusion area.
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Table 2.
Zero-flow pressure and slope obtained from diastolic pressure-flow
relationships under control condition
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Effects of basal NO production during progression of heart failure.
After intracoronary administration of L-NAME, a significant
increase in zero-flow pressure was observed [from 26.6 ± 1.3 to 35.2 ± 2.2 mmHg (P < 0.05) at the baseline
state, from 31.2 ± 1.2 to 40.6 ± 2.0 mmHg
(P < 0.05) at 3 wk, and from 29.1 ± 0.3 to
39.0 ± 0.8 mmHg (P < 0.05) at 5 wk of rapid
pacing], and the magnitudes of the increases were similar at each
stage. The differences in coronary blood flow at mean perfusion
pressures of 40, 50, and 60 mmHg without and with administration of
L-NAME are shown in Fig. 2.
The magnitude of the decrease in coronary blood flow after
L-NAME was larger after 3 wk than at baseline or after 5 wk
of rapid pacing at perfusion pressures of 50 and 60 mmHg, and this
trend was also observed at 40 mmHg.
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Fig. 2.
Changes in coronary blood flow after intracoronary
administration of
NG-nitro-L-arginine methyl ester
(L-NAME; 1 mg/kg, n = 12 at baseline and
after 3 wk, n = 6 after 5 wk of rapid pacing). The
differences between coronary blood flow in the nontreated condition and
after L-NAME administration at perfusion pressures of 40, 50, and 60 mmHg are shown.
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Endothelium-independent increase in coronary blood flow.
As shown in Fig. 3, intracoronary
injection of adenosine resulted in a decrease in the zero-flow pressure
[from 26.6 ± 1.3 to 22.7 ± 0.8 mmHg (P < 0.05) at the baseline state, from 31.2 ± 1.2 to 26.9 ± 1.0 mmHg (P < 0.05) after 3 wk, and from 29.1 ± 0.3 to 29.9 ± 0.5 mmHg (not significant) after 5 wk of rapid pacing]
and an increase in the slope of coronary pressure-flow relationships
[from 1.23 ± 0.12 to 6.05 ± 0.62 ml · min
1 · 100 g1 · mmHg1 (P < 0.05) at the baseline state, from 1.46 ± 0.20 to 5.32 ± 0.69 ml · min1 · 100 g1 · mmHg1 (P < 0.05) after 3 wk, and from 1.45 ± 0.16 to 5.06 ± 0.23 ml · min1 · 100 g1 · mmHg1 (P < 0.05) after 5 wk of rapid pacing]. The magnitude of the increase in
coronary blood flow induced by adenosine injection gradually decreased
with time (Fig. 4).
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Fig. 3.
Diastolic coronary pressure-flow relationships before and
after intracoronary injection of adenosine at baseline and after 3 and
5 wk of rapid pacing.
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Fig. 4.
Percent changes in coronary blood flow after adenosine
injection (coronary blood flow after adenosine injection/coronary blood
flow before adenosine injection × 100) at perfusion pressures of
40, 50, and 60 mmHg before and after 3 and 5 wk of rapid pacing.
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Endothelium-dependent increase in coronary blood flow.
The acetylcholine-induced increase in coronary blood flow at the
baseline state is shown in Fig. 5. The
slope of the coronary pressure-flow relationships increased [from
1.23 ± 0.12 to 2.38 ± 0.27 (0.01 µg/kg, P < 0.05 vs. control), 5.06 ± 0.98 (0.1 µg/kg, P < 0.01 vs. control), and 5.89 ± 0.58 ml · min1 · 100 g1 · mmHg1 (1.0 µg/kg,
P < 0.01 vs. control)] and zero-flow pressure
decreased [from 26.6 ± 1.3 to 26.3 ± 0.9 (0.01 µg/kg),
25.8 ± 1.2 (0.1 µg/kg), and 22.4 ± 1.2 mmHg (1.0 µg/kg,
P < 0.05 vs. control)] in a dose-dependent fashion.
Endothelium-dependent vasodilation was preserved until 3 wk but was
finally attenuated after 5 wk of rapid pacing (Fig. 6).
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Fig. 5.
Diastolic coronary pressure-flow relationships before and
after intracoronary injection of acetylcholine (ACh) at the baseline
state (n = 12).
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Fig. 6.
