286
Adrenergic Coronary Vasoconstriction Helps
Maintain Uniform Transmural Blood Flow
Distribution During Exercise
Alice H. Huang and Eric O. Feigl
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The hypothesis that a-adrenergic coronary vasoconstriction helps maintain a uniform transmural
distribution of myocardial blood flow during exercise was tested in dogs. Carotid artery loops were
surgically constructed and a splenectomy performed three weeks prior to study. On the day of study,
the dog was anesthetized briefly (fentanyl and nitrous oxide) for percutaneous catheterization, and
a-receptors in one myocardial region were blocked with phenoxybenzamine (0.25 mg/kg) infused
selectively into the left circumflex coronary artery. Recirculation of phenoxybenzamine was minimized
by drainage of coronary sinus outflow during the infusion. After the dog recovered from the anesthesia,
regional blood flow was measured at rest and during graded treadmill exercise with the microsphere
technique calibrated by reference blood samples. Average transmural flow was limited by avasoconstriction and was less in the region where a-receptors were intact than in the region where
they were blocked, as has been described by others. The ratio of inner layer myocardial blood flow
to outer layer flow was better maintained in the region with a-receptors intact than in the region with
a-receptors blocked when myocardial oxygen consumption was 150 /tl/min/g or greater (p<0.001).
Even though average transmural flow was limited by a-receptor activation, inner layer myocardial
blood flow was greater in the region with a-receptors intact than in the region with a-receptors blocked
when myocardial oxygen consumption was 500 fxVm\n/g or more (p<0.05). In conclusion, adrenergic
coronary vasoconstriction mediated by a-receptors helps to maintain a uniform transmural
distribution of myocardial blood flow during exercise in spite of limiting average transmural flow.
(Circulation Research 1988;62:286-298)
hen the coronary vessels are dilated pharmacologically with adenosine and the heart is
electrically paced from 100 to 250 beats/
min, the ratio of inner myocardial blood flow to outer
myocardial blood flow (inner/outer flow ratio) falls
dramatically from 1.0 to 0.4.' This is consistent with
the concept that myocardial compression impedes
blood flow to the inner layers of the myocardium more
than it does to the outer layers. Because a larger
proportion of each cardiac cycle is spent in systole as
heart rate increases, tachycardia tends to exaggerate the
effects of this transmural gradient of compression.
In contrast to the situation with adenosine and
pacing, when coronary vasodilation and tachycardia
develop in response to exercise, the transmural distribution of coronary blood flow changes little, and the
inner/outer flow ratio remains at or above l.O.2"4 This
suggests that some component of the physiological
response to exercise helps maintain the uniform transmural distribution of flow.
Several laboratories have demonstrated that adren-
W
ergic coronary vasoconstriction mediated by a-receptors is part of the physiological response to exercise.5"9
The resulting restriction of functional hyperemia seems
paradoxical because the metabolic demand for myocardial blood flow is greatly elevated during exercise.
However, the adrenergic vasoconstriction during exercise might improve the match between myocardial
metabolism and blood flow across the ventricular wall
by altering the transmural distribution of blood flow.
Radioactive microspheres were used to make paired
comparisons of flow between a-intact and a-blocked
regions of the left ventricle during graded treadmill
exercise. Coronary blood flow and its transmural distribution were analyzed as functions of myocardial oxygen
consumption, an index of exercise intensity directly
relevant to the myocardium. The transmural distribution
of blood flow was more uniform, and flow in the inner
layer of the left ventricle was better maintained with
a-receptors intact than with a-receptors blocked. This
indicates that coronary vasoconstriction mediated by
adrenergic a-receptors may be beneficial during exercise.
From the Department of Physiology and Biophysics, University
of Washington, Seattle, Washington.
Supported by National Institutes of Health grants HL-16910 and
HL-07090, and by a Dissertation Fellowship from the Educational
Foundation of the American Association of University Women.
Dr. Huang's present address: Institute of Applied Physiology,
University of Freiburg, Hermann Herder Strasse 7, D-7800 Freiburg, Federal Republic of West Germany.
Address for correspondence: Dr. Eric O. Feigl, Department of
Physiology and Biophysics, University cf Washington, SJ-40,
Seattle, WA 98195.
Received February 10, 1987; accepted August 7, 1987.
Materials and Methods
The general experimental strategy was to compare
the transmural distribution of myocardial blood flow in
a-receptor blocked and a-receptor intact regions of the
same left ventricle during rest and graded treadmill
exercise. The a-blocked region was selectively marked
with radioactive microspheres injected together with
the a-blocking agent so that this area could be identified
postmortem when sections of the left ventricle were
analyzed for radioactivity. Transmural coronary blood
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
flow in both regions was determined with other
radioactive microspheres injected into the left atrium
(Figure 1).
Experimental Groups
Mongrel dogs, 14.5-26.8 kg, were selected on the
bases of overall health, tractability, and enthusiasm for
treadmill exercise. These were divided into three
experimental groups. 1) a-blocked group (20 dogs).
Phenoxybenzamine infused selectively into the left
circumflex coronary artery blocked a-receptors in the
region perfused by that vessel. 2) a- and ^-blocked
group (15 dogs). In addition to phenoxybenzamine
selectively infused into the circumflex coronary artery,
the dogs in this group also received intravenous
propranolol. Because prejunctional a-receptors, involved in feedback inhibition of norepinephrine reDownloaded from http://circres.ahajournals.org/ by guest on September 30, 2016
Infusion
catheter
Coronary
>— sinus
- , drain
"
5 SVC
Coronary
' sinus
...Circumflex
coronary a.
287
lease, are blocked along with postjunctional areceptors by phenoxybenzamine,10" norepinephrine
release may be enhanced in the a-blocked region. The
additional blockade of )3-receptors prevents the increase in myocardial metabolism and the associated
metabolic vasodilation likely to result from this enhanced release of norepinephrine and thereby helps to
distinguish the direct effects of blocking postjunctional
coronary a-receptors from the indirect prejunctional
a-receptor-mediated effects (see "Discussion"). 3)
Vehicle group (17 dogs). Instead of phenoxybenzamine, only the vehicle for phenoxybenzamine was
infused into the left circumflex coronary artery. Differences between the myocardial regions, independent
of the effects of a-blockade, were measured in this
group.
Preliminary Training and Surgery
After each dog became familiar with the treadmill,
preliminary sterile surgery was performed under anesthesia induced with sodium thiamylal (Surital, 18
mg/kg i.v.) and maintained by spontaneous inhalation
of halothane. The common carotid arteries were
exteriorized in protective skin tubes to form arterial
loops.12 The spleen was removed. Postoperative discomfort was controlled with morphine (0.25 mg/kg
s.c). At least three weeks were allowed for recovery
from surgery and resumption of treadmill training
before study. The training protocol was not designed for
physical conditioning.
LAD-
FIGURE 1. Regional a-blockade. A: Phenoxybenzamine (or
vehicle) was infused via a catheter in the left circumflex coronary
artery. Radiolabeled microspheres included in the infusion
mixture marked the treated (stippled) region. Drainage of
coronary venous return from the coronary sinus minimized
recirculation of phenoxybenzamine. B: The left ventricular free
wall included a treated (stippled) region (perfused by the
circumflex artery) and an untreated region (perfused by the
anterior descending artery), cut into transmural sections as
shown. C.Inner, middle, andouter layers of transmural sections
were individually counted for radioactivity. Labeled pieces in
the center of the treated (stippled) region were mathematically
combined to reconstitute a treated region. A noncontiguous,
untreated region was similarly reconstitutedfor comparison (see
"Regional Analysis" in "Materials and Methods").
