© 1998 American Heart Association, Inc.
Original Contributions |
Autonomic Control of Vasomotion in the Porcine Coronary Circulation During Treadmill Exercise
Evidence for Feed-Forward ß-Adrenergic Control
From Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Correspondence to Dirk J. Duncker, MD, PhD, Experimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail Duncker{at}tch.fgg.eur.nl
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Abstract |
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Abstract—To date, no studies have investigated coronary vasomotor control of myocardial O2 delivery (MDO2) and its modulation by the autonomic nervous system in the porcine heart during treadmill exercise. We studied 8 chronically instrumented swine under resting conditions and during graded treadmill exercise. Exercise up to 85% to 90% of maximum heart rate produced an increase in myocardial O2 consumption (M
O2) from
163±16 µmol/min (mean±SE) at rest to 423±75 µmol/min
(P
0.05), which was paralleled by an increase in
MDO2, so that myocardial O2
extraction (79±1% at rest) and coronary venous O2
tension (cvPO2, 23.7±1.0 mm Hg at rest)
were maintained. ß-Adrenoceptor blockade blunted the exercise-induced
increase of MDO2 out of proportion compared
with the attenuation of the exercise-induced increase in
MO2, so that O2 extraction
rose from 78±1% at rest to 83±1% during exercise and
cvPO2 fell from 23.5±0.9 to 19.6±1.1
mm Hg (both P0.05). In contrast, 
-adrenoceptor
blockade, either in the absence or presence of ß-adrenoceptor
blockade, had no effect on myocardial O2 extraction or
cvPO2 at rest or during exercise. Muscarinic
receptor blockade resulted in a decreased O2 extraction and
an increase in cvPO2 at rest, an effect that
waned during exercise. The vasodilation produced by muscarinic receptor
blockade was likely due to an increased ß-adrenoceptor activity,
since combined muscarinic and ß-adrenoceptor blockade produced
similar changes in O2 extraction and
cvPO2, as did ß-adrenoceptor blockade alone.
In conclusion, in swine myocardium,
MO2 and MDO2 are
matched during exercise, which is the result of feed-forward
ß-adrenergic vasodilation in conjunction with minimal -adrenergic
vasoconstriction. ß-Adrenergic vasodilation is due to an increase in
sympathetic activity but may also be supported by withdrawal of
muscarinic receptor–mediated inhibition of ß-adrenergic
coronary vasodilation. The observation that
cvPO2 levels are maintained even during heavy
exercise suggests that a decrease in cvPO2 is
not essential for coronary vasodilation during exercise.
Key Words: coronary blood flow • exercise • myocardial O2 extraction • autonomic nervous system • myocardial O2 consumption
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the normal heart, coronary blood flow is tightly regulated in response to changing metabolic needs to maintain a consistently high level of myocardial O2 extraction. The close coupling of coronary blood flow and myocardial O2 demand has been proposed to depend primarily on messengers released from the myocardium and endothelium but is also modulated by the autononomic nervous system.1 2 Thus, in dogs, the treadmill exercise–induced increases in coronary blood flow and, hence, O2 delivery do not fully match the increase in myocardial O2 demand, so that even at mild to moderate levels of exercise (<70% of maximum heart rate), myocardial O2 extraction increases3 4 5 6 7 and cvPO2 decreases.5 7 8 9 The decrease in cvPO2 may represent a metabolic error signal needed for a negative-feedback control mechanism1 10 but is at least in part due to
-adrenergic vasoconstriction of coronary resistance
vessels.7 9 11 Conversely, the increase in
sympathetic nerve activity during exercise also results in
ß-adrenergic coronary vasodilation,5 12
which acts in a "feed-forward control" manner (ie, an open-loop
control system that does not require an error
signal13,14) to blunt the -adrenergic
vasoconstriction in dogs.
To our knowledge, the only other mammalian heart in which the balance
between MDO2 and O2
utilization has been studied during exercise is the human
heart.1 2 In humans, myocardial
O2 extraction,15 16 17 18 19 20
cvSO2,16 18 19 20
cvO2 content,15 16 19 20 21
or cvPO219 22 are,
in contrast to dogs, minimally affected during mild to moderate
exercise (<80% of maximum heart rate), but an increase in fractional
O2 extraction and a decrease in
cvO2 content occur during heavy exercise (>85%
of maximum heart rate).18 23 24 25 In humans, the
minimal changes in cvPO2 at low to
moderate levels of exercise could be due to an increased importance of
ß-adrenergic coronary vasodilation26 27
or decreased importance of -adrenergic vasoconstriction, but this
has not been studied in humans. However, these findings indicate that
considerable interspecies differences of coronary vasomotor
control may exist during exercise. Therefore, in the present study,
we investigated coronary vasomotor control of myocardial
O2 balance during treadmill exercise in another
mammalian species, ie, swine, and observed that fractional myocardial
O2 extraction and
cvPO2 did not change even during
heavy treadmill exercise (85% to 90% of maximum heart rate). We
hypothesized that this could be the result of (1) negligible
-adrenergic coronary vasoconstriction in
swine,28 (2) increased importance of feed-forward
ß-adrenergic vasodilation,12 13 14 or (3)
withdrawal of vagal constrictor tone.29 30 31 To
determine the relative contributions of each of these potential
mechanisms, we studied myocardial O2 balance in
swine during treadmill exercise in the absence and presence of single
and combined blockade of - and ß-adrenergic receptors and
muscarinic receptors.