Percent changes in coronary blood flow after ACh (0.01, 0.1, and 1.0 µg/kg) injection (coronary blood flow after ACh
injection/coronary blood flow before ACh injection × 100) at
perfusion pressures of 60 mmHg before (n = 12) and
after 3 wk (n = 12) and 5 wk (n = 6) of
rapid pacing. NS, not significant.
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| |
DISCUSSION |
The present study shows that basal coronary blood flow was
maintained until the late stage of heart failure, presumably by an
increase in endogenously released NO production during the early stage
and by other vasodilatory substances during the late stage of heart
failure. In addition, endothelium-dependent vasodilation in resistance
vessels stimulated by acetylcholine injection was preserved during the
early stage, whereas there was a gradual reduction in
endothelium-independent vasodilation after the administration of
adenosine, implying that coronary flow reserve appeared to decrease
with time in chronic heart failure, probably depending on its severity.
This study was conducted with chronically instrumented animals under
general anesthesia to avoid the influence of excessive autonomic
nervous input on coronary circulation due to transient loss of
consciousness during prolonged diastole. To evaluate coronary flow
dynamics, we used the diastolic pressure-flow relationship, because it
is negligibly influenced by the effects of cardiac contraction and
metabolic regulation (11, 20) and reflects coronary
vasomotor tone (11). However, using diastolic coronary pressure-flow relationships, the following points should be considered. First, several factors, especially capacitance effect, affect the
diastolic coronary pressure-flow relationship, so not only coronary
vasomotor tone but also other factors could influence our results
(6, 11). As for the capacitance effect, the difference in
the effect dependent on the procedure between the baseline and 3-5
wk after rapid pacing might be small because we used a similar method
to obtain the diastolic pressure-flow relationships. Second, linear
extrapolation of coronary pressure-flow relationships might not be
accurate at the lower perfusion pressure range (11). Finally, because the initial coronary pressure after rapid pacing for
3-5 wk decreases moderately in this model, as pointed out previously (6), the zero-flow pressure after rapid pacing
may be slightly underestimated compared with the baseline value. In addition, values of coronary flow per 100 g of left ventricular mass of the baseline and 3 wk after rapid pacing state may be affected
by the present method for estimating the mass of the left ventricular
wall, although the percent flow changes after drug interventions were
not modified by the error in the estimation of wall mass.
Several reports (18, 27) have suggested that
endothelium-dependent relaxation, especially that mediated by increased
production of NO, may be an important regulatory mechanism for
enhancing coronary blood flow in the early or mild stages of heart
failure. However, it should be noted that these results were obtained
by using isolated rings of the canine epicardial coronary artery but
not by using coronary resistance vessels from failing hearts. In
contrast, a recent clinical study (21) showed that basal release of NO is decreased in the coronary circulation in patients with
heart failure.
We (24) reported previously that basal NO production is
augmented in small coronary vessels in the situation of increased coronary flow in dogs with 3 wk of rapid pacing-induced heart failure.
Similar enhancement of NO production in the coronary circulation may be
present in the early compensated stage of chronic heart failure even in
clinical situations, as reported for the systemic circulation in
patients with chronic heart failure (7, 9, 41). In fact, a
clinical study (10) indicated that expression of inducible
NO synthase in the ventricular myocardium increased in human heart
failure. However, our study was not designed to examine which NO
synthase is predominant in the increase in NO production or how NO
production from endothelial cells or myocardial cells, if any, affects
coronary tone in heart failure.
In this study, rapid pacing was continued for 5 wk to induce advanced
heart failure. We obtained additional information. Basal coronary blood
flow was maintained until the late stage of heart failure, partly
through an increase in NO production during the early stage, which was
expected from a greater flow reduction after the administration of
L-NAME, and from other vasodilatory substances during the
late stage of heart failure. The latter seemed possible from the
finding that the L-NAME-induced flow reduction nearly
returned to the baseline (Fig. 2) while maintaining the resting flow
constant. Further study is needed to determine which vasodilatory
substances, such as endogenous adenosine (8), adrenomedullin (14), and/or brain natriuretic peptide
(22), play an important role in the maintenance of
coronary blood flow during the late stage of heart failure. In
addition, endogenous bradykinin has been reported to increase in
congestive heart failure (5).
