© 1998 American Heart Association, Inc.
Original Contributions |
ATP-Sensitive K+ Channels, Adenosine, and Nitric Oxide–Mediated Mechanisms Account for Coronary Vasodilation During Exercise
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.
Correspondence to Robert J. Bache, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail Bache001{at}maroon.tc.umn.edu
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Abstract |
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Abstract—We previously reported that combined blockade of adenosine receptors and ATP-sensitive K+ channels (K+ATP channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K+ATP channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K+ATP channel blockade with glibenclamide (50 µg · kg-1 · min-1 IC) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg IV), and after the addition of the NO synthase inhibitor NG-nitro-L-arginine (LNNA, 1.5 mg/kg IC). During control conditions, coronary blood flow was 49±3 mL/min at rest and increased to 92±8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K+ATP channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K+ATP channel and adenosine blockade decreased resting coronary flow to 27±3 mL/min (P<.05), but exercise still increased flow to 45±5 mL/min (P<.05). The subsequent addition of LNNA further decreased resting coronary flow to 20±2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20±0.03 mL · min-1 · mm Hg-1 at rest versus 0.24±0.04 mL · min-1 · mm Hg-1 during the heaviest level of exercise; P=.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K+ATP channels are critical for maintaining coronary vasodilation at rest and during exercise but that when K+ATP channels are blocked, both adenosine and NO act to increase coronary blood flow during exercise. In the presence of combined K+ATP channel blockade and adenosine receptor blockade, NO was able to produce approximately one quarter of the coronary vasodilation that occurred in response to exercise when all vasodilator systems were intact.
Key Words: blood flow • endothelium • K+ channel • ischemia • reactive hyperemia
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Introduction |
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Recent evidence indicates that hyperpolarization of the vascular smooth muscle cell membrane caused by opening of K+ATP channels is an important mechanism for metabolic coronary vasodilation.1 We previously reported that blockade of vascular smooth muscle K+ATP channels in chronically instrumented dogs decreased resting coronary blood flow but did not attenuate the increase in flow that occurred in response to treadmill exercise.2 However, after K+ATP channel blockade had been established, the subsequent addition of adenosine receptor blockade reduced the exercise-induced increase in coronary flow by more than half,3 indicating increased importance of adenosine in causing metabolic vasodilation after K+ATP channels are blocked. Nevertheless, even after the combination of K+ATP channel blockade and adenosine receptor blockade, exercise still produced a substantial increase in coronary flow.
Bernstein et al4 have reported that exercise causes increased NO production across the coronary circulation. We have previously observed that NO contributes to coronary vasodilation distal to a coronary artery stenosis, which results in hypoperfusion during exercise.5 It is possible that NO could similarly contribute to coronary vasodilation when K+ATP channel and adenosine receptor blockade have resulted in myocardial hypoperfusion during exercise. We consequently hypothesized that failure of the combination of adenosine receptor and K+ATP channel blockade to abolish coronary vasodilation in response to exercise could be accounted for by increased importance of endothelium-derived NO. To test this hypothesis, we examined the effect of NO synthase inhibition after the combination of adenosine receptor and K+ATP channel blockade on the increase in coronary blood flow produced by treadmill exercise in chronically instrumented dogs. To assess the hierarchy of importance of these three vasodilator systems, we also examined the effects of NO synthase inhibition alone and in combination with adenosine receptor blockade on exercise-induced coronary vasodilation in the absence of K+ATP channel blockade.
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Materials and Methods |
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Studies were performed in 31 adult mongrel dogs weighing 20 to 27 kg and trained to run on a motor-driven treadmill. All experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication 93–23, revised 1985) as approved by the Council of the American Physiological Society and with prior approval of the Animal Care Committee of the University of Minnesota.
Surgical Preparation
After sedation with acepromazine (0.5 mg/kg IM), dogs were
anesthetized with sodium pentobarbital (30 to 35 mg/kg IV),
intubated, and ventilated with a mixture of oxygen (30%) and room air
(70%) to maintain arterial blood gases within the
physiological range. A left thoracotomy was
performed in the fifth intercostal space, and a polyvinyl chloride
catheter (outer diameter, 3.0 mm) filled with heparinized saline
was inserted into the internal thoracic artery and advanced into the
ascending aorta. The heart was suspended in a pericardial cradle, and
catheters were introduced into the left atrium through the atrial
appendage and into the left ventricle through the apical dimple. A
solid-state micromanometer (model P5, Konigsberg
Instrument Co) was also introduced into the left ventricle at the apex.
A final catheter was introduced into the right atrial appendage,
manipulated into the coronary sinus ostium, and advanced into
the great cardiac vein until the tip could be palpitated within 1 cm of
the interventricular sulcus to allow selective sampling of
coronary venous blood draining the myocardium
perfused by the LAD. Approximately 1.5 cm of the proximal LAD was
dissected free, and a Doppler velocity probe (Craig Hartley) was
positioned around the artery. Immediately distal to the velocity probe,
a hydraulic occluder was placed around the vessel. A silicone catheter
(inner diameter, 0.3 mm) bonded to a larger silicone catheter
(inner diameter, 1.6 mm) was introduced into the LAD immediately
distal to the hydraulic occluder. Miniature 10-MHz Doppler crystals
for measurement of myocardial wall thickening were sutured onto the
epicardium in the regions perfused by the LAD and the left circumflex
coronary artery (control region), respectively. The pericardium
was then loosely closed, and the catheters and electrical leads were
tunneled subcutaneously to exit at the base of the neck. The chest was
closed in layers, and the pneumothorax was evacuated. Catheters were
flushed daily with heparinized saline.
Hemodynamic Measurements
Studies were performed 2 to 3 weeks after surgery with the
animal either resting quietly in a sling or exercising on a
motor-driven treadmill. Phasic and mean aortic pressure was measured
with a Gould P23XL pressure transducer positioned at midchest level. LV
pressure was measured with the micromanometer
calibrated with the fluid-filled LV catheter. LV dP/dt was obtained via
electrical differentiation of the LV pressure signal. Coronary
blood flow velocity was measured with a Doppler flowmeter system
(Craig Hartley). Data were recorded on an eight-channel
direct-writing oscillograph (Coulbourn Instruments).
Myocardial Oxygen Consumption
In 16 dogs, myocardial oxygen consumption was measured at rest
and during exercise. Blood specimens were maintained in iced syringes
until completion of each exercise study. Measurements of
PO2,
PCO2, and pH were then immediately
performed with an Instrumentation Laboratory model 113 blood gas
analyzer. Hemoglobin content was determined with the
cyanmethemoglobin method. Hemoglobin oxygen saturation was determined
from the blood PO2, pH, and
temperature by using the oxygen dissociation curve for canine
blood.6 Blood oxygen content was computed
as follows: (hemoglobinx1.34x% O2
saturation)+(0.0031xPO2). Oxygen
consumption in the region of myocardium perfused by the LAD
was calculated as the product of blood flow determined from the
Doppler flow velocity probe (see "Data Analysis") and
the difference in oxygen content between aortic and coronary
venous blood.