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Materials and Methods |
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Eight crossbred LandracexYorkshire pigs (5 male and 3 female) were used in the present study. All experiments were performed in accordance with the Guiding Principles in the Care and Use of Laboratory Animals as approved by the Council of the American Physiological Society and with the prior approval of the Animal Care Committee of the Erasmus University Rotterdam. Adaptation of animals to the laboratory conditions started 1 week before the day of surgery and continued until 10 days after surgery. Full details of the experimental procedures have been published previously.32 33 34
Surgical Procedures
After an overnight fast, pigs (23±1 kg) were sedated with 30
mg/kg IM ketamine (Ketalin, Apharmo BV), anesthetized
with thiopental (10 mg/kg IV, Nesdonal, Rhône-Poulenc Rorer BV),
intubated, and mechanically ventilated with a mixture of
O2 and nitrous oxide (1:2), to which 0.2% to 1%
(vol/vol) isoflurane (Forene, Abbott BV) was added.
Anesthesia was further maintained with midazolam (2
mg/kg+1 mg · kg-1 ·
h-1 IV, Dormicum, Roche BV) and fentanyl (10
µg · kg-1 ·
h-1 IV, Fentanyl-Janssen, Janssen-Cilag BV).
Under sterile conditions, the chest was opened via the fourth left
intercostal space, and an 8F fluid-filled PVC catheter was inserted
into the aortic arch (for the measurement of central aortic blood
pressure and collection of arterial blood samples) and
secured with a purse-string suture. After the pericardium was opened, a
high-fidelity pressure transducer (model P4.5,
Konigsberg Instruments Inc) was inserted into the LV via the apical
dimple for recording of LV pressure and its first derivative
(LV dP/dt, obtained via electrical differentiation). An 8F PVC catheter
was also inserted into the LV for calibration of the Konigsberg
transducer signal; another 8F PVC catheter was inserted into the
pulmonary artery for administration of drugs. A Doppler
flow probe (inner diameter, 2.0 to 3.0 mm;
f0, 20 MHz) was placed around the proximal part
of the LAD to measure the coronary Doppler shift. A small
angiocatheter (inner/outer diameter, 0.8 mm/1.1 mm) connected
to a larger Tygon catheter (inner/outer diameter, 0.8 mm/2.4
mm) was inserted directly into the anterior
interventricular vein to allow sampling of coronary
venous blood.35 Electrical wires and catheters
were tunneled subcutaneously to the back, the chest was closed, and the
animals were allowed to recover. All electrical wires and catheters
were protected with a vest.
Postsurgical Period
During the first week after surgery animals received
intravenous injections of 25 mg/kg amoxicillin (Clamoxil,
Beecham Farma BV) and 5 mg/kg gentamicin (Ad Usum Veterinarium) on a
daily basis to prevent infection. Catheters were flushed daily with
physiological saline containing 2000 IU/mL
heparin.
Experimental Protocols
Studies were performed 10 to 20 days after surgery with animals
exercising on a motor-driven treadmill. With swine lying quietly on the
treadmill, resting hemodynamic measurements, consisting
of LV pressure, LV dP/dt, aortic blood pressure, and the
coronary Doppler shift, were obtained, and
arterial and coronary venous blood samples were
collected. In 2 of the 8 animals, samples could not be obtained from
the coronary venous catheter. Hemodynamic
measurements were repeated, and rectal temperature was measured with
animals standing on the treadmill. Subsequently, a 5-stage treadmill
exercise protocol was started (1, 2, 3, 4, and 5 km/h); each exercise
stage lasted 2 to 3 minutes. LV pressure, LV dP/dt, aortic blood
pressure, and coronary blood flow were continuously measured,
and blood samples were collected during the last 30 seconds of each
exercise stage, when hemodynamics had reached a steady
state. After completing the exercise protocol, animals were allowed to
rest on the treadmill.
After 90 minutes of rest, animals underwent 1 of 4 protocols, which
were performed in random order and with each protocol performed on a
different day. In protocol 1, we studied the reproducibility of 2
consecutive exercise periods. For this purpose, animals received (via
the pulmonary artery catheter) an intravenous
infusion of saline (10 mL) at a rate of 2 mL/min; 5 minutes after the
infusion, resting measurements were obtained, and the 5-stage exercise
protocol was repeated. In protocol 2, we studied -adrenergic
vasomotor control of the coronary circulation during exercise.
For this purpose, animals received an intravenous infusion
of phentolamine (1 mg/kg in 10 mL saline, administered over 5
minutes) to produce -adrenergic receptor blockade. We have
previously shown that this dose of phentolamine results in
>95% inhibition of the intra-arterial
noradrenaline (0.3 µg/kg)–induced increase in carotid
vascular resistance in anesthetized
swine.36 Five minutes after completion of the
infusion, resting measurements were obtained, and the exercise protocol
was repeated. In protocol 3, we studied ß-adrenergic vasomotor
control of the coronary circulation during treadmill exercise
and studied the -adrenergic vasomotor control of the
coronary circulation in the presence of ß-adrenergic receptor
blockade. For this purpose, animals received an intravenous
infusion of propranolol (0.5 mg/kg, dissolved in 10 mL
saline administered over 5 minutes) to produce ß-adrenergic receptor
blockade. This dosage regimen results in >95% inhibition of
isoproterenol-induced increases in heart rate and LV
dP/dtmax in awake swine.32
Five minutes later, the exercise protocol was repeated. After another
90 minutes of rest, propranolol (0.2 mg/kg IV, in 4 mL
saline) was readministered. We have previously shown that this dosage
regimen of propranolol produces identical responses during
2 consecutive exercise protocols.34 Five minutes
later, -adrenergic receptor blockade was produced by infusing
phentolamine in a dose of 1 mg/kg IV (in 10 mL of saline) at a
rate of 2 mL/min, and the exercise protocol was repeated. In protocol
4, we studied muscarinic control of the coronary circulation
and studied ß-adrenergic vasomotor control of the coronary
circulation in the presence of muscarinic receptor blockade. For this
purpose, animals received an intravenous infusion of
atropine (30 µg · kg-1 ·
min-1 at a rate of 1 mL/min) to produce
muscarinic receptor blockade. This dose was considered to produce
complete vagal blockade, because higher doses did not produce further
increases in heart rate. Ten minutes after the start of the infusion,
when hemodynamics had reached a new steady state,
resting measurements were obtained, and the exercise protocol was
repeated. After completion of the exercise protocol, the atropine
infusion was interrupted, and animals were allowed to rest for another
90 minutes. Then, animals received an intravenous infusion
of propranolol (0.5 mg/kg, dissolved in 10 mL saline)
administered at a rate of 2 mL/min. After completion of
propranolol administration, the infusion of atropine (30
µg · kg-1 ·
min-1 IV) was restarted, and 10 minutes later,
the exercise protocol was repeated.