Experimental Preparation
On the day of study, the dog was anesthetized for
about 2 hours with fentanyl citrate (0.25 mg/kg i.v. for
induction, plus 1.0-mg supplements every 30 minutes
or as needed) and nitrous oxide (80% in oxygen,
ventilation with Harvardrespiratorpump, model 607).
Prophylactic heparin sodium (100 U/kg s.c.) was given
at this time, complementing the effect of aspirin (324
mg p.o.) given 12-18 hours earlier. End-expired CO2
was monitored (Beckman LB-2 Medical Gas Analyzer)
and maintained at about 5% by adjustments in ventilatory rate, and standard base excess in arterial blood
was maintained above —4.0 meq/1 with NaHCO3
(8.4% solution i.v.). A catheter introducer sheath
(USCI Hemaquet, F8) was inserted percutaneously into
each carotid artery loop with the Seldinger technique,13
then the left circumflex region of the myocardium was
selectively treated, and the dog was instrumented as
described below. The skin and subcutaneous tissues of
the neck were infiltrated with a long-acting local
anesthetic (bupivicaine hydrochloride, 0.0625%), and
general anesthesia wasreversedwith a combination of
narcotic antagonists: naloxone hydrochloride (0.2
mg/kg i.v.), which was very rapid and short-acting, and
naltrexone hydrochloride (0.1 mg/kg i.m.), which was
slow and long-acting. During recovery, the dog was
given water to drink and was allowed to roam about the
laboratory at will. A supplement of naloxone (0.2
mg/kg i.v.) was given before exercise began, following
2l/i hours of recovery.
288
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Regional a-Receptor Blockade
Phenoxybenzamine hydrochloride (Dibenzyline, 50
mg/ml) was diluted to 4 mg/ml with normal saline and
mixed with radionuclide-labeledmicrospheres(l x 103
beads) for marking the distribution of phenoxybenzamine. This was suspended in 24 ml of arterial blood and
infused at 11.5 ml/min (Harvard syringe pump, model
945) via a 7.5F Sones catheter (USCI 007561) passed
down the right carotid artery and, under fluoroscopic
guidance, into the left circumflex coronary artery
(Figure 1A). The intracoronary dose of phenoxybenzamine was 0.25 mg/kg, which has been shown to
effectively block adrenergic coronary vasoconstriction
during a carotid sinus reflex or intracoronary norepinephrine infusion.14
Recirculation of phenoxybenzamine was minimized
by draining coronary sinus effluent, during and for 1
minute after the selective coronary infusion, via a
modified 14F Foley catheter with its tip in the coronary
sinus. The Foley catheter was introduced via the right
jugular vein underfluoroscopicguidance and sealed in
the coronary sinus ostium with its balloon. The drained
blood was discarded and the volume (about 200 ml)
replaced with 10% dextran (10 dogs) or with blood
drawn from the dog about 3 weeks beforehand (42
dogs) and stored with CPDA-1 (anticoagulant citrate
phosphate dextrose adenine solution) at 4.5° C. The
coronary arterial and sinus catheters were then removed. The vehicle group was treated identically
except that the vehicle in which Dibenzyline was
supplied (48.5% ethanol and 0.5% HC1 in propylene
glycol) was diluted and infused instead of Dibenzyline.
Instrumentation
The left atrium was catheterized transseptally via the
left jugular vein, with a modified version of the
technique described by Phillips et al." A Swan-Ganz
catheter (American Edwards 93-111-7F) was secured
in the left atrium by inflating its balloon (Figure 2).
A 7.5F Sones catheter (USCI 007561) was passed
down therightjugular vein andfluoroscopicallyguided
into the coronary sinus. Postmortem, the catheter tip
was found to lie 22-60 mm beyond the coronary sinus
ostium where it selectively sampled coronary venous
blood.16
A catheter-tipped manometer (Millar Instruments
PC-470, Houston, Texas) inserted via the introducer
sheath in the right carotid artery was positioned at the
level of the heart in the descending aorta for continuous
recording of arterial pressure and heart rate during
exercise.
An 8F polyurethane catheter was positioned with its
tip 1 cm beyond the end of the introducer sheath in the
left carotid artery for withdrawal of reference blood
samples."
Experimental Protocol
Five predetermined conditions were obtained by
adjusting the speed and grade of the treadmill. Successive target heart rates were 1) resting, 2) moderate
warm-up, 3) near-maximal (judged from previous
Circulation Research
Vol 62, No 2, February 1988
Microsphere
reference
sample
SVC
Cath
tip
manometer
Cor—
sinus
ostium
FIGURE 2. Instrumentation for experimental protocol. Microspheres were injected via a catheter placed transseptally in the
left atrium. Arterial samples for calibrating microsphere
measurements and for blood gas analysis were drawn from the
carotid artery. Coronary venous samples for blood gas analysis
were drawn from the coronary sinus. Arterial pressure was
monitored with a catheter-tip manometer in the descending
aorta.
exercise training sessions), 4) intermediate between
warm-up and near-maximal, and 5) intermediate betweenrestingand warm-up. Rest periods after each run
allowed heart rate and arterial pressure to return to
near the resting levels. After the protocol was completed, the dog was sacrificed with intravenous sodium
pentobarbital.
When the dog had a steady heart rate and blood
pressure, arterial and coronary sinus blood samples
were drawn, and radionuclide-labeled microspheres
were infused into the left atrium over 15-30 seconds.
A reference blood sample was drawn (7.47 ml/min,
Harvard syringe pump, model 968) starting at least 15
seconds before, and continuing for 90 seconds after, the
infusion began.
In the a- and /3-blocked group, systemic /3-blockade
was imposed with propranolol hydrochloride (2.0
mg/kg i.v.) at least 10 minutes prior to the first infusion
of microspheres. Heart rate responses to isoproterenol
hydrochloride (bolus doses, 0.003-10.0 /i.g/kg i.v. in
half-log increments) were recorded before propranolol
and again after completion of the exercise protocol.
After /3-blockade, the isoproterenol dose-response
curve was shifted 1.6 orders of magnitude to the right.
Thus, )3-receptors were effectively blocked.
Blood Samples
Arterial and coronary sinus blood samples were
heparinized for blood gas analysis (Instrumentation
Laboratories 1302 pH/blood gas analyzer) and for
measurement of oxygen content (Lex O2 Con, Lexington Instruments). The microsphere reference blood
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
samples were mixed with EDTA and sodium bisulfite
and centrifuged at 1,500 rpm for 10 minutes at 4° C.
Then, the plasma was collected for analysis of catecholamine content by high-performance liquid chromatography with electrochemical detection (performed by the clinical laboratory of University
Hospital, University of Washington, Seattle, with a
modified version of the technique of Hallman et al18)-
289
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Analysis of Radioactivity
The microspheres used (10 fim diameter in 15 dogs,
15 /xm diameter in 37 dogs) were labeled with **Sc,
"Nb, IO3Ru, " 3 Sn, 51Cr, and 141Ce and were supplied by
New England Nuclear, Boston, Massachusetts, in
10% dextran with 0.01% Tween 80. One isotope (31Cr
or l4lCe) was used to mark the treated region (described
above), and the other five isotopes, in random order,
were used to measure blood flow. The microsphere dose
(usually 2.24 x 106 beads) was calculated, with adjustments for radioactive decay, so that at least 400 beads,
emitting at least 10,000 counts in 1,000 seconds, were
trapped in each layer of each myocardial region. Each
dose was diluted to 2.5 ml with normal saline and
subjected to ultrasonication and intermittent vortexmixing, to disperse the microspheres, for 2 hours
before infusion.