Regional Myocardial Function Measurements
Regional myocardial wall thickening was measured using
single epicardial 10-MHz ultrasonic pulsed Doppler crystals (Craig
Hartley). The onset of systole was taken as the initiation of the
upstroke of LV pressure recorded from the
micromanometer; end systole was taken 20
milliseconds before peak negative dP/dt. Maximum systolic
excursion (SE) was recorded at a range-gate depth (D) of 9 mm.
Percent myocardial systolic wall thickening (%WT) was
calculated as follows: %WT=SE/D.
Experimental Protocols
Efficacy of Pharmacological Antagonists
Degree of Adenosine Receptor Blockade by 8-PT
In 7 resting dogs, the magnitude and selectivity of adenosine receptor blockade produced by 8-PT was determined. For this purpose, we measured the increases in coronary blood flow caused by intracoronary adenosine (0.5 to 25 µg · kg-1 · min-1), the K+ATP channel opener pinacidil (0.2 to 5 µg · kg-1 · min-1), and sodium nitroprusside (0.3 to 3 µg · kg-1 · min-1), infused in random order. After completion of these measurements, adenosine receptor blockade was produced with 8-PT (5 mg/kg) infused intravenously over 10 minutes. Ten minutes after completion of drug administration, intracoronary infusions of adenosine (2 to 25 µg · kg-1 · min-1), pinacidil (0.2 to 5 µg · kg-1 · min-1), and nitroprusside (0.3 to 3 µg · kg-1 · min-1) were repeated. To establish the duration of adenosine receptor blockade produced by 8-PT, we again measured the increases in coronary flow caused by intracoronary adenosine (1 to 25 µg · kg-1 · min-1) 90 minutes after 8-PT administration in 4 dogs. An additional dose of 8-PT (2.5 mg/kg) was then infused intravenously over 5 minutes. Ten minutes after completion of drug administration, intracoronary infusions of adenosine (2 to 25 µg · kg-1 · min-1) were repeated while coronary blood flow responses were recorded.
Degree of K+ATP
Channel Blockade by Glibenclamide
The magnitude and selectivity of glibenclamide as a
K+ATP channel blocker was
assessed in 5 resting dogs. For this purpose, we measured the increases
in coronary blood flow produced by the
K+ATP channel opener pinacidil
(0.25 to 2.5 µg · kg-1 ·
min-1) infused into the coronary artery
catheter. After washout of pinacidil, an intracoronary infusion
of glibenclamide at a dose of 50 µg ·
kg-1 · min-1 at a
rate of 1.5 mL/min was started. Five minutes later, while the
glibenclamide infusion was continued, the pinacidil infusions were
repeated (0.5 to 5 µg · kg-1 ·
min-1). On separate days, we studied the effects
of glibenclamide on the increases in coronary blood flow
produced by nitroprusside (0.6 to 6 µg ·
kg-1 · min-1, n=4)
and adenosine (1 to 50 µg ·
kg-1 · min-1,
n=5).
Inhibition of NO Production by LNNA
The magnitude and selectivity of LNNA as a NO synthase
inhibitor was assessed in 7 resting dogs. For this purpose,
we measured the increases in coronary blood flow produced by
intracoronary acetylcholine (0.1 to 4 µg ·
kg-1 · min-1) and
nitroprusside (0.3 to 3 µg · kg-1
· min-1), infused in random order. After
completion of these measurements, LNNA was administered in an
intracoronary dose of 1.5 mg/kg over a period of 15 minutes at
a rate of 0.6 mL/min. Ten minutes after completion of drug
administration, coronary blood flow responses to
intracoronary infusions of acetylcholine (0.1 to 4 µg
· kg-1 · min-1)
and nitroprusside (0.3 to 3 µg ·
kg-1 · min-1) were
repeated.
Reactive Hyperemia
The effects of glibenclamide combined with 8-PT on the reactive
hyperemic responses to brief coronary artery occlusions
were studied with and without NO synthase inhibition in 6 dogs. With
dogs resting quietly in a sling, baseline measurements of systemic
hemodynamics and coronary blood flow were
performed. Then reactive hyperemic responses to
coronary occlusions 5, 10, 20, and 30 seconds in duration were
recorded in duplicate. A 3-minute interval was allowed between
occlusions. Subsequently, 8-PT was administered
intravenously in a dose of 5 mg/kg over 10 minutes. Ten
minutes after completion of drug administration, intracoronary
infusion of glibenclamide in a dose of 50 µg ·
kg-1 · min-1 was
started into the coronary artery at a rate of 1.5 mL/min. Five
minutes later, hemodynamic measurements were collected,
and the reactive hyperemic responses to coronary artery
occlusions 5, 10, 20, and 30 seconds in duration were obtained in the
presence of 8-PT and glibenclamide. The glibenclamide infusion was then
discontinued, and NO synthase inhibition was produced with LNNA at a
dose of 1.5 mg/kg IC over 15 minutes at a rate of 0.6 mL/min. Ten
minutes after completion of LNNA, the glibenclamide infusion was
restarted at a dose of 50 µg ·
kg-1 · min-1. Five
minutes later, hemodynamic measurements were obtained,
and the reactive hyperemic responses to coronary artery
occlusions 5, 10, 20, and 30 seconds in duration were repeated
in the presence of combined adenosine receptor blockade, NO
synthase inhibition, and K+ATP channel
blockade.
Exercise Protocol
Group 1
On a different day, 12 dogs underwent graded treadmill exercise. With the dogs standing quietly on the treadmill, resting hemodynamics and wall thickening measurements were obtained, and arterial and coronary venous blood samples were collected. Subsequently, a four-stage treadmill exercise protocol was begun (4.8 km/h at 0% grade, 6.4 km/h at 0% grade, 6.4 km/h at 5% grade, and 6.4 km/h at 10% grade). Each exercise stage was 3 minutes in duration. LV and aortic pressures, coronary blood flow, and systolic wall thickening were measured, and blood samples were collected during the last 30 seconds of each exercise stage.
After 90 minutes of rest, adenosine receptor blockade was produced with 8-PT (5 mg/kg IV). Ten minutes later, an intracoronary infusion of glibenclamide (50 µg · kg-1 · min-1) was started. Five minutes after beginning the glibenclamide infusion, the four-stage exercise protocol was repeated during adenosine receptor blockade and glibenclamide infusion. After completion of exercise, the glibenclamide infusion was discontinued, and the dogs were allowed to rest for 90 minutes. Then 8-PT was again administered in a dose of 2.5 mg/kg over 5 minutes. Ten minutes later, LNNA was infused into the coronary artery in a dose of 1.5 mg/kg over 15 minutes at a rate of 0.6 mL/min. Ten minutes after completion of the LNNA infusion, the intracoronary glibenclamide infusion was restarted (50 µg · kg-1 · min-1). Five minutes after beginning the glibenclamide infusion, the exercise protocol was repeated during combined adenosine receptor blockade, NO synthase inhibition, and K+ATP channel blockade.
Group 2
To determine whether combined adenosine blockade and NO
blockade inhibits coronary vasodilation during exercise, the
four-stage treadmill exercise protocol was performed during control
conditions, after intracoronary infusion of LNNA (1.5 mg/kg),
and after LNNA combined with 8-PT (5 mg/kg IV) in 6 dogs. Dogs were
allowed to rest for 90 minutes between exercise trials.