Hemodynamic Measurements
Aortic blood pressure was measured using a Combitrans pressure
transducer (Braun) with the reference point at midchest level. LV
pressure was measured with the Konigsberg
micromanometer, which was calibrated with the
fluid-filled LV catheter. The coronary Doppler shift was
measured with a high-velocity pulsed Doppler
velocimeter (model HVPD-20, Crystal Biotech).
Blood Gas Measurements
Blood samples were maintained in iced syringes until the
conclusion of each exercise trial. Measurements of
PO2 (mm Hg),
PCO2 (mm Hg), and pH were then
immediately performed with a blood gas analyzer (Acid-Base
Laboratory model 505, Radiometer).
SO2 and Hb (g/100 mL) were measured
with a hemoximeter (OSM2, Radiometer). Blood O2
content (µmol/mL) was computed as follows:
(Hbx0.621xSO2)+(0.00131xPO2).
MDO2 was computed as the product
of LAD coronary blood flow and arterial blood
O2 content;
MO2 in the region of
myocardium perfused by the LAD was calculated as the
product of coronary blood flow and the difference in
O2 content between arterial and
coronary venous blood. Myocardial O2
extraction was computed as the ratio of the arteriovenous
O2 content difference and the
arterial O2 content.
Data Acquisition and Analysis
Hemodynamic data were recorded and digitized
on-line using an 8-channel data-acquisition program (ATCODAS, Dataq
Instruments Inc) and stored on a computer for later postacquisition
off-line analysis with a program written in MatLab (The
Mathworks Inc). A minimum of 15 consecutive beats was selected for
analysis of the digitized hemodynamic signals.
From these selected beats, the LV peak systolic and LV
end-diastolic blood pressure, mean aortic blood pressure,
and mean coronary Doppler shift were determined for each
beat and averaged.
Mean coronary blood flow was computed from the mean
Doppler shift using the following equation: Q=1.25 ·
f · d2, where Q is the coronary
blood flow (mL/min), f is the Doppler shift (kHz), and d is the
internal diameter of the coronary artery (mm) within the flow
probe.37 The factor 1.25 is a constant derived
from the speed of sound in tissue (c=1.5x105
cm/s), the frequency of the emitted sound beam
(f0=20 MHz), the cosine of the angle at which the
sound beam is emitted (45o), and unit conversion
factors: (cx0.75
)/(2f0xcos
45o).37 Since in
chronically instrumented animals the flow probe is tightly adhered to
the coronary artery, the internal diameter of the flow probe is
equal to the external diameter of the artery. To obtain the inner
diameter of the coronary artery, we subtracted 10% of the
external diameter of the coronary artery, which is
approximately the arterial wall thickness. In this way, any
error in computation of the coronary internal diameter would
affect control and intervention conditions equally. Coronary
vascular resistance was computed as the ratio of mean aortic pressure
and coronary blood flow.
Statistical analysis was performed using 2-way (exercise and
treatment) ANOVA for repeated measures. When a significant effect of
exercise was observed, post hoc testing was performed using the Dunnett
test. When a significant effect of treatment was observed, post hoc
testing was performed using the Student-Newman-Keuls test. A value of
P0.05 was considered statistically significant (2-tailed).
All data are presented as mean±SE.
Drugs
Phentolamine (10 mg/mL, Regitine, CIBA-Geigy BV) was
dissolved in water containing glucose (35 mg/mL) and further diluted in
saline to produce a final concentration of 1 mg ·
kg-1 · 10 mL-1.
Propranolol (Sigma-Aldrich NV) was dissolved in 30°C
saline to produce a concentration of 0.5 mg ·
kg-1 · 10 mL-1.
Atropine (Sigma-Aldrich NV) was dissolved in 30°C saline to
produce a concentration of 30 µg ·
kg-1 · mL-1. Fresh
drug solutions were prepared on each day.
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Results |
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Reproducibility of Responses to Exercise
Hemodynamics
A representative example of the effects of saline on the hemodynamic data in an individual animal at rest and during exercise is shown in Figure 1
;
average data for all animals are presented in Figure 2. Exercise resulted in increases in
heart rate (from 114±5 bpm at rest to 242±3 bpm at 5 km/h), LV
systolic pressure (from 118±4 to 149±4 mm Hg), and LV
dP/dtmax (from 3110±240 to 6600±380
mm Hg/s) (all P0.05) but had no significant effects on
mean aortic pressure and LV end-diastolic pressure
(8±2 mm Hg at rest). LAD blood flow increased from 40±3 mL/min
at rest to 89±11 mL/min during exercise at 5 km/h. After 90 minutes of
rest, at a time when all hemodynamic variables had
returned to baseline resting values, the second period of exercise
resulted in nearly identical hemodynamic responses to
exercise.