The gamma activity of each tissue and blood sample
was analyzed in a Packard Auto-Gamma Scintillation
Spectrometer, and the counts from the six different
nuclide labels were separated by the simultaneous
equation method described by Baer et al."
The separated counts were calibrated in units of flow
according to the activities of the reference samples
(counts/minute/milliliter).17 The number of microspheres present was also calculated from the separated
counts according to the activities of samples containing
known numbers of microspheres counted under a
microscope.
marked contiguous transmural sections were included
only if they had marker densities at least 1.75 times the
mean, and until the treated region contained at least
three sections with at least 400 microspheres and
10,000 counts of each label in each layer. Similarly, the
untreated region included all contiguous transmural
sections with no more than one tenth the mean marker
density, provided they were not contiguous with any
section having a marker density greater than or equal
to the mean. These criteria separated the two regions
and minimized inclusion of partially treated tissue in
either region (Figure 1).
Experiments were rejected when the regional selectivity of the treatment was poor according to the
following criteria: 1) if fewer than three transmural
sections were included in each myocardial region (six
dogs), because such small regions suggest that the
circumflex region was poorly perfused with the treatment mixture and/or that the rest of the myocardium
was contaminated by it; and 2) if the density of marker
microspheres in peripheral tissues was high, because
this suggests that part of the treatment mixture infused
into the left circumflex coronary artery refluxed into the
aorta and was distributed systemically. Ten dogs were
rejected because the right ventricular density was
greater than one tenth the mean left ventricular density.
One dog was rejected because the marker density of the
renal cortex was greater than the mean left ventricular
density.
The counts from each section in a region were added
together, and the region was analyzed as a single sample
divided into inner, middle, and outer layers. For each
nuclide, transmural flow (miymin/g) was calculated for
each region from the total counts summed over all three
layers of all sections and divided by the total mass of
the region corrected for dehydration in formaldehyde.
Count densities and flows were also calculated for each
layer. The inner/outer flow ratio was calculated from
the layer count densities (rather than layer flows), for
computational precision: inner/outer ratio = count density of inner layer/count density of outer layer.
Total flow to the left ventricular free wall (ml
blood/min/g) was calculated for each nuclide (total
counts in all layers of all sections divided by total mass
calibrated with the reference samples), and multiplied
by the arteriovenous difference in oxygen content
across the left ventricular myocardium, yielding average myocardial oxygen consumption (/xl Oj/min/g),
according to the Fick equation.
Regional Analysis
Myocardial regions were defined on the basis of the
density of marker microspheres in each transmural
section (number of marker microspheres present per
unit mass of tissue) relative to the mean marker density
(total number of marker microspheres present in the
sampled left ventricular myocardium divided by its
total mass). The treated region was defined by the
following prospective criteria: 1) all contiguous transmural sections with at least twice the mean marker
density were included; and 2) successive less densely
Analysis of Error in Microsphere Method
In a flow measurement made with microspheres, the
relative error due to the stochastic nature of microsphere distribution is defined as the deviation of the
measurement from the true flow, relative to the
magnitude of the true flow. According to Dole et al,20
the 95% confidence limits for the relative error are then
± 1.96(1/NT+ 1/NJ"2, where NT and NR refer to the
number of microspheres (with a given label) trapped in
the tissue and in the reference sample, respectively.
These confidence limits were calculated for each layer
Tissue Samples
The left ventricular free wall was cut into 30—45
transmural sections (Figure IB); each was trimmed of
epicardium, epicardial fat, large vessels, and papillary
muscles, and each was divided into three layers, inner,
middle, and outer myocardium, of equal thickness
(Figure 1C). These, plus a sample of the right ventricular free wall (1-1.5 g) and 4 cortical samples from
each kidney (about 0.4 g each, 44 dogs), were fixed in
37% formaldehyde solution.
290
of each region; they were within ± 10% for 94.5% of
the observations and were never greater than ± 15%.
In 42 dogs, microsphere distributions to the two
kidneys differed by less than 10% in 94.2% of the
observations, and never by more than 16.9%, indicating that the microspheres were adequately mixed with
the cardiac output. Two dogs from which renal cortical
samples were taken were excluded from this analysis
because of evidence of errors in the tissue sampling
procedure.
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Statistical Analyses
The general statistical approach was to fit a separate
least-squares regression line to the observations from
each dog versus myocardial oxygen consumption (as in
Figure 5). These individual regression lines from
different dogs were then summarized by multiple linear
regression computed with the SPSS program.21 The
difference in response between the two myocardial
regions in each dog was analyzed as the dependent
variable to preserve the paired nature of the observations. The differences between regions within each
group were tested with paired t tests, and the differences
between groups were tested with unpaired t tests.
Differences in regression slopes reflected the overall
relation between dependent variables and myocardial
oxygen consumption. Differences in the magnitude
of the dependent variables varied with the level of
myocardial oxygen consumption. Accordingly, tests of
differences in magnitude were performed at intervals
of 50 fi\ Cymin/g to estimate the level of myocardial
oxygen consumption at which the responses became
significant.
The multiple regression calculation required symmetry in the data sets, so for each missing observation,
the mean of the other four flow measurements in the
same dog was substituted. This maneuver restored
symmetry without changing the average value, the
slope, or the intercept of the individual regression line
that the multiple linear regression analysis is based on.
There were four missing data points, one from each of
three dogs in the vehicle group (three observations out
of 85) and one missing point in the a-blocked group
(one observation out of 100).
Because the logarithmic transformation of a ratio
variable tends to be more normally distributed than the
ratio itself is, analyses were performed with In (inner/
outer ratios) in addition to the usual inner/outer flow
ratio. The results were not meaningfully different, so
the data and analyses are presented here in terms of the
conceptually more direct, untransformed variables.
The variability of the data is shown in the figures.
Figure 5 shows the scatter of individual observations
around the simple linear regression lines for each
region in one dog (within-dog variability). Figures 6,
7, and 8 (Panels B and C) show the variability of the
simpleregressionlines calculated for each dog (amongdog variability). Figures 9 and 10 show the residual
(within-dog) variability of the observations, scattered
around the mean lines calculated by multiple linear
regression, which accounts for the differences among
Circulation Research
Vol 62, No 2, February 1988
dogs. Tests of the effect of a-blockade were based on
the paired differences (treated, left circumflex region
versus untreated, left anterior descending region) and
the residual variability, as plotted in Figures 9 and 10.
Results
General Response to Exercise
The dogs ran on the treadmill at speeds up to 9.6
km/hr in combination with grades from 0.0% to 20%.
The average resting myocardial oxygen consumption
in the vehicle group was 122 ± 12 (SEM) /il/min/g and
increased to an average maximum of 454 ±25
/xl/min/g. In the a-receptor blocked group, the average
myocardial oxygen consumption values at rest and
maximum exercise were 156 ±12 and 559 ±42
/il/min/g,respectively./3-Receptor blockade markedly
attenuated the cardiac exercise response. The average
resting value was 112 ± 7 fil O^min/g and increased to
an average maximum value of only 289 ±14 fi\
O/min/g in the a- and /3-receptor blocked group.