Effects of Restoring Coronary Blood Flow
To determine whether the decrease in systolic wall
thickening and myocardial oxygen consumption after the combination of
glibenclamide and 8-PT with LNNA resulted from impaired myocardial
perfusion, the effect of restoring coronary blood flow to the
control pretreatment level was examined in 5 dogs. The study was
performed while dogs were standing quietly in a sling.
Hemodynamics, coronary blood flow, and systolic wall thickening were obtained during basal conditions and during intracoronary infusion of nitroprusside (1.5 µg · kg-1 · min-1; infusion rate, 0.15 mL/min). Measurements were repeated during infusion of glibenclamide (50 µg · kg-1 · min-1 IC) combined with 8-PT (5 mg/kg IV) and after the addition of LNNA (1.5 mg/kg IC over 15 minutes). Five minutes after the infusion of drugs, intracoronary infusion of nitroprusside (1.5 µg · kg-1 · min-1) was started to restore coronary blood flow to the control pretreatment level. After 5 minutes of infusion of nitroprusside, hemodynamics, coronary blood flow, and systolic wall thickening were again measured.
Data Analysis
Heart rate, LV and aortic pressures, coronary blood
flow, and regional wall thickening were measured from the strip-chart
recordings. Coronary blood flow was computed from the
Doppler shift using the equation Q=2.5xfxD2, where Q is the coronary
flow (mL/min), f is the Doppler shift (kHz), and D is the internal
diameter of the coronary artery. The factor 2.5 is a constant
derived from the speed of sound in tissue
(c=1.5x105 cm/s), the frequency of the emitted
sound beam (f0=10 MHz), the cosine of the angle
at which the sound beam is emitted (45°), and unit conversion
factors: (cx
/4x3)/(2f0xcos 45°). In
chronically instrumented animals, the flow velocity probe is tightly
adherent to the coronary artery, so that the internal diameter
of the probe is equal to the external diameter of the artery. To obtain
the inner diameter of the coronary artery, we subtracted the
arterial wall thickness, which in our experience is 
20%
of the external diameter of the coronary
artery.7 In this way, any error in computation of
the coronary internal diameter affects control and intervention
conditions equally. Coronary vascular conductance was
calculated by dividing mean coronary blood flow by mean aortic
pressure.
Total blood flow during reactive hyperemia was determined by electrical integration of the Doppler shift tracing. Reactive hyperemia flows were calculated as follows: blood flow debt (mL)=control blood flow rate (mL/s)xduration of occlusion (seconds); excess reactive hyperemia flow (mL)=total flow during reactive hyperemia (mL)-[control blood flow rate (mL/s)xduration of reactive hyperemia (seconds)]. The duration of reactive hyperemia was taken as the time from release of coronary occlusion to the point at which flow returned to within 5% of control.
Statistical comparisons of hemodynamic measurements, coronary blood flow, and myocardial function were performed using two-way (exercise level and treatment) ANOVA for repeated measures. When a significant effect of treatment was observed, comparisons within groups were performed using one-way ANOVA followed by Scheffé's test. The effect of treatment on the relation between two variables was analyzed by ANCOVA. Statistical significance was accepted at P<.05. All data are presented as mean±SEM.
Drugs
8-PT was dissolved in dimethyl sulfoxide and deionized water (pH
10.0 to 11.0). Glibenclamide was dissolved in deionized water (pH 8.0
to 8.5). LNNA was dissolved in deionized water (pH 8.2 to 8.6).
Adenosine was dissolved in warm
physiological saline. Pinacidil was dissolved in
deionized water (pH 6.0 to 6.5). Sodium nitroprusside was dissolved in
5% dextrose. Acetylcholine was dissolved in physiological
saline.
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Results |
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Efficacy of Pharmacological Antagonists
Degree of Adenosine Receptor Blockade by 8-PT
During resting conditions, intracoronary infusions of adenosine had no effect on heart rate (116±10 bpm) or mean aortic pressure (84±6 mm Hg). Infusion of the K+ATP opener pinacidil caused a small increase in heart rate from 117±11 bpm during control conditions to 122±11 bpm at the highest dose (P<.05), with no significant effect on aortic pressure. Sodium nitroprusside decreased mean aortic pressure from 85±5 to 80±5 mm Hg (P<.05) and increased heart rate from 124±8 to 130±10 bpm (P<.05). 8-PT had no effect on mean aortic pressure or heart rate and did not alter the systemic responses to adenosine, pinacidil, or nitroprusside. The increases in coronary flow produced by intracoronary infusions of adenosine were markedly attenuated by 8-PT with 82±6% inhibition of the increase in coronary flow produced by adenosine in a dose of 10 µg · kg-1 · min-1, but the coronary flow responses to pinacidil and nitroprusside were not altered (Fig 1
). It should be noted
that the degree of adenosine blockade was likely
underestimated, since the lower blood flow rates during
adenosine infusion after 8-PT resulted in less dilution of
adenosine and thus higher coronary blood
concentrations. Ninety minutes after administration of 8-PT, the
adenosine blockade had partially subsided (55±6% inhibition
of the increase in coronary flow produced by adenosine,
10 µg · kg-1 ·
min-1); at this time the addition of 8-PT in a
dose of 2.5 mg/kg restored adenosine blockade (83±5%
attenuation of the increase in coronary flow produced by
adenosine, 10 µg · kg-1
· min-1).
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) and in the presence of 8-PT (5
mg/kg IV) (
). In 4 dogs, adenosine was also infused 1.5
hours after 8-PT (
). In these animals, a second dose of 8-PT (2.5
mg/kg) was then administered, and the dose-response analysis
was repeated (
). Data are mean±SEM.
Degree of K+ATP Channel Blockade by
Glibenclamide
Glibenclamide did not significantly alter the systemic
hemodynamic responses to adenosine or sodium
nitroprusside but abolished the slight increase in heart rate produced
by pinacidil during control conditions. Glibenclamide had no effect on
the increase in coronary blood flow produced by nitroprusside
but markedly decreased the coronary vasodilation caused by
pinacidil with 85±5% inhibition of the response to pinacidil at a
dose of 2.5 µg · kg-1 ·
min-1 (Fig 2). The
coronary blood flow responses to adenosine were also
significantly attenuated; the degree of inhibition of the response to
adenosine, 10 µg · kg-1
· min-1, was similar for 8-PT (82±6%) and
glibenclamide (81±6%).
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Degree of NO Inhibition by LNNA
Intracoronary LNNA (1.5 mg/kg) had no effect on mean
aortic blood pressure (90±5 mm Hg) or heart rate (121±7 bpm).
Intracoronary infusions of acetylcholine in doses of 0.1 to 4
µg · kg-1 ·
min-1 had no effect on blood pressure
(92±6 mm Hg) or heart rate (118±9 bpm). Coronary blood
flow increased from 47±5 mL/min at baseline to 143±15 mL/min during
infusion of acetylcholine at a dose of 4 µg ·
kg-1 · min-1 (Fig 3). After LNNA, this dose of
acetylcholine increased coronary flow from 44±5 mL/min at
baseline to 74±7 mL/min, representing 69±7% inhibition
of the response to acetylcholine. This is likely an underestimate of
the degree of blockade, since the decreased coronary flow rates
during acetylcholine infusion after LNNA would result in higher blood
concentrations than during the control infusion. Intracoronary
infusion of nitroprusside in doses of 0.3 to 3 µg ·
kg-1 · min-1
decreased mean blood pressure from 96±9 mm Hg at baseline to
86±7 mm Hg during the highest dose (P<.05), with a
tendency for heart rate to increase from 113±10 to
128±14 bpm (P=NS). After LNNA administration, nitroprusside
infusion caused similar changes in mean aortic pressure and heart rate.