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P
Myocardial O2 Balance
Exercise resulted in a slight decrease in arterial
PCO2 (from 44±2 mm Hg at rest
to 40±2 mm Hg at 5 km/h) and an increase in pH (from 7.43±0.01
to 7.46±0.01) (both P0.05) but had no effect on
arterial SO2 (96±1% at
rest, lying, and during exercise at 5 km/h). Arterial Hb
concentration (8.1±0.2 g% at rest and 9.1±0.4 g% at 5 km/h) and,
hence, the arterial O2 content
(4.95±0.16 µmol/mL at rest and 5.54±0.20 µmol/mL at 5
km/h) increased by 
12% at the highest level of exercise compared
with resting conditions (both P0.05), whereas
cvPCO2 (57±2 mm Hg at rest and
58±1 mm Hg at 5 km/h), cvpH (7.36±0.01 at rest and 7.37± 0.01
at 5 km/h), cvPO2 (23.7±1.0
mm Hg at rest and 23.4 ±1.3 mm Hg at 5 km/h),
cvSO2 (20.2±0.6% at rest and
20.1±1.2%), and cvO2 content (1.04±0.06
µmol/mL at rest and 1.17±0.11 µmol/mL at 5 km/h) did not
change from their respective resting values.
MO2 increased from 163±16 to
423±75 µmol/min, whereas MDO2
delivery increased from 193±18 to 539±99 µmol/min (both
P0.05), so that myocardial O2
extraction (ie, the ratio between
MDO2 and
MO2) was not altered during
exercise (Figure 3). All variables
returned to baseline resting values within 90 minutes; a second period
of exercise resulted in highly reproducible responses.
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Effects of -Adrenergic Receptor Blockade
Hemodynamics
Phentolamine produced a decrease in mean aortic pressure
at rest and during treadmill exercise, which was accompanied by
increases in heart rate and LV dP/dtmax, but no
effect on LV peak systolic pressure or LV
end-diastolic pressure (Figures 2
and 4). Coronary blood flow was not
significantly altered under resting conditions, but at higher levels of
exercise, coronary blood flow increased compared with control
exercise.
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Myocardial O2 Balance
Phentolamine had no effect on arterial
PCO2, pH, or
SO2 at rest or during exercise. In
the presence of phentolamine arterial Hb
concentration (8.3±0.3 g% at rest and 8.6±0.4 g% at 5 km/h,
P=NS); hence, the arterial
O2 content no longer increased during exercise.
Phentolamine had no significant effects on
cvPCO2, cvpH,
cvPO2,
cvSO2, or cvO2
content, either at rest or during exercise, except at 5 km/h, when pH
was slightly reduced (7.34±0.01) compared with control exercise
(7.38±0.01, P0.05). The relations between
MO2 and
cvPO2 or between
MO2 and
O2 extraction were not altered (Figure 3).
However, because arterial O2 content
no longer increased during exercise, the relation between
MO2 and coronary blood
flow shifted slightly upward toward higher blood flows compared with
control exercise (not shown).
Effects of ß-Adrenergic Receptor Blockade
Hemodynamics
Propranolol produced decreases in heart rate, LV
dP/dtmax, and coronary blood flow and
increases in LV end-diastolic pressure but had no effect on
mean aortic pressure or LV systolic pressure in resting swine
(Figures 2 and 5).
Propranolol also markedly blunted the exercise-induced
increases in heart rate, LV systolic pressure, LV
dP/dtmax, and coronary blood flow
compared with control exercise.
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Myocardial O2 Balance
Propranolol had no effect on arterial
PCO2, pH,
SO2, or Hb concentration; hence,
there was no effect on the arterial
O2 content either at rest or during exercise.
Similarly, cvPCO2 and cvpH were also
not altered by propranolol, but
cvPO2,
cvSO2, and cvO2
content, which were not affected by propranolol during
resting conditions, decreased progressively during exercise in the
presence of propranolol (Figure 3). Consequently, the
relation between MO2 and
cvPO2 was shifted downward, and the
relation between MO2 and
O2 extraction was shifted upward.
Effects of -Adrenergic Receptor Blockade in the Presence of
ß-Adrenergic Receptor Blockade
Hemodynamics
In the presence of propranolol, phentolamine
produced decreases in mean aortic pressure and LV systolic
pressure at rest and during treadmill exercise that were similar to the
effects of phentolamine in animals with intact
ß-adrenoceptors, but the increases in heart rate and LV
dP/dtmax were abolished, whereas there was now a
modest reduction in LV end-diastolic pressure (Figures 2 and 5). Phentolamine had no significant effect on
coronary blood flow or coronary vascular resistance at
rest or during exercise compared with propranolol
alone.
Myocardial O2 Balance
After propranolol, phentolamine had no effect
on arterial PCO2, pH, or
SO2 at rest or during exercise.
Arterial Hb concentration and, hence, the
arterial O2 content failed to
increase during exercise in the presence of phentolamine.
cvPCO2 and cvpH were not affected by
phentolamine in the presence of propranolol, except
at 5 km/h, when pH was slightly reduced (7.37±0.01) compared with
propranolol treatment (7.39±0.01, P0.05).
Phentolamine failed to increase
cvPO2,
cvSO2, or cvO2
content and failed to produce changes in the relation between
MO2 and
cvPO2 or between
MO2 and
O2 extraction (Figure 3). Similarly, the relation
between MDO2 and
MO2 was not altered by
phentolamine in the presence of propranolol (Figure 6). However, because arterial
O2 content failed to increase during exercise,
the relation between MO2 and
coronary blood flow was shifted upward toward higher blood
flows to compensate for the lower O2 carrying
capacity of the blood (Figure 6).