Heart rate increased from as low as 52 beats/min at
rest to as high as 291 beats/min during exercise (Figure
3). The average resting heart rate was 79.4 ±4.7
beats/min (SEM) in the vehicle group, 100.4±5.9
beats/min in the a-receptor blocked group, and
81.4±5.2 beats/min in the a- and /3-blocked group.
The average maximum heart rate was 238.3±4.8
beats/min in the vehicle group, 245.2±6.5 beats/min
in the a-blocked group, and 189.0±3.1 beats/min in
the a- and /3-blocked group. Systolic blood pressure
increased significantly (/?<0.0001) during exercise in
all experimental groups, while diastolic blood pressure
changed little with exercise (Figure 3). The dogs
hyperventilated during exercise, with a significant
(p<0.0001) progressive decline in Paco2 from approximately 31-32 mm Hg at rest to approximately
24-26 mm Hg during maximal exercise. This was
accompanied by a small increase in Pao2 from approximately 87-91 mm Hg at rest to approximately 94-96
mm Hg during maximal exercise, which was statistically significant (p<0.05) in the two groups with
a-blockade. Arterial plasma epinephrine and norepinephrine concentrations, indicative of the degree of
sympathetic activation, increased dramatically in all
groups from less than 300 pg/ml at rest to 500-1,400
pg/nil during maximal exercise. Interestingly, the
catecholamine response was more marked in the two
groups with a-blockade than in the vehicle group.
Transmural Coronary Flow
Coronary blood flow increased consistently with
exercise intensity in all three experimental groups
(Figure 4). Flow increased approximately in proportion
with myocardial oxygen consumption in the a-blocked
and vehicle groups, so there were no significant
changes in coronary sinus oxygen tension (approximately 16-17 mm Hg) or in the coronary arteriovenous
difference in oxygen content (approximately 12-13 ml
Oj/100 ml blood). In contrast, in the group with both
a- and )3-blockade, coronary sinus oxygen tension fell
significantly (from approximately 16 to 11 mm Hg,
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
ALPHA BLOCKED
291
ALPHA-BETA BLOCKED
VEHICLE
HEART RATE (beats/min)
300-
x/x
x
200100 99 obMTvatkn
20 dogs
15 dogs
17 dops
75 observations
82 observatloni
0AORTIC PRESSURE (mm Hg)
X
syaotic
syaoBc
syuoHc
k
200-
*x
^-
X
%,
X
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1
" ^ "
•?•
10020 dcxjB
15 dogB
99 observations
75 observations
17 dogs
danolk;
82 otnenrtition*
1—
500
500
1000
1000
500
1000
MYOCARDIAL OXYGEN CONSUMPTION (JJI 0 3 / m i n / g )
FIGURE 3. Hemodynamic responses to exercise plotted as functions of myocardial oxygen consumption. Individual points illustrate
variability within and among dogs. Lines were calculated by multiple linear regression.
p<0.0001), and the arteriovenous difference in oxygen
content widened (from approximately 13 to 15 ml
Oj/100 ml blood, p<0.0001) with exercise.
Regional Transmural Coronary Flow
The magnitude of the regional a-receptor blockade
may be estimated as the difference inflowbetween the
paired regions, relative to the flow in the circumflex
region. In the a-blocked group, theflowin the a-intact
(anterior descending) region averaged 12.2% less than
in the a-blocked (circumflex) region. In the vehicle
group, the flow in the anterior descending region
averaged 6.3% less than in the circumflex region. Thus,
the differential effect of a-receptor blockade was
approximately 6% (12.2% minus 6.3%), and this
difference was significant (p<0.0\) when myocardial
oxygen consumption was 200 /il/min/g or more. This
demonstrates that a-receptors in the circumflex region
were effectively blocked.
The left ventricular inner/outer blood flow ratio
decreased with increasing levels of exercise in all
experimental groups (Figures 5-8). The a-intact left
anterior descending region had a more favorable
inner/outer blood flow ratio than the a-blocked
circumflex region in the same heart (Figure 6). In
contrast, the inner/outer flow relation between anterior descending and circumflex regions was reversed
in the vehicle group (Figure 7). The difference in
inner/outer ratio between the a-blocked and a-intact
regions was significant (p<0.01) when myocardial
oxygen consumption was 150 ixVmxnJg or greater. A
similar trend in the inner/outer flow ratio was ob-
served between the a-intact and a-blocked regions in
the group with prior /3-blockade; however, myocardial
oxygen consumption was very limited, and a significant difference could be predicted only by extrapolation (Figure 8).
The paired differences in inner/outer flow ratio
between the circumflex and anterior descending regions
for the a-blocked and vehicle groups are compared in
Figure 9. The inner/outer flow ratio was greater in the
circumflex region than in the anterior descending
region in the vehicle (a-receptors intact) group, and this
did not change with exercise. In contrast, when the
circumflex region was selectively a-blocked, the inner/outer ratio in this region was less than in the paired
anterior descending region, and this difference widened with increasing levels of exercise. These results
indicate that a-receptor activation during exercise
helps maintain a more uniform transmural blood flow
in the left ventricle.
Because the inner/outer ratio may be affected by
changes in both subepicardial and subendocardial blood
flow, a further comparison of bloodflowsto just the inner
myocardial layer was made. The paired differences in
inner layer blood flow between the circumflex and
anterior descending regions for the a-blocked and
vehicle groups are compared in Figure 10. Flow to the
inner layer was greater in the circumflex region than in
the anterior descending region in the vehicle (areceptors intact) group, and this difference increased
with exercise. In contrast, when the circumflex region
was selectively a-blocked, this effect of exercise was not
observed (Figure 10). The paired differences in cir-
292
Circulation Research
ALPHA
BLOCKED
Discussion
The results presented here indicate that coronary
vasoconstriction mediated by a-receptors, during exercise, helps maintain a uniform distribution of coronary blood flow across the left ventricular wall when
myocardial oxygen consumption exceeds approximately 150 /il/min/g.
10 n
8
6-
General Response to Exercise
The hemodynamic response to exercise, with increases in heart rate and blood pressure, observed in the
4
o
i a
intact
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ALPHA-BETA BLOCKED
6 -
15 dogs
=0
75 observations
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4 -
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P < 0.001 a b o «
200is Ch/mn/g
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Vol 62, No 2, February 1988
Intact
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<
g
1 -
VEHICLE
1 dog
o
8
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5 observations
0
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a:
61.4-1
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o : anterior
descending
a intact
anterior descendng
2O
200
400
600
800
1000
1.2-
MYOCARDIAL OXYGEN CONSUMPTION (ul 0 2 /min/g)
FIGURE 4. Paired observations of regional transmural flow in
the treated (circumflex) and the untreated (anterior descending)
regions, plotted against total left ventricular myocardial oxygen
consumption, illustrate the variability of the data within and
among dogs. Lines were calculated by multiple linear regression. The slopes of the two lines in each panel were significantly
different (p<0.001, 0.025, and 0.005 for Panels A, B, andC,
respectively), so the differences in regional transmural flow
between paired regions became statistically significant when
exercise elicited high rates of myocardial oxygen consumption,
as shown.
a blocked
clramilex
O
1.0-
o
5
0.8
1 dog
0
100
5 observations
200
300
400
500
MYOCARDIAL OXYGEN CONSUMPTION (ul 0 2 /min/g)
cumflex minus anterior descending inner layer flow for
the a-blocked group and vehicle group became significantly different (/?<0.05) when myocardial oxygen
consumption was 500 /xl/min/g or greater. This indicates
that, despite the vasodilation caused by both the prejunctional and postjunctional a-receptor blocking actions of phenoxybenzamine, flow to the inner layer of
the circumflex region (relative to the paired reference
flow to the inner layer of the anterior descending region)
was greater when a-receptors were intact than when they
were blocked (see "Discussion").