The responses of coronary flow to nitroprusside were not
altered by LNNA (Fig 3).
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Reactive Hyperemia
During control conditions, heart rate and mean aortic pressure
were 115±10 bpm and 88±6 mm Hg, respectively. These values were
not significantly altered by 8-PT combined with intracoronary
glibenclamide. The addition of LNNA to 8-PT and glibenclamide caused a
slight increase in mean aortic blood pressure to 97±4 mm Hg
(P<.05) with no change in heart rate (120±10 bpm). An
example of a reactive hyperemic response to a 20-second
coronary artery occlusion is shown in Fig 4. The combination of 8-PT and
glibenclamide decreased basal coronary blood flow, decreased
peak blood flow during reactive hyperemia, and shortened the
duration of reactive hyperemia after 5, 10, 20, and 30-second
coronary occlusions. As a result, reactive hyperemia
excess flow was markedly attenuated by the combination of 8-PT and
glibenclamide (Table 1). The addition of
LNNA to the combination of 8-PT and glibenclamide further decreased
basal coronary blood flow, decreased peak blood flow during
reactive hyperemia, shortened the duration of reactive
hyperemia, and decreased reactive hyperemia excess flow
(Table 1).
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Exercise
Group 1
Systemic Hemodynamics
The hemodynamic responses to increasing levels of
exercise are shown in Table 2; data
recorded from a representative dog are shown in Fig 5. Exercise caused significant increases
in heart rate, mean aortic pressure, LV systolic pressure, LV
end-diastolic pressure, and maximal LV dP/dt. The
combination of 8-PT and glibenclamide caused significant increases of
heart rate and LV end-diastolic pressure at rest but had no
effect on any other systemic hemodynamic variable.
During exercise, the combination of the two drugs did not alter heart
rate or mean aortic pressure. However, the combination of 8-PT and
glibenclamide caused decreases in LV systolic pressure and LV
dP/dtmax and significant elevations of LV
end-diastolic pressure. During resting conditions, the
addition of LNNA caused a decrease in LV dP/dtmax
(P<.05) but had no effect on the other variables.
During exercise, the addition of LNNA significantly decreased LV
systolic pressure and LVdP/dtmax compared
with the combination of 8-PT and glibenclamide. LV
end-diastolic pressure tended to be increased by the
addition of LNNA, although this achieved statistical significance only
during the first level of exercise (Table 2).
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Th, systolic wall thickening
in the control circumflex perfused coronary artery; LAD
Coronary Hemodynamics
As shown in Table 3, myocardial
oxygen consumption in the region perfused by the LAD increased from
4.3±0.4 mL/min at rest to 10.5±0.9 mL/min during the heaviest level
of exercise (P<.01). The increase in oxygen consumption was
accounted for by an increase in coronary flow from 49±3 mL/min
at rest to 92±8 mL/min during the highest level of exercise
(P<.01), an increase in hemoglobin from 9.5±0.4 g/dL at
rest to 10.8±0.4 g/dL (P<.05), and an increase in the
coronary arteriovenous oxygen content difference from 9.4±0.4
mL/dL at rest to 12.0±0.4 mL/dL (P<.01). The increase in
myocardial oxygen extraction from 77±2% at rest to 86±1% during the
highest level of exercise (P<.01) caused a decrease in
coronary venous oxygen tension from 20±1 to 14±1 mm Hg
(P<.01).
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When 8-PT was combined with glibenclamide, coronary blood flow
was significantly lower at rest and during each level of exercise
(Table 3
), resulting in a downward shift in the slope of the relation
between coronary blood flow and heart rate
(41.9±7.2x10-2 mL/beat during control versus
23.7±5.1x10-2 mL/beat during 8-PT combined
with glibenclamide, P<.05) as well as the rate-pressure
product (19.2±6.3x10-4 mL/beat
· mm Hg versus 11.2±2.8x10-4
mL/beat · mm Hg, P<.01) (Fig 6). The decrease in coronary
blood flow was accompanied by a widening of the coronary
arteriovenous oxygen content difference and an increase in oxygen
extraction (Table 3). Infusion of glibenclamide in the presence of
adenosine receptor blockade caused a downward shift of the
relationship between coronary venous oxygen tension and
myocardial oxygen consumption (P<.05), indicating
impairment of the myocardial oxygen supply (Fig 7).
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). Data are mean±SEM.
*P<.05 vs control; 
P<.05 vs 8-PT+Glib
(using ANCOVA).
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The addition of LNNA significantly further decreased coronary
blood flow at rest and during each level of exercise compared with
combined 8-PT and glibenclamide (Table 3 and Fig 6). After the addition
of LNNA, coronary blood flow underwent a borderline significant
increase from 20±2 mL/min at rest to 29±5 mL/min during the highest
level of exercise (P=.073). This small residual increase in
coronary blood flow in response to exercise resulted
principally from an increase in mean aortic pressure
(P<.05) without a significant change in coronary
vascular conductance (P=.22) (Fig 6).
The slopes of the relation between coronary blood flow and both
heart rate and rate-pressure product were further decreased by the
addition of LNNA (12.4±4.1x10-2 mL/beat and
5.2±1.7x10-4 mL/beat · mm Hg;
P<.05 and P<.03, respectively) compared with
combined adenosine receptor and
K+ATP channel blockade
(23.7±5.1x10-2 mL/beat and
11.2±2.8x10-4 mL/beat · mm Hg)
(Fig 5), although the slopes of both relationships remained
significantly different from zero (P<.05). Myocardial
oxygen extraction was further increased with the addition of LNNA to
combined 8-PT and glibenclamide (Table 3), so that for any level of
oxygen consumption coronary venous oxygen
tension was further reduced (P<.05) (Fig 6).
Regional Myocardial Contractile Function
During control conditions, LV transmural systolic wall
thickening increased from 21±2% at rest to 30±3%
(P<.01) during the heaviest level of exercise in the
LAD-perfused region and from 20±3% to 29±4% (P<.01) in
the posterior control region (Fig 8).
Combined 8-PT and glibenclamide caused significant decreases in
systolic wall thickening at rest and during each level of
exercise compared with control conditions, so that systolic
wall thickening was decreased to 3±0.3% during the highest level of
exercise (P<.01). Systolic wall thickening in the
posterior control region was not altered by the LAD infusion of 8-PT
and glibenclamide. The addition of LNNA to 8-PT plus glibenclamide
caused a slight further decrease in systolic wall thickening in
the LAD-perfused region, which was significant under resting
conditions. The addition of LNNA also tended to reduce systolic
wall thickening in the posterior control region, but this failed to
reach statistical significance.