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Effects of Muscarinic Receptor Blockade
Hemodynamics
Atropine produced increases in heart rate, LV systolic
pressure, LV dP/dtmax, and coronary blood
flow and decreases in LV end-diastolic pressure but had no
effect on mean aortic pressure under resting conditions (Figures 7 and 8).
The effects of atropine gradually waned at progressively higher levels
of exercise.
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Myocardial O2 Balance
Atropine had no effect on arterial
PCO2, pH,
SO2, Hb concentration, or
O2 content either at rest or during exercise,
except at 4 km/h, when PCO2 was
slightly higher (43±2 mm Hg) compared with control exercise
(41±1 mm Hg, P0.05);
cvPCO2 and cvpH were also not
affected by atropine. In contrast,
cvPO2, cvSo2,
and cvO2 content increased significantly at rest
and during exercise at 1 and 2 km/h, but these values were no longer
different from control conditions at higher levels of exercise.
Consequently, the relation between
MO2 and
cvPO2 shifted upward in the lower
MO2 range, whereas the
relation between MO2 and
O2 extraction shifted downward (Figure 9).
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Effects of ß-Adrenergic Receptor Blockade in the Presence of
Muscarinic Receptor Blockade
Hemodynamics
The addition of ß-adrenergic receptor blockade with
propranolol to muscarinic receptor blockade with atropine
resulted in decreases in heart rate, LV systolic pressure, LV
dP/dtmax, and coronary blood flow at rest
and during exercise and an increase in LV end-diastolic
pressure but had no effect on mean aortic pressure (Figures 7 and 8).
Myocardial O2 Balance
The addition of propranolol to atropine had no effect
on arterial PCO2, pH,
SO2, Hb concentration, and
O2 content either at rest or during exercise.
Similarly, cvPCO2 and cvpH were also
not affected by propranolol.
cvPO2,
cvSO2, and cvO2
content were decreased both at rest and during exercise, so that the
relation between MO2 and
cvPO2 was shifted downward, and the
relation between MO2 and
O2 extraction was shifted upward (Figure 9).
Importantly, the effects of combined atropine and
propranolol on the relations between
MO2 and
cvPO2 or O2
extraction were not different from the effects of
propranolol alone.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study describes for the first time MDO2 and extraction of the LV and its modulation by the autonomic nervous system in awake swine at rest and during treadmill exercise. The major findings of the present study were as follows: (1) in swine, myocardial O2 extraction and cvPO2 were not altered from resting levels during treadmill exercise at levels up to 85% to 90% of maximum heart rate; (2)
-adrenergic receptor blockade did
not alter the relation between
MO2 and myocardial
O2 extraction or the relation between
MO2 and
cvPO2 (either in the absence or
presence of ß-adrenoceptor blockade), indicating that minimal
-adrenergic vasoconstriction occurs at rest and during exercise in
swine; (3) ß-adrenergic receptor blockade did not alter myocardial
O2 extraction or
cvPO2 under resting conditions but
produced progressively greater myocardial O2
extraction and produced a decrease in
cvPO2 during treadmill exercise,
indicating that ß-adrenoceptor activity was minimal under resting
conditions but contributed in a feed-forward manner to coronary
vasodilation during exercise; (4) muscarinic receptor blockade
decreased myocardial O2 extraction and increased
cvPO2 at rest and during mild
exercise, but this effect disappeared at higher levels of exercise,
indicating that muscarinic receptor activity exerted a vasoconstrictor
influence on the coronary circulation only at rest and during
low levels of exercise; and (5) the muscarinic vasoconstriction was
most likely the result of inhibition of ß-adrenergic vasodilator
influence, since the effects of combined ß-adrenergic receptor and
muscarinic receptor blockade on the relation between
MO2 and either myocardial
O2 extraction or
cvPO2 were not different from the
effects of ß-adrenergic receptor blockade alone. The implications of
these findings, which could not be explained by changes in
arterial or coronary venous
PCO2 or pH, will be discussed in
detail.
Myocardial O2 Extraction During Treadmill
Exercise
In dogs, the increase in coronary blood flow produced by
treadmill exercise does not fully match the increased myocardial
O2 demand; thus, even during mild to moderate
levels of exercise (<70% of maximum heart rate), an increase in
O2 extraction3 4 5 6 7 and,
hence, a decrease in cvPO2
occur.5 7 8 9 In contrast, in humans, minimal
changes in O2 extraction occur at mild to
moderate levels of exercise,15 16 17 18 19 20 although an
increase in O2 extraction and a decrease in
cvO2 content have been reported in humans during
heavy exercise (>85% of maximum heart
rate).18 23 24 25 The present study indicates
that at mild to moderate levels of exercise, swine resemble humans more
closely than dogs. However, in contrast to dogs and humans, swine also
maintain a constant level of myocardial O2
extraction and cvPO2 during heavy
exercise, indicating that the exercise-induced increase in
MDO2 matches the increase in
O2 consumption. A decrease in
cvPO2 has been proposed to
represent a metabolic error signal needed for a
negative-feedback metabolic control
mechanism,1 10 which is necessary for the
increase in coronary blood flow during exercise. The findings
in the present study indicate that a decrease in
cvPO2 is not essential for the
increase in coronary blood flow in the normal heart during
heavy treadmill exercise.