FIGURE 5. Paired observaxions in the a-receptor blocked and
the a-receptor intact regions of the left ventricular myocardium
of a single dog illustrate within-dog variability. Lines were
calculated by simple linear regression for each region. A:
Transmural blood flow in both regions increased with myocardial oxygen consumption and was consistently less in the region
with a-receptors intact than in the region with a-receptors
blocked. B: The inner)'outerflow ratio in both regions decreased
as myocardial oxygen consumption increased and was consistently greater in the region with a-receptors intact than in the
region with a-receptors blocked.
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
293
ALPHA BLOCKED GROUP
A
1.4-
o
0.6 20 dogs
I - 2 S i ot ™
P<0.01 ibovf 150ul0,/n«n/
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0.2 -
06
200
400
600
800
1000
fc
MYOCARDIAL OXYGEN CONSUMPTION Cut 0 2 / m i n / g )
FIGURE 6. Inner/outer flow ratio vs. myocardial oxygen consumption in the a-blocked group. A: Lines summarize observations in
the a-receptor intact (anterior descending) region and in the a-receptor blocked (circumflex) region according to multiple linear
regression analysis. The slopes of the two lines were different (p<0.05). The inner/outer flow ratio of the a-blocked region was below
the paired a-intact region when myocardial oxygen consumption was 150 [tlOJminlg or more (p<0.01). B andC: Simple regression
lines calculated for the a-intact (anterior descending) and a-blocked (circumflex) regions of each dog illustrate the variability among
dogs.
VEHICLE GROUP
1.4-
1.0o
o
0.6
17 (Jogi
1 = 2 S.E. of mean drfftfenct*
P< 0.001 ibOTt lOOulOj/nm/j
0.2 -
0.6 J,
200
400
600
800
1000
MYOCAflDIAL OXYGEN CONSUMPTION (ul 0 2 / m i n / g )
FIGURE 7. Inner/outer flow ratio vs. myocardial oxygen consumption in the vehicle group. A: Lines summarize observations in the
control (anterior descending) region and in the vehicle-treated (circumflex) region according to multiple linear regression analysis.
The slopes of the two lines were not significantly different (0.8<p<0.9). The inner/outer ratio in the circumflex region was significantly
higher than in the paired anterior descending region when myocardial oxygen consumption was 100 yJUminlg or more (p<0.001).
B and C: Simple regression lines calculated for the control (anterior descending) and vehicle-treated (circumflex) regions of each
dog illustrate the variability among dogs.
Circulation Research
294
Vol 62, No 2, February 1988
ALPHA-BETA BLOCKED GROUP
1.4 -
••8 -
a
intKl jnteriot
d«cendjng
O
LLJ
h-
o
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0.2 -
200
400
600
800
1000
o
MYOCARDIAL OXYGEN CONSUMPTION
500
IOOO
Uil02/min/g)
FIGURE 8. Inner! outer flow ratio vs. myocardial oxygen consumption in the a- and ^-blocked group. A: Lines summarize observations
in the a-intact (anterior descending) region and a-blocked (circumflex) region according to multiple linear regression analysis. Dotted
lines illustrate values predicted at high rates of myocardial oxygen consumption by extrapolation of regression lines. The slopes of
the two lines were significantly different (p<0.005). The inner/outer ratio of the a-blocked region became significantly less than in
the a-intact region when myocardial oxygen consumption is extrapolated beyond 400 fj.llminig (p<0.05). B andC: Simple regression
lines calculated for the a-intact (anterior descending) and a-blocked (circumflex) regions of each dog illustrate the variability among
dogs.
present experiments was similar to that observed by
others.22 The resting values of heart rate and myocardial
oxygen consumption reported here are not truly basal
because the animals were waiting to run on a treadmill
in a laboratory where they had been trained to exercise.
The dogs hyperventilated during exercise and developed arterial hypocapnia and hyperoxia. As described
by Bainton and Mitchell,23 hyperventilation occurs in
response to both increased heat load and exercise per
se. Rectal temperature was measured in 19 dogs in the
present study and increased significantly (p<0.001)
from 38.9° C at rest to 39.4° C after the maximum
exercise run, and all dogs panted. Clifford et al24
recently reported that arterial hypocapnia developed in
dogs even during mild exercise in a cool ambient
temperature. Unfortunately, neither body temperatures
nor the occurrence of panting were reported. When
exercise is severe enough to result in net lactate
production, respiratory compensation for the metabolic acidosis also results in arterial hypocarbia and
hyperoxia, as has been described in humans. 2326
The arterial concentrations of epinephrine and norepinephrine increased during exercise, as previously
described for the dog by PeYonnet et al27 and Chilian et
al.8 Splenic contraction is a normal component of the
exercise response in dogs and results in an increased
hematocrit.28"30 Because increases in hematocrit make
the inner/outer flow ratio more sensitive to stress,31
splenectomy was performed in each dog in the present
study, and hematocrit never increased by more than 1 %
during the experimental protocol.
The increase in coronary blood flow during exercise has
been documented many times.8-9J2~34 A widening of the
arteriovenous oxygen content difference across the coronary circulation and/or a fall in coronary venous oxygen
tension during exercise has been observed in some
studies4-33 but not others.7 In the present study, the
coronary arteriovenous oxygen content difference widened, and the coronary sinus oxygen tension fell during
exercise in the a- and ^-blocked group, but not in the
vehicle or a-blocked groups. The present experimental
design does not elucidate a mechanism for this difference.
Regional Transmural Coronary Flow
The paired experimental design provided simultaneous measurements of blood flow in the circumflex
and left anterior descending regions at rest and during
four graded levels of exercise in each dog. In the vehicle
group, the circumflex region was treated with only the
phenoxybenzamine vehicle and marker microspheres.
Under these conditions, the inner/outer flow ratio was
greater in the circumflex region than in the paired
anterior descending region (Figure 7), and this difference is similar to that previously reported by Wusten
et al.36 Because Wusten's experiments did not involve
phenoxybenzamine vehicle, the difference is probably
due to an inherent difference between the circumflex
and anterior descending regions. However, the present
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
INNER/OUTER
FLOW RATIO
DIFFERENCE
0.4 -i
o
0.2 H
,
0.0-
J?
-0.2 -
~
-0.4-
o
IWjJOj/rrtn/g
0
200
400
600
800
1000
MYOCARDIAL OXYGEN CONSUMPTION (ul 0 2 /min/g)
vasodilation. The present experiments combining aand /3-blockade were designed to examine the hypothesis free of the effects mediated by /3-receptors,
secondary to prejunctional a-receptor blockade. The
results in the a- and /3-blocked group are consistent
with the hypothesis that vasoconstriction mediated by
postjunctional a-receptors helps maintain a uniform
transmural blood flow during exercise. However, the
cardiac exercise response was so blunted by /3-blockade
that a significant difference could be predicted (Figure
8) only when the exercise response was extrapolated to
values observed in the other groups without /3-blockade
(Figures 6 and 7).