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Group 2
Systemic Hemodynamics
The systemic hemodynamic responses to graded
treadmill exercise during control conditions, with LNNA, and with LNNA
plus 8-PT are shown in Table 4. LNNA
tended to increase heart rate as well as mean aortic and LV
systolic pressures both at rest and during exercise, but these
changes did not reach statistical significance. The addition of 8-PT
tended to further increase mean aortic and LV
systolic pressure during exercise, but this was not
significantly different from LNNA alone.
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Coronary Hemodynamics
As shown in Table 5, during control
conditions coronary blood flow increased from 46±5 mL/min at
rest to 93±6 mL/min during the heaviest level of exercise
(P<.01). Myocardial oxygen consumption increased from
5.9±0.6 mL/min at rest to 12.7±0.6 mL/min during peak exercise
(P<.01), and this was associated with a significant
decrease in coronary venous oxygen tension. LNNA tended to
increase coronary blood flow and decrease coronary
venous oxygen tension both at rest and during exercise compared with
control, resulting in a significant increase in myocardial oxygen
consumption during the two heaviest levels of exercise. The addition of
8-PT to LNNA had no effect on coronary
hemodynamics. The relationships between rate-pressure
product and coronary blood flow and between myocardial
oxygen consumption and coronary venous oxygen tension (Fig 9) were not altered by either LNNA alone
or LNNA combined with 8-PT.
|
|
|
Effects of Increasing Coronary Blood Flow
As shown in Table 6 and Fig 10, during control conditions
intracoronary infusion of sodium nitroprusside (1.5 µg
· kg-1 · min-1)
increased coronary blood flow with no change of
systolic wall thickening or myocardial oxygen consumption.
Glibenclamide plus 8-PT decreased coronary blood flow,
systolic wall thickening, and myocardial oxygen consumption,
with further significant decreases after the addition of LNNA.
Restoring coronary blood flow to the baseline level by infusion
of nitroprusside caused normalization of regional myocardial function
and myocardial oxygen consumption. These findings indicate that the
decrease of regional contractile function produced by 8-PT and
glibenclamide with or without LNNA resulted from the reduction of
coronary blood flow and myocardial oxygen availability produced
by these agents.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study identifies the principal mechanisms that account for coronary vasodilation during exercise. Previously, we reported that adenosine receptor blockade had no effect on coronary blood flow at rest or during exercise8 and that K+ATP channel blockade decreased resting coronary blood flow but did not attenuate the increase in coronary flow that occurred in response to exercise.2 In the presence of K+ATP channel blockade, the addition of adenosine receptor blockade did not further decrease resting coronary flow but attenuated the increase in flow produced by exercise by approximately half,3 suggesting that the coronary constriction that followed K+ATP channel blockade resulted in augmented myocardial adenosine production during exercise, which caused coronary vasodilation. In the present study, the addition of NO synthase inhibition, which under normal conditions tended to increase coronary flow at rest and during exercise, caused a further decrease in resting coronary blood flow and nearly abolished coronary vasodilation in response to exercise. The findings imply that K+ATP channels are of critical importance for maintaining coronary vasodilation at rest and during exercise but that when the K+ATP channels are blocked, increased production of adenosine and NO mediates coronary vasodilation in response to exercise.
Coronary Blood Flow at Rest
In vivo studies have failed to demonstrate a critical role for NO
in maintaining coronary blood flow during basal conditions.
Thus, studies in anesthetized9 10 11 12 and
awake4 5 13 14 15 16 dogs failed to show a decrease in
basal coronary blood flow after NO synthase inhibition with
intracoronary LNNA,4 5 9 12 13 14 16
L-NMMA,10 11 12 or L-NAME.15
However, there is evidence that NO can interact with other
endogenous vasodilator systems. Thus, in isolated perfused
guinea pig hearts, inhibition of NO production with L-NAME
increased adenosine release from 23±5 pmol/min during control
conditions to 41±7 pmol/min.17 In isolated
rabbit hearts, L-NAME (30 µmol/L) caused a reduction in
myocardial infarct size comparable to that produced by ischemic
preconditioning; this protective effect was prevented by
adenosine receptor blockade with 8-sulfophenyl theophylline,
indicating that L-NAME exerted its protective effect by causing
increased adenosine production.18
Although these studies demonstrate that NO synthase inhibition can
augment myocardial adenosine production, neither in
anesthetized dogs11 nor in the
present study did the addition of adenosine receptor
blockade to L-NAME or LNNA cause a decrease in resting coronary
flow. These findings demonstrate that in the normal blood-perfused
heart in vivo neither adenosine nor NO alone or in combination
is essential to maintain coronary flow during resting
conditions.
Several investigators have examined the effect of K+ATP channel blockade on basal coronary blood flow.19 20 Imamura et al19 observed that intracoronary glibenclamide (50 µg · kg-1 · min-1) caused a 40% decrease in basal coronary blood flow in open-chest dogs. Similarly, we observed that glibenclamide (50 µg · kg-1 · min-1 IC) caused a 20% to 30% decrease in coronary blood flow in resting awake dogs (References 2 and 32 3 and the present study). After K+ATP channel blockade had been established, the subsequent addition of adenosine receptor blockade did not further decrease coronary flow.3 However, in the presence of combined K+ATP channel blockade and adenosine receptor blockade, inhibition of NO synthesis with LNNA caused a decrease in resting coronary flow, myocardial oxygen consumption, and systolic wall thickening. The decrease in myocardial oxygen consumption and systolic wall thickening was not the result of a direct negative inotropic effect, since restoration of coronary flow to the control level with sodium nitroprusside caused recovery of contractile performance. The findings support the conclusion that under resting conditions K+ATP channels are the main mediators of metabolic dilation but that when these channels are blocked, NO contributes significantly to coronary dilation but cannot fully compensate for the loss of K+ATP channel activity.
Coronary Reactive Hyperemia
In isolated guinea pig hearts,17 21 22 open
chest dogs,11 and awake
dogs,13 14 NO synthase inhibition with
LNNA,13 14 21 22
L-NMMA,11 or L-NAME17
decreased total reactive hyperemia flow principally by
attenuating the late phase of the hyperemic response, with some
investigators also reporting a decrease in the peak flow
rate.15 23 The decrease in the late phase of
reactive hyperemia likely occurred because shear-mediated
NO-dependent vasodilation is delayed relative to metabolic
small-vessel vasodilation. Thus, Hintze and
Vatner24 observed that after release of a
15-second coronary occlusion, peak blood flow rates
(metabolic resistance vessel dilation) occurred within 5 to
6 seconds, whereas flow-mediated vasodilation of the epicardial
coronary artery required 45 to 60 seconds to occur. Similarly,
Kuo et al25 reported that flow-mediated
vasodilation required several minutes in perfused coronary
microvessels. It is consequently not surprising that NO synthase
blockade would attenuate the late phase of reactive hyperemia,
when flow-mediated vasodilation would be expected to occur. However,
after K+ATP channel and
adenosine receptor blockade in the present study, LNNA
decreased both the peak blood flow rate and the duration of the
response. This suggests that
K+ATP and adenosine
blockade caused vasoconstriction, which increased
endothelial shear and NO production, so that
LNNA reduced the peak flow rate.