Although swine lack a native collateral circulation, it could be argued that the instrumentation of a coronary artery may have resulted in collateralization of the myocardium perfused by the instrumented LAD. The collateral vessels could potentially supply the LAD bed with additional blood, thereby contributing to a maintained cvPO2. Messina et al38 demonstrated that significant collateral blood flow does not occur until the intercoronary pressure gradient exceeds 70 mm Hg. Clearly, in the normal coronary circulation such intercoronary pressure gradients are not likely to occur even when a coronary artery is chronically instrumented.39 Consequently, alterations in coronary artery blood flow measured with a flow probe around the proximal artery are virtually identical to the increments in myocardial tissue blood flow measured with radioactive microspheres even under conditions of moderate coronary artery stenosis, which produces an intercoronary pressure gradient of <50 mm Hg.39 In addition, nearly identical treadmill exercise–induced increases in blood flow have been observed with simultaneous flow probe (to 321% of resting values) and microsphere (to 315% of resting values) measurements in swine.40 In our laboratory, we previously observed that the vascular resistance responses to dopamine receptor stimulation were similar when measured with a Doppler coronary flow probe or radioactive microspheres.33 Finally, we observed in 5 swine that coronary artery blood flow increased from 40±3 mL/min at rest to 71±6 mL/min (176±8% of resting values) during exercise at 3 to 4 km/h, while simultaneous microsphere measurements demonstrated an increase in myocardial blood flow from 1.52±0.07 mL · min-1 · g-1 at rest to 2.82±0.32 mL · min-1 · g-1 (184±18% of resting values) (authors' unpublished data, 1998). All these studies clearly indicate that under conditions of normal arterial inflow, no discernible collateral blood flow occurs in chronically instrumented hearts, so that the maintained cvPO2 in swine during exercise cannot be explained by the presence of collateral blood flow.
Adrenergic Control of Coronary Blood Flow and Myocardial
O2 Extraction During Treadmill Exercise
-Adrenoceptors
Although a decrease in cvPO2
during exercise has been proposed to represent a
metabolic error signal,1 10 it is at
least in part due to -adrenergic
vasoconstriction,7 9 11 indicating that an
increase in -adrenergic coronary vasoconstriction can
compete with metabolic vasodilation during exercise in
dogs. There are some conflicting reports regarding the functional
significance of -adrenergic receptors in the porcine
coronary resistance vessels. Thus, Schulz et
al28 infused the selective
1- and 2-receptor
agonists methoxamine and BHT-933, respectively, into the
coronary artery of open-chest vagotomized and ß-blocked
swine, while coronary blood flow was maintained constant to
prevent metabolic counterregulatory mechanisms from masking
-adrenergic constriction. Methoxamine had no effect on
coronary artery pressure, whereas BHT-933 produced minimal
increases, suggesting that no significant 1-
and minimal 2-receptors exist in porcine
coronary resistance vessels.28 In
contrast, a recent study reported that gallbladder distension resulted
in significant reflex-mediated coronary vasoconstriction,
resulting in a decrease in coronary blood flow that was
amenable to -adrenergic blockade with
phentolamine41; the -receptor subtype
responsible for the contraction was not investigated but, on the basis
of a report by Schulz et al,28 would likely be of
the 2 subtype. The observation in the
present study that nonselective -blockade with
phentolamine had no influence on coronary vasomotor
tone during exercise is consistent with the concept that the
predominant -receptor involved in coronary resistance vessel
constriction during exercise is of the 1
type,2 9 11 which swine appear to
lack.28 In addition to
adrenoreceptors of both the 1
and 2 subtypes that are located on
postjunctional vascular smooth muscle cells,
2-adrenoreceptors are also
found prejunctionally, where they inhibit the release of
catecholamines from sympathetic nerve
endings.42 Consequently, phentolamine
could have increased coronary blood flow and, hence, increase
cvPO2 and decrease
O2 extraction indirectly by increasing vascular
ß-adrenoceptor stimulation. The observation that
phentolamine, either in the absence or presence of
ß-adrenoceptor blockade, had no effect on
cvPO2 or O2
extraction suggests that prejunctional
2-mediated control of
catecholamine release is of minor importance in the porcine
coronary circulation.
Although -adrenergic blockade had no effect on the relation between
MO2 and
MDO2 or
cvPO2, -adrenergic blockade
produced an upward rotation of the relation between
MO2 and coronary blood
flow (Figure 2). The latter was necessitated by the -adrenoceptor
blockade–induced blunting of the exercise-induced 12±2% increase in
Hb. Compared with swine, in dogs, horses, and sheep,
O2 delivery to the myocardium is
facilitated by even more prominent increases in Hb concentration (20%
to 50%) during exercise and by the resultant increase in the
O2-carrying capacity of arterial
blood.3 4 43 44 45 The increase in Hb concentration
is virtually abolished after splenectomy,43 44
indicating that exercise elicits splenic contraction that expresses
erythrocyte-rich blood into the general circulation. In dogs,
splenectomy also necessitated a greater increase in coronary
blood flow at comparable levels of
MO2 during
norepinephrine infusion.45 In sheep,
pretreatment with the nonselective -adrenergic receptor blocker
phenoxybenzamine markedly blunted the increase in Hb concentrations,
indicating that contraction of the spleen is mediated by -adrenergic
receptor activation during exercise.46 Similarly,
in the present study, the increase in Hb was prevented by
phentolamine, indicating that splenic contraction in swine is
also mediated by -adrenoceptors.