There is considerable evidence that coronary flow reserve,
endothelium-independent vasodilation in resistance vessels, is diminished in human chronic heart failure (3, 4, 23, 25, 28, 29,
36, 40, 42). To evaluate coronary flow reserve, exercise
(23, 42), atrial pacing (40), coronary sinus
pacing (29), and administration of dipyridamole (3,
4, 25, 28, 36) have been used. In this study, adenosine was
selected to evaluate the potential of an endothelium-independent
vasodilator. Adenosine is not a pure endothelium-independent
vasodilator that participates, in part, in endothelium-dependent
vasodilation (13). In our preliminary study,
papaverine was also used to evaluate endothelium-independent
vasodilation; because the same data were obtained as with adenosine, we
selected adenosine for this study. Several doses of adenosine were
tested in the preliminary study, and 0.015 mg/kg intracoronary
administration for 30 s was large enough to eliminate reactive
hyperemia after 10 s of coronary occlusion in the baseline and
failing states and not too large to decrease systemic aortic pressure.
Our results agree with the report by Spinale et al. (31),
in which coronary flow reserve induced by intravenous infusion of
adenosine (1.5 mg · kg1 · min1) was
diminished in tachycardia-induced heart failure. However, as far as we
know, our data are the first to show quantitatively that
endothelium-independent vasodilation in resistance vessels becomes
reduced with progression of chronic heart failure. The mechanism is
unclear, but several possibilities have been suggested from animal
studies with pacing-induced heart failure. Markedly elevated left
ventricular end-diastolic pressure causes impaired regional
subendocardial coronary flow reserve (30). Interstitial edema (2, 39), increased myocardial water content
(31) and vascular congestion (2), or medial
swelling of the intramyocardial coronary artery (39) may
impair coronary flow reserve. Further study is needed to test
these possibilities.
It has been shown that the acetylcholine-induced vasodilation capacity
of the coronary epicardial artery is enhanced in early heart failure
(18). Another experiment using the coronary
epicardial artery showed that 
2-adrenergic
agonist-induced vasodilation is enhanced by increased NO production
(27). However, clinical studies (12, 15, 16, 19,
38) have reported that endothelium-dependent vasodilation in
resistance vessels is impaired in chronic heart failure. On the other
hand, in this study using a tachycardia-induced heart failure model,
the preservation of endothelium-dependent vasodilation was finally
attenuated at the late stage of heart failure, suggesting that
endothelium-dependent vasodilation in resistance vessels might be time
dependent after heart failure. A recent study by Sun et al.
(34) showed similar findings to this study, that is,
NO-dependent coronary arteriolar dilation was not substantially altered
after 3 wk of pacing (no clear evidence of heart failure) but was
reduced after 4 wk of pacing (severe heart failure). The mechanisms as
to why NO responses changed over time are not clarified in this study,
but several reasons are plausible. At the early stage of heart failure,
the NO response is enhanced by increased functional activity of
Gi protein, which is blocked by pertussis toxin (18,
27). Moreover, activation of constitutive NO synthase, the
calcium-dependent enzyme responsible for NO production, may be enhanced
by hypertrophy and/or hyperplasia of the vascular endothelial cells or
the more efficient activity of guanylate cyclase, allowing generation
of more NO (18). Another possibility of maintenance of
endothelium-dependent vasodilation in heart failure is due to
increased production of endothelium-dependent hyperpolarizing factor
induced by acetylcholine, which is shown in coronary resistance vessels
of the failing hamster heart (37). Because heart failure
is advanced with cardiac decompensation, those high NO response become
exhausted and the NO-dependent vasodilation is reduced over time
(34). In addition, inactivation of NO by oxygen free
radicals is enhanced in heart failure (1). Further experiments are needed to clarify the reason for this phenomenon showing time-dependent changes of NO related endothelium-dependent vasodilation. However, whatever the reason, if anti-heart failure therapy is successful, it is probable that endothelium-dependent vasodilation would be reversed (15). Finally, the
discrepancies in data concerning the changes in basal coronary blood
flow and the NO-releasing capacity in chronic heart failure might be
partly due to different phases or durations of heart failure. The
present results suggest that endothelium-dependent vasodilation in
resistance vessels is not necessarily impaired in the early stage,
whereas a gradual reduction of endothelium-independent vasodilation may appear during the progression of chronic heart failure.
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ACKNOWLEDGEMENTS |
This study was supported by Grant-in-Aid for Scientific Research
08670813 from the Ministry of Education, Science, and Culture, Japan.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: Y. Maruyama, First Dept. of Internal Medicine, Fukushima Medical
Univ., Hikarigaoka 1, Fukushima 960-1247, Japan (E-mail:
maruyama{at}fmu.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12 July 2001; accepted in final form 20 September 2001.
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ABSTRACT
INTRODUCTION