Combined blockade of K+ATP channels, adenosine receptors, and NO synthase did not fully block reactive hyperemia. The residual vasodilation might be ascribed to incomplete blockade caused by the competitive inhibitors used in the present study. It is also possible that other vasodilators such as prostacyclin26 or endothelium-derived hyperpolarizing factor27 could be responsible for the residual vasodilation. Alternatively, metabolic alterations, such as decreased pH, increased PCO2,28 or direct sensing by arteriolar smooth muscle of the decreased oxygen tension during coronary occlusion, could contribute to the residual vasodilation.29 Finally, a part of the increase in coronary inflow can be accounted for by refilling of coronary capacitance vessels, which were emptied during the occlusion.30 However, this could not account for the progressively greater increases in coronary inflow during reactive hyperemia that followed occlusions of longer duration.
Coronary Blood Flow During Exercise
NO synthase blockade did not significantly alter coronary
flow, possibly because of the relatively small number of animals
studied, but it did increase myocardial oxygen consumption during the
heavier levels of exercise. Coronary venous oxygen tension
tended to be lower after LNNA, suggesting that NO normally makes a
modest contribution to coronary vasodilation during exercise.
Nevertheless, LNNA combined with 8-PT did not alter coronary
conductance during exercise, indicating that NO and adenosine
are not essential for coronary vasodilation during exercise
when K+ATP channels are
intact. In contrast, K+ATP
channel blockade with glibenclamide decreased coronary blood
flow by 20% to 30% both at rest and during exercise but did not alter
the slope of the relationship between coronary flow and
myocardial oxygen demand.2 3 After
K+ATP channel blockade,
the subsequent addition of adenosine blockade did not further
decrease resting coronary blood flow but attenuated the
increase in coronary flow during exercise by approximately
half.3 This was accompanied by decreases in
coronary venous oxygen tension and myocardial contractile
performance, which were most pronounced during the higher
levels of exercise. These findings suggest that after
K+ATP channel
blockade, increasing levels of exercise are associated with progressive
deterioration of the myocardial oxygen supply-demand balance, thereby
resulting in progressive augmentation of adenosine
production. Nevertheless, the addition of adenosine
blockade after K+ATP
channel blockade only partially attenuated the coronary
vasodilation in response to exercise. However, after inhibition of
K+ATP channels and
adenosine receptors, the addition of NO synthase blockade
essentially abolished coronary vasodilation during exercise.
The residual tendency for coronary flow to increase in response
to exercise was principally related to the increase in blood pressure
without a significant increase in coronary conductance. Thus,
NO-dependent mechanisms contribute to coronary vasodilation
during exercise when other vasodilator systems have been inhibited.
The greater coronary vasoconstriction produced by LNNA during exercise after K+ATP channel blockade is analogous to the effect of NO synthase blockade on blood flow to myocardial regions perfused by a stenotic coronary artery. When a coronary stenosis caused myocardial hypoperfusion during exercise, intracoronary LNNA caused a further decrease in coronary flow with no change in perfusion pressure distal to the stenosis.5 This indicates that when a coronary stenosis results in myocardial ischemia during exercise, NO contributes to vasodilation of the distal vessels. Similarly, in the present study when the combination of glibenclamide and 8-PT caused myocardial hypoperfusion with contractile dysfunction, the addition of LNNA further reduced coronary blood flow. It is possible that blocking of K+ATP channels and adenosine causes enhanced production of NO. NO production could be augmented by several mechanisms. First, the myocardial hypoperfusion produced by K+ATP channel and adenosine blockade might directly increase NO production. In support of this, Pohl and Busse31 observed that hypoxia led to release of an endothelium-derived relaxing factor in feline mesenteric vessels. Similarly, myocardial hypoxia resulted in enhanced production of NO in isolated guinea pig hearts.21 22 It is thus possible that in the present study NO production was augmented by a direct effect of low tissue oxygen on the coronary endothelium.32 Another possible mechanism is that the vasoconstriction produced by K+ATP channel and adenosine blockade augmented NO release via an increase in shear stress.25 Finally, it is likely that NO normally contributes to coronary vasodilation during exercise but that compensation by other vasodilator systems acts to minimize the decrease in coronary blood flow produced by NO synthase blockade. Only when other vasodilator mechanisms are blocked does inhibition of NO synthase cause an absolute decrease of coronary flow. Future studies, including measurements of coronary arteriovenous NO production after K+ATP channel blockade, will be needed to resolve these questions.
By comparing measurements of coronary conductance during
combined blockade of K+ATP
channels, adenosine receptors, and NO synthase with
measurements obtained when only
K+ATP channels and
adenosine receptors were blocked, it is possible to estimate
the influence of NO on coronary conductance. At rest,
coronary conductance was 0.51±0.04 mL ·
min-1 ·
mm Hg-1 during control conditions; during
combined K+ATP channel and
adenosine blockade, conductance decreased to 0.27±0.03
mL · min-1 · mm Hg-1
and fell further to 0.20±0.03
mL · min-1 · mm Hg-1
with the addition of LNNA, a decrease of 0.07
mL · min-1 · mm Hg-1
attributable to NO-dependent vasodilation. The decrease in
coronary conductance following NO blockade was greater
during exercise; during the heaviest level of exercise, conductance
during control conditions was 0.93±0.08
mL · min-1 · mm Hg-1
and decreased to 0.43±0.05
mL · min-1 · mm Hg-1
in the presence of K+ATP
channel and adenosine blockade. Conductance fell to 0.24±0.04
mL ·
min-1 · mm Hg-1
with the addition of LNNA, a decrease of 0.19
mL · min-1 · mm Hg-1
attributable to NO-dependent vasodilation. The greater contribution of
NO during exercise suggests that greater endothelial
shear associated with the higher coronary flow rates during
exercise augments NO production. Alternatively, sympathetic
activation during exercise might enhance endothelial
2-adrenoceptor–mediated NO
production.33 LNNA could then
aggravate hypoperfusion by leaving 1-
and 2-adrenergic coronary
vasoconstriction unopposed. This concept is in agreement with
studies16 reporting that treadmill exercise
caused epicardial artery dilation, which was converted to
vasoconstriction after NO synthase inhibition or
endothelial denudation, and is further supported by the
finding that constriction of coronary microvessels in response
to norepinephrine was enhanced after NO synthase
inhibition.33
Limitations
Interpretation of the role of
K+ATP channels in the
regulation of coronary vascular resistance is predicated on the
assumption that glibenclamide is not acting as a nonspecific
constrictor of vascular smooth muscle. Any intervention that decreases
coronary blood flow relative to myocardial oxygen demands
(pharmacological vasoconstriction, arterial
stenosis, or closing
K+ATP channels) likely
results in recruitment of vasodilator mechanisms, which may not be
mandatory for maintaining coronary vasodilation during normal
arterial inflow. Khayyal et
al34 demonstrated that when
coronary flow was decreased to approximately half the basal
level by intracoronary infusion of vasopressin, contractile
force was decreased and lactate production occurred. Despite
this evidence for ischemia, vasodilator reserve was not
exhausted, as indicated by an increase in flow in response to
adenosine. Endogenous vasodilator mechanisms also
were not exhausted, since coronary occlusion resulted in some
degree of reactive hyperemia. We observed analogous findings
during K+ATP channel
blockade. Thus, glibenclamide decreased resting coronary blood
flow but did not impair the ability of flow to increase during the
metabolic stimulus produced by exercise. After
glibenclamide, the ability to increase flow in response to exercise is
mediated by adenosine and NO production in the heart.