ß-Adrenoceptors
Under resting conditions, we observed minimal ß-adrenergic
vasodilator influences on coronary vasomotor tone, which is in
agreement with earlier studies in awake dogs5 12
and humans.26 However, a progressive increase in
ß-adrenergic activity contributed to coronary vasodilation in
a feed-forward manner during exercise. Jorgensen et
al27 examined the effect of ß-adrenergic
blockade with propranolol on coronary blood flow in
healthy young adult male human subjects performing upright bicycle
exercise. Exercise loads were adjusted to achieve heart rates of 120
bpm during control conditions and after propranolol. At
matched heart rates, MO2
levels were similar during control conditions and after ß-adrenergic
blockade, but coronary blood flow was 25% less after
ß-adrenergic blockade and was accompanied by an increase in
myocardial O2 extraction. Also, in young male
volunteers, ß-adrenergic blockade with sotalol (10 mg IV) decreased
myocardial blood flow during supine bicycle exercise out of proportion
to the reduction of MO2, so
that myocardial O2 extraction rose and
coronary sinus O2 content
fell.26 Finally, in dogs, nonselective
ß-adrenergic blockade with propranolol also decreased
coronary blood flow more than expected from the decrease in
MO2, resulting in a
significant further increase in myocardial O2
extraction during treadmill exercise.5 12
Miyashiro and Feigl14 demonstrated that the
ß-adrenoceptor–mediated vasodilation in open-chest dogs produced by
infusion of norepinephrine balances the -adrenergic
vasoconstriction. In contrast, in swine that lack significant
-adrenergic vasoconstriction of coronary resistance vessels
during exercise, "unopposed" ß-adrenergic vasodilation produced
vasodilation that matched the increased O2 demand
so that cvO2 content and
PO2 were maintained. Only when
ß-adrenoceptors were blocked did exercise result in increased
O2 extraction and decreased
cvPO2. The latter possibly served as
a metabolic error signal to produce coronary
vasodilation during exercise in the presence of ß-adrenoceptor
blockade.
Parasympathetic Control of Coronary Blood Flow at Rest and
During Treadmill Exercise
The coronary resistance vessels are richly
innervated by the parasympathetic division of the autonomic
nervous system.1 In dogs pretreated with
propranolol and paced to maintain a constant heart rate,
stimulation of the vagosympathetic trunk produces coronary
vasodilation independent of the cardiac effects of vagal
stimulation.47 The coronary vasodilation
produced by vagal stimulation is blocked by atropine and is mimicked by
acetylcholine, which involves the release of
endothelial nitric oxide in the
dog.47 48 In contrast, the nitric oxide–mediated
acetylcholine-induced vasodilation in swine is outweighed by a direct
vasoconstrictor effect of acetylcholine, resulting in a net
vasoconstrictor response to acetylcholine29 30 31
or vagal nerve stimulation.29 Despite ample
evidence that stimulation of the parasympathetic system can influence
coronary vasomotor tone, the effects of vagal activity under
basal resting conditions are generally considered to be negligible,
even during basal resting conditions, when vagal activity is
high.1 30 However, previous studies have been
conducted principally in anesthetized animal models, which
could have blunted vagal tone.49 In addition,
coronary flow was not related to O2
consumption, which, in view of potential cardiac effects of vagal
inhibition, makes interpretation of these studies difficult. The
present study demonstrates that in awake swine, blockade of
muscarinic receptors elicited a vasodilator response in the
coronary resistance vessels under resting conditions that waned
during exercise. Vasodilation was likely the result of increased
ß-adrenergic activity, since it was fully blocked by the addition of
propranolol, so that propranolol alone or in
combination with atropine resulted in similar downward shift of the
relation between O2 consumption and
coronary PO2 and upward shift
of the relation between O2 consumption and
O2 extraction. Thus, the constrictor influence
that was exerted by the parasympathetic nervous system was due to
inhibition of ß-adrenergic vasodilator activity, so that withdrawal
of vagal tone could have contributed to ß-adrenergic vasodilation at
lower levels of exercise.
It cannot be determined from the present study whether the increased ß-adrenergic vasodilation resulted from disinhibition of norepinephrine release at terminal nerve endings within the coronary bed or was due to an increase in circulating catecholamines. There is evidence that vagal stimulation can produce a direct negative inotropic response in the LV independent of its effects on heart rate and sympathetic activity.50 In the present study, atropine produced marked increases in LV dP/dtmax that could be due to disinhibition of ß-adrenoceptor activity or a direct effect on the myocardium. The observation that LV dP/dtmax in resting swine after propranolol alone (2240±110 mm Hg/s) was not different from LV dP/dtmax observed after combined propranolol and atropine (2370±170 mm Hg/s) suggests that intrinsic muscarinic activity in the resting state decreased contractility primarily via inhibition of ß-adrenergic activity, with no discernible direct effect on the myocardium. Therefore, the increase in LV dP/dtmax produced by atropine reflects mostly an increase in sympathetic activity. At comparable levels of LV dP/dtmax, ie, under resting conditions in the presence of atropine (4370±250 mm Hg/s) versus exercise at 2 and 3 km/h under control conditions (4480±210 and 4900±290 mm Hg/s at 2 and 3 km/h, respectively), atropine still produced an increase in cvPO2. Furthermore, over the entire range of exercise intensities during control conditions, cvPO2 was not altered despite marked increments in sympathetic activity. Taken together, these findings could be interpreted to suggest that the interaction between the parasympathetic and sympathetic nervous system did not occur at the level of circulating catecholamines but at the level of the resistance vessels. Parasympathetic and sympathetic nerve fiber endings are found at the adventitial-medial border in coronary resistance vessels, indicating that parasympathetic fibers could directly inhibit the release of norepinephrine from the terminal nerve endings in the coronary bed, thereby reducing ß-adrenergic vasodilation.1 Further studies using intracoronary administration of atropine and propranolol are necessary to determine whether the increased ß-adrenergic vasodilation was the result of increased circulating levels of catecholamines, a local interaction at the nerve endings in the coronary resistance vessels, or both.