Because the inner/outer flow ratio may be altered by
changes in flow in either the inner or outer layer, an
additional comparison of only the inner layer flows was
made. The paired differences in inner layer blood flow
between the circumflex and anterior descending regions
are presented in Figure 10. The inner layer blood flow
in the untreated anterior descending region was used as
a paired reference to avoid the variability associated
with differences in left ventricular diastolic pressure,
aortic pressure, cardiac output, hematocrit, and other
variables that combine to influence myocardial oxygen
consumption among different dogs. In the vehicle
group, the inner layer flow in the circumflex region was
INNER MYOCARDIAL FLOW
DIFFERENCE
1.0-
0
o '• 9
D x Q Oft
o
_J
LJ_
JJ
0.5—
^(MOl
WER F
° = vehicte (TOUJ
oB-O *^ o
d& "tf P JJi&rJ!*rZ'- -
^
(ml/min/
•
D
experimental design would not separate effects due to
region from those due to vehicle. When the a-receptors
were blocked selectively in the circumflex region, the
inner/outer flow ratio was less in that region than in the
simultaneously paired anterior descending region
(Figure 6). Thus, the inner/outer flow ratio is normally
greater in the circumflex region than in the anterior
descending region, but selective a-blockade in the
circumflex region reverses this relation. The comparison of the inner/outer ratio differences between the
circumflex and anterior descending areas for the vehicle
and a-blocked groups is given in Figure 9, which
indicates that the inner/outer flow ratio was greater with
a-receptors intact. These results demonstrate that the
transmural distribution of flow during exercise is more
uniform when a-receptors are intact than when they are
blocked.
Coronary adrenergic vasoconstriction is mediated
postjunctionally by both a,- and a 2 -receptors. 9J437J *
Thus, a combined a,- and a r receptor antagonist was
chosen for these experiments. However, there are also
prejunctional a2-receptors involved in feedback inhibition of norepinephrine release from sympathetic
nerves. 10 " Therefore, blockade of prejunctional a2receptors results in an augmented norepinephrine
release during exercise.34 The augmented norepinephrine concentration stimulates myocardial /3-receptors,
thereby magnifying inotropic effects that increase
myocardial oxygen consumption and local metabolic
JNI) "
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FIGURE 9. Paired differences in the inner/outer flow ratio
between the circumflex (a-blocked or vehicle treated) and
anterior descending (a-intact, control) regions in the a-blocked
and vehicle groups. In each group, the anterior descending
region served as the paired, a-intact, control region. Lines
indicate the mean differences calculated for each group by
multiple linear regression, and individual points show the
residual variance within dogs, plotted around the regression
lines. The slopes of the two regression lines were significantly
different (p<0.05), and the difference in the a-blocked group
was significantly less than in the vehicle group when myocardial
oxygen consumption was 150 ydlminJg or more (p<0.001).
Thus, the inner/outer flow ratio in the circumflex region was
better maintained when a-receptors were intact (vehicle group)
than when they were blocked (a-blocked group).
295
o.o-
]"•'"
1
a
-0.5-
btockod grou)
o
/
0
P<0.06 abort 500JO 2
200
400
600
800
1000
MYOCARDIAL OXYGEN CONSUMPTION OulOjArin/g)
FIGURE 10. Paired differences in the inner layer myocardial
blood flow between the circumflex (a-blocked or vehicle treated)
and anterior descending (a-intact, control) regions in the
a-blocked and vehicle groups. In each group, the anterior
descending region served as the paired, a-intact, control
region. Lines indicate the mean differences calculated for each
group by multiple linear regression, and individual points show
the residual variance within dogs, plotted around the regression
lines. The slopes of the two regression lines were significantly
different (p<0.01), and the difference in the a-blocked group
was significantly less than in the vehicle group when myocardial
oxygen consumption was 500 ydlminlg or greater (p<0.05).
Thus, inner myocardial blood flow in the circumflex region was
better maintained when a-receptors were intact (vehicle group)
than when they were blocked (a-blocked group), despite the
prejunctional and postjunctional vasodilating effects of ablockade.
296
Downloaded from http://circres.ahajournals.org/ by guest on September 30, 2016
greater than the inner layer flow in the anterior
descending region, and this difference widened with
increasing levels of exercise. This indicates an intrinsic
regional difference between the two areas. In contrast,
when the circumflex region was selectively a-blocked,
the inner layer flow in this region differed from the
vehicle group. This difference between groups was
significant (/?<0.05) when myocardial oxygen consumption was 500 /xl/min/g or greater (Figure 10).
Thus, when myocardial oxygen consumption exceeded
500 /xl/min/g, the inner layer blood flow in the
circumflex region was greater with a-receptors intact
(vehicle) than with a-receptors blocked (the inner layer
anterior descending region serving as a simultaneous
paired reference). The inner layer blood flow was
greater with a-receptors intact than blocked, despite the
coronary vasodilatory effects of both prejunctional and
postjunctional a-blockade, as discussed above.
The present results may be an underestimate of the
true effect of a-receptor-mediated coronary vasoconstriction on transmural flow distribution for several
reasons: 1) phenoxybenzamine was used because it
binds noncompetitively and irreversibly by alkylation
of a-receptors,39 properties that were necessary for the
paired region experimental design. However, the 2.5minute exposure time of the drug may have been too
short for optimal blockade. 2) Because some 35% of
left circumflex coronary artery blood flow leaves the
myocardium via Thebesian veins40 and, therefore,
could not be captured by the coronary sinus drain, some
phenoxybenzamine recirculated and partially blocked
the anterior descending region. 3) Although phenoxybenzamine was infused into the circumflex region via
a catheter with its tip beyond the bifurcation between
the anterior descending and circumflex coronary arteries, the distribution of marker microspheres indicated some reflux into the anterior descending artery
and even into the right coronary artery in some cases
(see "Regional Analysis" in "Materials and Methods").
4) The findings of Constantine and Lebel41 that phenoxybenzamine does not completely block a2-receptors
in the dog and the observation by Holtz et al37 that
canine coronary adrenergic vasoconstriction is mediated by a2-, as well as a,-receptors, suggest that
adrenergic coronary vasoconstriction may not have
been completely blocked.
All of these shortcomings (brief exposure time,
recirculation, reflux, and incomplete a2-blockade)
would limit the differences between the two regions and
make it more difficult to demonstrate an a-receptormediated effect. In the present study, the coronary
vasoconstrictor effect mediated by a-receptors during
exercise was approximately 6%, which is smaller than
reported in other studies. Using a sequential experimental design, Mohrman and Feigl14 observed a 30%
a-receptor-mediated constrictor effect on flow in a
carotid sinus baroreceptor reflex in anesthetized dogs.
The 6% vasoconstrictor effect observed in the present
study may be compared to a 14% a-vasoconstrictor
effect observed by Heyndrickx et al7 or a 30% effect
found by Gwirtz et al9 when exercise was studied
Circulation Research
Vol 62, No 2, February 1988
sequentially before and after a-blockade. If the true
a-receptor-mediated coronary vasoconstrictor effect
during exercise is 14-30%, rather than the approximate
6% observed in the present study, then the true
adrenergic effect on transmural flow distribution may
be several times larger than the 0.1-0.2 effect on the
inner/outer flow ratio observed here (Figure 9).
The disadvantage of the simultaneously paired
experimental design used in the present study is that
only a small differential regional a-blockade was
achieved. The advantage is that heart rate, diastolic left
ventricular pressure, aortic pressure, catecholamine
levels, etc., are the same for both regions, obviating the
attempt to match these variables at different exercise
levels before and after a-blockade that a sequential
design would require.