The results of the present study are unique because glibenclamide
is not an agonist vasoconstrictor but acts to interrupt the common
pathway for endogenous vasodilator mechanisms which require
opening of K+ATP channels
to produce their effect (metabolic coronary
vasodilation and autoregulation). Central to our hypothesis is the
question of whether glibenclamide is a selective inhibitor
of K+ATP channels or
whether it produces coronary vasoconstriction in a nonspecific
manner. Glibenclamide produced a high degree of
K+ATP channel blockade
without blunting the vasodilation produced by nitroprusside. In rat
portal vein preparations, glibenclamide inhibited both
K+ATP channels and
K+ATP and
K+Ca2+
channels.35 However, in porcine
coronary artery vascular smooth muscle
cells36 and in isolated rat
heart,37 there was no overlap in the
pharmacological actions of glibenclamide and known blockers of
K+Ca2+ channels, including
large- and small-conductance
K+Ca2+ channels
(charybdotoxin) or blockers of the delayed rectifier
K+ current (E-1403). Glibenclamide is
generally regarded as the most potent and selective
K+ATP channel blocker
available in coronary arterial
vasculature.38 Nevertheless, we cannot
exclude the alternate interpretation that closing
K+ATP channels with a
pharmacological agent such as glibenclamide might constrict the vessels
to a greater degree than simply withdrawing the endogenous
signals that cause vasodilation by opening these channels.
Hierarchy of Coronary Vasodilator Systems
Although coronary vasodilation produced by exercise was
nearly abolished after combined blockade of
K+ATP channels,
adenosine receptors, and NO synthase, blockade of any one of
these vasodilator mechanisms alone failed to blunt the increase in
coronary flow in response to
exercise.8 13 However, LNNA tended to
decrease coronary venous oxygen tension, suggesting that NO
normally makes a modest contribution to coronary vasodilation,
especially during low levels of exercise. After combined blockade of
adenosine receptors and NO synthase, blood flow at rest and
during exercise was not less than control flow. Although blockade of
K+ATP channels did not
prevent the exercise-induced coronary vasodilation, it did
result in lower coronary flow rates both at rest and during
exercise, and this was associated with contractile dysfunction and
increased myocardial release of adenosine, suggestive of
ischemia.3 These findings are best
explained by the concept that opening of
K+ATP channels is the
principal mechanism of metabolic coronary
vasodilation but that when
K+ATP channels are blocked
and ischemia ensues, both adenosine and NO act to
increase coronary blood flow during exercise. When
K+ATP channels and
adenosine receptors were blocked, NO produced approximately one
quarter of the coronary vasodilation that usually occurred in
response to exercise when all vasodilator mechanisms were intact.
Intrinsic Coronary Vascular Tone
When all three vasodilator mechanisms were blocked,
coronary blood flow both at rest and during exercise was
reduced below the level observed at rest during control conditions.
This finding suggests that the intrinsic state of the coronary
resistance vessels is one of marked vasoconstriction, with messengers
generated by the myocardial myocytes and endothelium
acting to cause vasorelaxation. -Adrenergic activation contributes
to coronary vasoconstriction during exercise, but this
mechanism is probably of negligible importance under resting
conditions.39 Consequently, the high level
of vasomotor tone is likely an intrinsic characteristic of the
coronary resistance vessels. Skeletal muscle resistance vessels
also maintain a high level of vasoconstrictor tone during basal
conditions that has been attributed to myogenic
mechanisms.40 It is unclear whether similar
myogenic mechanisms also exist in the coronary resistance
vessels.
|
Selected Abbreviations and Acronyms |
|---|
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|
Acknowledgments |
|---|
This study was supported by US Public Health Service grants HL-20598, HL-32427, and HL-21872 from the National Heart, Lung, and Blood Institute and a Grant-in-Aid from the Minnesota Affiliate of the American Heart Association. We wish to acknowledge the expert technical assistance of Todd Pavek, Melanie Crampton, Bryan Jones, and Paul Lindstrom. Pinacidil was a gift from Lilly Research Laboratories, Indianapolis, Ind.
Received July 28, 1997; accepted November 3, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker KCa+ channels contribute to exercise-induced coronary vasodilation in swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097. [Abstract] [Full Text] [PDF]
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D. Merkus, O. Sorop, B. Houweling, F. Boomsma, A. H. van den Meiracker, and D. J. Duncker NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2075 - H2081. [Abstract] [Full Text] [PDF]
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D. Merkus, D. B. Haitsma, O. Sorop, F. Boomsma, V. J. de Beer, J. M. J. Lamers, P. D. Verdouw, and D. J. Duncker Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2082 - H2089. [Abstract] [Full Text] [PDF]
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N. Westerhof, C. Boer, R. R. Lamberts, and P. Sipkema Cross-talk between cardiac muscle and coronary vasculature. Physiol Rev, October 1, 2006; 86(4): 1263 - 1308. [Abstract] [Full Text] [PDF]
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 W. G. Schrage, N. M. Dietz, and M. J. Joyner Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise J Appl Physiol, May 1, 2006; 100(5): 1506 - 1512. [Abstract] [Full Text] [PDF]
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 H. Hibino and Y. Kurachi A New Insight Into the Pathogenesis of Coronary Vasospasm Circ. Res., March 17, 2006; 98(5): 579 - 581. [Full Text] [PDF]
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R. Kakkar, B. Ye, D. A. Stoller, M. Smelley, N.-Q. Shi, K. Galles, M. Hadhazy, J. C. Makielski, and E. M. McNally Spontaneous Coronary Vasospasm in KATP Mutant Mice Arises From a Smooth Muscle-Extrinsic Process Circ. Res., March 17, 2006; 98(5): 682 - 689. [Abstract] [Full Text] [PDF]
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 P. Zong, J. D. Tune, and H. F. Downey Mechanisms of Oxygen Demand/Supply Balance in the Right Ventricle Experimental Biology and Medicine, September 1, 2005; 230(8): 507 - 519. [Abstract] [Full Text] [PDF]
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R. R. Martinez, S. Setty, P. Zong, J. D. Tune, and H. F. Downey Nitric oxide contributes to right coronary vasodilation during systemic hypoxia Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1139 - H1146. [Abstract] [Full Text] [PDF]
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D. Merkus, B. Houweling, M. van Vliet, and D. J. Duncker Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1306 - H1313. [Abstract] [Full Text] [PDF]
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J. Zhang, G. Gong, Y. Ye, T. Guo, A. Mansoor, Q. Hu, K. Ochiai, J. Liu, X. Wang, Y. Cheng, et al. Nitric oxide regulation of myocardial O2 consumption and HEP metabolism Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H310 - H316. [Abstract] [Full Text] [PDF]
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C. Penna, P. Pagliaro, R. Rastaldo, F. Di Pancrazio, G. Lippe, D. Gattullo, D. Mancardi, M. Samaja, G. Losano, and I. Mavelli F0F1 ATP synthase activity is differently modulated by coronary reactive hyperemia before and after ischemic preconditioning in the goat Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2192 - H2200. [Abstract] [Full Text] [PDF]
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J. D. Tune, M. W. Gorman, and E. O. Feigl Matching coronary blood flow to myocardial oxygen consumption J Appl Physiol, July 1, 2004; 97(1): 404 - 415. [Abstract] [Full Text] [PDF]
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H. M. O. Farouque, S. G. Worthley, and I. T. Meredith Effect of ATP-Sensitive Potassium Channel Inhibition on Coronary Metabolic Vasodilation in Humans Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 905 - 910. [Abstract] [Full Text]