Conclusions
The present study described the
MDO2 and extraction patterns of the
LV and its modulation by the autonomic nervous system in awake swine at
rest and during treadmill exercise. O2 extraction
and cvPO2 were not altered from
resting levels during treadmill exercise at levels up to 85% to 90%
of maximum heart rate. The maintained levels of
cvPO2 were the result of feed-forward
ß-adrenergic coronary vasodilation during exercise in
conjunction with minimal -adrenergic vasoconstriction. The
ß-adrenergic vasodilation was likely due to a direct increase in
sympathetic activity but may have been supported at lower levels of
exercise by withdrawal of muscarinic receptor–mediated inhibition of
ß-adrenergic vasodilation.
Although there are a few studies of ß-adrenergic control of
MDO2 in
humans,26 27 there are, to our knowledge, no
human data regarding -adrenergic or muscarinic control of vasomotor
tone in coronary resistance vessels and their relative
contribution to regulation of coronary resistance vessel tone
at rest or during exercise. Consequently, concepts of mechanisms of
coronary blood flow regulation in the human heart during
exercise have, so far, been based largely on exercise data obtained in
the dog.1 2 The present study demonstrates
significant interspecies differences in coronary vasomotor
response and its autonomic control during exercise, warranting studies
of autonomic vasomotor control of coronary resistance vessels
in humans.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The research of Dr Duncker has been made possible by a Research Fellowship of the Royal Netherlands Academy of Arts and Sciences. The authors gratefully acknowledge Dineke de Bruyn for her secretarial assistance in the preparation of the manuscript.
Received July 28, 1997; accepted March 26, 1998.
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References |
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 D. J. Duncker, D. B. Haitsma, D. A. Liem, P. D. Verdouw, and D. Merkus Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction Cardiovasc Res, March 1, 2005; 65(4): 889 - 896. [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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D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880. [Abstract] [Full Text] [PDF]
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J. van der Velden, D. Merkus, B.R. Klarenbeek, A.T. James, N.M. Boontje, D.H.W. Dekkers, G.J.M. Stienen, J.M.J. Lamers, and D.J. Duncker Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction Circ. Res., November 26, 2004; 95(11): e85 - e95. [Abstract] [Full Text]
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E. O. Feigl Berne's adenosine hypothesis of coronary blood flow control Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1891 - H1894. [Abstract] [Full Text] [PDF]
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T. W. Hein, C. Zhang, W. Wang, and L. Kuo Heterogeneous {beta}2-Adrenoceptor Expression and Dilation in Coronary Arterioles Across the Left Ventricular Wall Circulation, October 26, 2004; 110(17): 2708 - 2712. [Abstract] [Full Text] [PDF]
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D. J. C. Alders, A. B. J. Groeneveld, F. J. J. de Kanter, and J. H. G. M. van Beek Myocardial O2 consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2 delivery Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1353 - H1361. [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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D. Merkus, B. Houweling, A. Zarbanoui, and D. J. Duncker Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1114 - H1123. [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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D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [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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D. B Haitsma, D. Bac, N. Raja, F. Boomsma, P. D Verdouw, and D. J Duncker Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations Cardiovasc Res, December 1, 2001; 52(3): 417 - 428. [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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D. J. Duncker, H. H. Oei, F. Hu, R. Stubenitsky, and P. D. Verdouw Role of KATP+ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H22 - H33. [Abstract] [Full Text] [PDF]
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M. W. Gorman, J. D. Tune, K. N. Richmond, and E. O. Feigl Feedforward sympathetic coronary vasodilation in exercising dogs J Appl Physiol, November 1, 2000; 89(5): 1892 - 1902. [Abstract] [Full Text] [PDF]
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M. W. Gorman, J. D. Tune, K. N. Richmond, and E. O. Feigl Quantitative analysis of feedforward sympathetic coronary vasodilation in exercising dogs J Appl Physiol, November 1, 2000; 89(5): 1903 - 1911. [Abstract] [Full Text] [PDF]
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J. P. van Kats, D. J. Duncker, D. B. Haitsma, M. P. Schuijt, R. Niebuur, R. Stubenitsky, F. Boomsma, M. A. D. H. Schalekamp, P. D. Verdouw, and A. H. J. Danser Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction : Role of Tissue Angiotensin II Circulation, September 26, 2000; 102(13): 1556 - 1563. [Abstract] [Full Text] [PDF]
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D. J. Duncker, R. Stubenitsky, P. A.L. Tonino, and P. D. Verdouw Nitric oxide contributes to the regulation of vasomotor tone but does not modulate O2-consumption in exercising swine Cardiovasc Res, September 1, 2000; 47(4): 738 - 748. [Abstract] [Full Text] [PDF]
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K. N. Richmond, J. D. Tune, M. W. Gorman, and E. O. Feigl Role of K+ATP channels in local metabolic coronary vasodilation Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2115 - H2123. [Abstract] [Full Text] [PDF]
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J. Bartunek, W. Wijns, G. R. Heyndrickx, and B. de Bruyne Effects of Dobutamine on Coronary Stenosis Physiology and Morphology : Comparison With Intracoronary Adenosine Circulation, July 20, 1999; 100(3): 243 - 249. [Abstract] [Full Text] [PDF]
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T. Yada, K. N. Richmond, R. van Bibber, K. Kroll, and E. O. Feigl Role of adenosine in local metabolic coronary vasodilation Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1425 - H1433. [Abstract] [Full Text] [PDF]
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D. J. Duncker, R. Stubenitsky, and P. D. Verdouw Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1663 - H1672. [Abstract] [Full Text] [PDF]
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M. Takamura, R. Parent, and M. Lavallee Enhanced contribution of NO to exercise-induced coronary responses after alpha -adrenergic receptor blockade Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H508 - H515. [Abstract] [Full Text] [PDF]
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D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [Abstract] [Full Text] [PDF]
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