Possible Mechanisms
There are several possible mechanisms that could be
involved in the maintenance of more uniform transmural distribution of blood flow when a-receptors
remain intact.
1) The simplest mechanism is that either sympathetic
a-receptor density or coronary innervation is greater in
the outer layers of the left ventricle than in the inner
layers. A transmural gradient of coronary postsynaptic
a-receptors has not been observed in four studies that
used norepinephrine infusions to examine the
question842"44; thus, it seems an unlikely mechanism at
this time. Johannsen et al42 did not find evidence for a
transmural gradient of sympathetic coronary innervation under normal conditions but did find an appropriate gradient during pharmacological hyperemia
produced with adenosine. They postulate a differential
prejunctional interaction between adenosine and sympathetic norepinephrine release across the left ventricular wall. To the extent that adenosine is involved in the
cardiac response during exercise, this is an interesting
possibility.
2) Nathan and Feigl44 observed a beneficial effect of
adrenergic coronary vasoconstriction on transmural
flow distribution during hypoperfusion. The mechanism for this effect was an anti-transmural steal
whereby a-receptor-mediated vasoconstriction in the
outer layer of the left ventricle helped maintain the
perfusion pressure for the inner layer. Chilian and
Ackell45 also observed an adrenergic antitransmural
steal mechanism distal to a coronary stenosis in
exercising dogs. The basis of a vascular steal is that the
arterial pressure distal to a flow restriction is below the
autoregulatory range so that a change in vascular
resistance in one parallel vascular bed alters the
perfusion pressure for a second parallel vascular bed.
An anti-transmural steal mechanism is unlikely to
explain the present results because there was no
coronary artery stenosis, and even unintended stenosis
secondary to surgery was avoided with the closed-chest
technique.
3) An additional mechanism for transmural redistribution of coronary flow by adrenergic vasoconstriction is based on changes in vascular capacitance and
Huang and Feigl
a-Receptors and Transmural Flow in Exercise
Downloaded from http://circres.ahajournals.org/ by guest on September 30, 2016
vessel wall stiffness associated with vasoconstriction,
as suggested by Hoffman et al.46 Myocardial vessels are
narrowed by systolic compression; thus, some diastolic
time is spent reexpanding narrowed vessels and filling
their capacitance before flow through the vessels
resumes. Stiffening of vessel walls, as by vasoconstriction, may help the vessels resist narrowing during
systole and also facilitate reexpansion during diastole.
Furthermore, vascular capacitance tends to be reduced
by vasoconstriction so that less blood is required for
filling the capacitance and more of the diastolic inflow
is available for tissue perfusion. Thus, vasoconstriction
may facilitate flow through inner myocardial vessels,
which are particularly subject to narrowing by systolic
compression. Flow through vessels in the outer myocardium, subject to lower myocardial compression than
those in the inner myocardium, would be affected more
by the reduction of vessel diameter (increased resistance to flow) than by the changes in wall stiffness and
vessel capacitance with vasoconstriction, so the net
effect of vasoconstriction in outer myocardial vessels
would be to reduce flow.
Although the results reported here demonstrate a
beneficial effect of sympathetic coronary vasoconstriction during exercise, other investigators have observed
that coronary a-adrenergic vasoconstriction can be
detrimental under some circumstances. Heusch and
Deussen47 observed that a 2 -receptor-mediated coronary vasoconstriction was augmented in the presence
of coronary stenosis and was powerful enough to induce
ischemia. In a preliminary report, Seitelberger et al48
indicate that a2-adrenergic vasoconstriction during
exercise depresses the inner myocardial blood flow,
inner/outer flow ratio, and systolic wall thickening in
myocardium distal to a coronary stenosis. In both these
studies, it is possible that slight vasoconstriction of the
epicardial artery at the site of the stenosis increased its
severity enough for the effect of transmural hypoperfusion to dominate over the beneficial transmural
effects observed in the present and other studies.4445
Gwirtz and coworkers report that the rate of shortening
of myocardial segment length (but not percent segment
shortening) was enhanced by a,-blockade during
exercise.9 However, this does not necessarily indicate
that normal adrenergic coronary vasoconstriction during exercise interferes with myocardial function by
making the myocardium ischemic, because increasing
coronary flow in nonischemic myocardium augments
cardiac function by the Gregg effect.32
In conclusion, the present results indicate that
adrenergic coronary vasoconstriction has a beneficial
effect on left ventricular transmural blood flow distribution during exercise in normal dogs without coronary
artery stenosis. This observation may answer the
paradox as to why there is sympathetic coronary
vasoconstriction during exercise, when myocardial
oxygen consumption is so great.
Acknowledgments
Many thanks to Stephanie Belanger and Fellner D.
Smith for their expert technical assistance. We are
297
indebted to Dr. Margaret A. Kenny for providing the
analysis of plasma catecholamines. Dibenzyline was
generously provided by Smith Kline & French, Philadelphia, Pennsylvania; fentanyl by Janssen Pharmaceuticals Inc.; and naltrexone HC1 by E.I. DuPont
Company, Wilmington, Delaware.
References
1. Bache RJ, Cobb FR: Effect of maximal coronary vasodilation
on transmural myocardial perfusion during tachycardia in the
awake dog. Circ Res 1977;41:648-653
2. Ball RM, Bache RJ: Distribution of myocardial blood flow in
the exercising dog with restricted coronary artery inflow. Circ
Res 1976;38:60-66
3. Ball RM, Bache RJ, Cobb FR, Greenfield JC: Regional
myocardial blood flow during graded treadmill exercise in the
dog. J Clin Invest 1975;55:43-49
4. Von Restorff W, Holtz J, Bassenge E: Exercise induced
augmentation of myocardial oxygen extraction in spite of
normal coronary dilatory capacity in dogs. Pflugers Arch
1977;372:181-185
5. Murray PA, Vatner SF: a-Adrenoceptor attenuation of the
coronary vascular response to severe exercise in the conscious
dog. Circ Res 1979;45:654-660
6. Gwirtz PA, Stone HL: Coronary blood flow and myocardial
oxygen consumption after a/p/ia-adrenergic blockade during
submaximal exercise. J Pharmacol Exp Ther 1981 ;217:92-98
7. Heyndrickx GR, Muylaert P, Pannier JL: a-Adrenergic control
of oxygen delivery to myocardium during exercise in conscious
dogs. Am J Physiol 1982;242:H805-H809
8. Chilian WM, Harrison DG, Haws CW, Snyder WD, Marcus
ML: Adrenergic coronary tone during submaximal exercise in
the dog is produced by circulating catecholamines. Evidence
for adrenergic denervation supersensitivity in the myocardium
but not in coronary vessels. Circ Res 1986;58:68-82
9. Gwirtz PA, Overn SP, Mass HJ, Jones CE: a-Adrenergic
constriction limits coronary flow and cardiac function in
running dogs. Am J Physiol 1986;250:H1117-H1126
10. Starke K, Montel H, Schumann HJ: Influence of cocaine and
phenoxybenzamine on noradrenaline uptake and release.