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 C. S. Broberg, G. D. Giraud, J. M. Schultz, K. L. Thornburg, A. R. Hohimer, and L. E. Davis Fetal anemia leads to augmented contractile response to hypoxic stress in adulthood Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R649 - R655. [Abstract] [Full Text] [PDF]
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D. Merkus, B. Houweling, A. Mirza, F. Boomsma, A. H van den Meiracker, and D. J Duncker Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation Cardiovasc Res, September 1, 2003; 59(3): 745 - 754. [Abstract] [Full Text] [PDF]
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D. Merkus, D. B. Haitsma, T.-Y. Fung, Y. J. Assen, P. D. Verdouw, and D. J. Duncker Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H424 - H433. [Abstract] [Full Text] [PDF]
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H. M. O. Farouque and I. T. Meredith Relative contribution of vasodilator prostanoids, NO, and KATP channels to human forearm metabolic vasodilation Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2405 - H2411. [Abstract] [Full Text] [PDF]
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H. M. O. Farouque and I. T. Meredith Inhibition of vascular ATP-sensitive K+ channels does not affect reactive hyperemia in human forearm Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H711 - H718. [Abstract] [Full Text] [PDF]
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D. Merkus, D. J. Duncker, and W. M. Chilian Metabolic regulation of coronary vascular tone: role of endothelin-1 Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1915 - H1921. [Abstract] [Full Text] [PDF]
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 M. B. Gordon, R. Jain, J. A Beckman, and M. A Creager The contribution of nitric oxide to exercise hyperemia in the human forearm Vascular Medicine, August 1, 2002; 7(3): 163 - 168. [Abstract] [PDF]
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 B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, and G. K. McConell Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects Diabetes, August 1, 2002; 51(8): 2572 - 2580. [Abstract] [Full Text] [PDF]
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 Y. Chen, J. H. Traverse, R. Du, M. Hou, and R. J. Bache Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart Circulation, July 9, 2002; 106(2): 273 - 279. [Abstract] [Full Text] [PDF]
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J. P. Walker, J. C. Barbato, and L. G. Koch Cardiac adenosine production in rat genetic models of low and high exercise capacity Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R168 - R173. [Abstract] [Full Text] [PDF]
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J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]
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A. J. M. Cornelissen, J. Dankelman, E. VanBavel, and J. A. E. Spaan Balance between myogenic, flow-dependent, and metabolic flow control in coronary arterial tree: a model study Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2224 - H2237. [Abstract] [Full Text] [PDF]
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J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl Control of Coronary Blood Flow during Exercise Experimental Biology and Medicine, April 1, 2002; 227(4): 238 - 250. [Abstract] [Full Text] [PDF]
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 T Reffelmann, H G Klues, P Hanrath, and E R Schwarz Post-stenotic coronary blood flow at rest is not altered by therapeutic doses of the oral antidiabetic drug glibenclamide in patients with coronary artery disease Heart, January 1, 2002; 87(1): 54 - 60. [Abstract] [Full Text] [PDF]
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V. Borutaite, A. Matthias, H. Harris, S. Moncada, and G. C. Brown Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2256 - H2260. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, K. Arimura, Y. Machida, T. Ide, H. Tsutsui, H. Shimokawa, and A. Takeshita Increased inactivation of nitric oxide is involved in impaired coronary flow reserve in heart failure Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2619 - H2625. [Abstract] [Full Text] [PDF]
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B. J. Hart, X. Bian, P. A. Gwirtz, S. Setty, and H. F. Downey Right ventricular oxygen supply/demand balance in exercising dogs Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H823 - H830. [Abstract] [Full Text] [PDF]
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J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl KATP+ channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H868 - H875. [Abstract] [Full Text] [PDF]
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N. Paolocci, P. Pagliaro, T. Isoda, F. W. Saavedra, and D. A. Kass Role of Calcium-Sensitive K+ Channels and Nitric Oxide in In Vivo Coronary Vasodilation From Enhanced Perfusion Pulsatility Circulation, January 2, 2001; 103(1): 119 - 124. [Abstract] [Full Text] [PDF]
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Y. Chen, R. Du, J. H. Traverse, and R. J. Bache Effect of sildenafil on coronary active and reactive hyperemia Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2319 - H2325. [Abstract] [Full Text] [PDF]
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 B. A. KINGWELL Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease FASEB J, September 1, 2000; 14(12): 1685 - 1696. [Abstract] [Full Text]
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K. N. Richmond, J. D. Tune, M. W. Gorman, and E. O. Feigl Role of KATP+ channels and adenosine in the control of coronary blood flow during exercise J Appl Physiol, August 1, 2000; 89(2): 529 - 536. [Abstract] [Full Text] [PDF]
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J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl Role of Nitric Oxide and Adenosine in Control of Coronary Blood Flow in Exercising Dogs Circulation, June 27, 2000; 101(25): 2942 - 2948. [Abstract] [Full Text] [PDF]
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P. Pagliaro, N. Paolocci, T. Isoda, W. F Saavedra, G. Sunagawa, and D. A Kass Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide Cardiovasc Res, March 1, 2000; 45(4): 1001 - 1009. [Abstract] [Full Text] [PDF]
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S. J. Duffy, S. F. Castle, R. W. Harper, and I. T. Meredith Contribution of Vasodilator Prostanoids and Nitric Oxide to Resting Flow, Metabolic Vasodilation, and Flow-Mediated Dilation in Human Coronary Circulation Circulation, November 9, 1999; 100(19): 1951 - 1957. [Abstract] [Full Text] [PDF]
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S. J Duffy, G. New, R. W Harper, and I. T Meredith Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation Cardiovasc Res, August 15, 1999; 43(3): 721 - 730. [Abstract] [Full Text] [PDF]
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D. J. Duncker, J. H. Traverse, Y. Ishibashi, and R. J. Bache Effect of NO on transmural distribution of blood flow in hypertrophied left ventricle during exercise Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1305 - H1312. [Abstract] [Full Text] [PDF]
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M. F Bellamy, J. Goodfellow, A. C Tweddel, F. D.J Dunstan, M. J Lewis, and A. H Henderson Syndrome X and endothelial dysfunction Cardiovasc Res, November 1, 1998; 40(2): 410 - 417. [Abstract] [Full Text] [PDF]
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R. J. Bache Vasodilator Reserve : A Functional Assessment of Coronary Health Circulation, September 29, 1998; 98(13): 1257 - 1260. [Full Text] [PDF]
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S. Setty, J. D. Tune, and H. F. Downey Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H696 - H703. [Abstract] [Full Text] [PDF]
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A. J. M. Cornelissen, J. Dankelman, E. VanBavel, and J. A. E. Spaan Balance between myogenic, flow-dependent, and metabolic flow control in coronary arterial tree: a model study Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2224 - H2237. [Abstract] [Full Text] [PDF]
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