Naunyn Schmiedebergs Arch Pharmacol 1971;270:210-214
11. Yamaguchi N, de Champlain J, Nadeau RA: Regulation of
norepinephrine release from cardiac sympathetic fibers in the
dog by presynaptic alpha- and beta-receptors. Circ Res 1977;
41:108-117
12. Meier MA, Long DM: Carotid artery loop for repeated
catheterization of the left ventricle in dogs. Surgery 1971;70:
797-799
13. Seldinger SI: Catheter replacement of the needle in percutaneous arteriography—A new technique. Ada Radiol 1953;
39:368-376
14. Mohrman DE, Feigl EO: Competition between sympathetic
vasoconstriction and metabolic vasodilation in the canine
coronary circulation. Circ Res 1978;42:79-86
15. Phillips HR, Stack RS, Rembert JC, Greenfield JC Jr: A
technique to inject microspheres into the left atrium of awake
dogs without thoracotomy. Am J Physiol 1982;243:H488-H490
16. Koberstein RC, Pittman DE, Klocke FJ: Right atrial admixture
in coronary venous blood. Am J Physiol 1969;216:531-535
17. Domenech RJ, Hoffman JIE, Noble MIM, Saunders KB,
Henson JR, Subijanto S: Total and regional coronary blood flow
measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 1969;25:581-596
18. Hallman H, Farnebo LO, Hamberger B, Jonsson G: A sensitive
method for the determination of plasma catecholamines using
liquid chromatography with electrochemical detection. LifeSci
1978;23:1049-1052
19. Baer RW, Payne BD, Verrier ED, Vlahakes GJ, Molodowitch
D, Uhlig PN, Hoffman JIE: Increased number of myocardial
blood flow measurements with radionuclide-labeled microspheres. Am J Physiol 1984;246:H418-H434
20. Dole WP, Jackson DL, Rosenblatt JI, Thompson WL: Relative
error and variability in blood flow measurements with radio-
298
Downloaded from http://circres.ahajournals.org/ by guest on September 30, 2016
labeled microspheres. Am J Physiol 1982;243:H371-H378
21. Hull CH, Nie NH (eds): SPSS Update 7-9: New Procedures and
Facilities for Releases 7-9. San Francisco, McGraw-Hill Book
Company, 1981
22. Vatner SF, Pagani M: Cardiovascular adjustments to exercise:
Hemodynamics and mechanisms. Prog Cardiovasc Dis 1976;
19:91-108
23. Bainton CR, Mitchell RA: Effect of skin cooling on exercise
ventilation in the awake dog. J Appl Physiol 1971;30:370-377
24. Clifford PS, Litzow JT, Coon RL: Arterial hypocapnia during
exercise in beagle dogs. J Appl Physiol 1986;61:599-602
25. Wasserman K: Breathing during exercise. N Engl J Med
1978;298:780-785
26. Whipp BJ: The control of exercise hyperpnea, in Hornbein TF
(ed): Regulation of Breathing (Part II). New York, Marcel
Dekkerlnc, 1981, pp 1069-1139
27. Peronnet F, Nadeau RA, de Champlain J, Magrassi P, Chatrand
C: Exercise plasma catecholamines in dogs: Role of adrenals and
cardiac nerve endings. Am J Physiol 1981; 241: H243-H247
28. Barcroft J, Stephens JG: Observations upon the size of the
spleen. J Physiol (Lond) 1927;64:l-22
29. Vatner SF, Higgins CB, Millard RW, Franklin D: Role of the
spleen in the peripheral vascular response to severe exercise in
untethered dogs. Cardiovasc Res 1974;8:276-282
30. Longhurst JC. Musch TI, Ordway GA: O2 consumption during exercise in dogs—Roles of splenic contraction and aadrenergic vasoconstriction. Am J Physiol 1986;251:
H502-H509
31. Surjadhana A, Rouleau J, Boerboom L, Hoffman JIE: Myocardial blood flow and its distribution in anesthetized polycythemic dogs. Circ Res 1978;43:619-631
32. Feigl EO: Coronary physiology. Physiol Rev 1983;63:1-205
33. Liang IYS, Stone HL: Changes in diastolic coronary resistance
during submaximal exercise in conditioned dogs. J Appl Physiol:
Respirat Environ Exercise Physiol 1983;54: 1057-1062
34. Heyndrickx GR, Vilaine JP, Moerman EJ, Leusen I: Role of
prejunctional a2-adrenergic receptors in the regulation of
myocardial performance during exercise in conscious dogs.
Circ Res 1984;54:683-693
35. Heyndrickx GR, Pannier JL, Muylaert P, Mabilde C, Leusen
I: Alteration in myocardial oxygen balance during exercise after
a-adrenergic blockade in dogs. J Appl Physiol: Respirat
Environ Exercise Physiol 1980;49:28-33
36. Wiisten B, Flameng W, Schaper W: The distribution of
myocardial flow. Part I: Effects of experimental coronary
Circulation Research
Vol 62, No 2, February 1988
occlusion. Basic Res Cardiol 1974;69:422-434
37. Holtz J, Saeed M, Sommer O, Bassenge E: Norepinephrine
constricts the canine coronary bed via post-synaptic a2adrenoceptors. Eur J Pharmacol 1982;82:199-202
38. Jones CE, Liang IYS, Maulsby MR: Cardiac and coronary
effects of prazosin and phenoxybenzamine during coronary
hypotension. J Pharmacol Exp Ther 1986;236:204-211
39. Harvey SC, Nickerson M: Reactions of dibenamine and some
congeners with substances of biological interest in relation to
the mechanism of adrenergic blockade. J Pharmacol Exp Ther
1954;112:274-290
40. Moir TW, Driscol TE, Eckstein RW: Thebesian drainage in the
left heart of the dog. Circ Res 1964; 14:245-249
41. Constantine JW, Lebel W: Complete blockade by phenoxybenzamine of a,- but not of a2-vascular receptors in dogs and
the effects of propranolol. Arch Pharmacol 1980;314:149-156
42. Johannsen UJ, Mark AL, Marcus ML: Responsiveness to
cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine. Circ Res 1982;
50:510-517
43. Buffington CW, Feigl EO: Effect of coronary artery pressure on
transmural distribution of adrenergic coronary vasoconstriction
in the dog. Circ Res 1983;53:613-621
44. Nathan HJ, Feigl EO: Adrenergic vasoconstriction lessens
transmural steal during coronary hypoperfusion. Am J Physiol
1986;250:H645-H653
45. Chilian WM, Ackell PH: Sympathetic coronary tone during
exercise prevents transmural steal in the presence of a stenosis
(abstract). Fed Proc 1986;45:533
46. Hoffman JIE, Baer RW, Hanley FL, Messina LM, Grattan MT:
Regulation of transmural myocardial bloodflow,in Mates RE,
Nerem RM, Stein PD (eds): Mechanics of the Coronary
Circulation. New York, American Society of Mechanical
Engineers, 1982, pp 1-17
47. Heusch G, Deussen A: The effects of cardiac sympathetic nerve
stimulation on perfusion of stenotic coronary arteries in the
dog. Circ Res 1983;53:8-15
48. Seitelberger R, Guth BD, Heusch G, Katayama K, Lee JD,
Ross J Jr: Regional alpha 2 blockade improves function and
flow in the ischemic dog myocardium during exercise
(abstract). J Am Coll Cardiol 1986;7:252A
KEY WORDS
alpha-blockade
consumption
alpha-receptors
beta-blockade
microspheres
beta-receptors
•
myocardial oxygen
Adrenergic coronary vasoconstriction helps maintain uniform transmural blood flow
distribution during exercise.
A H Huang and E O Feigl
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Circ Res. 1988;62:286-298
doi: 10.1161/01.RES.62.2.286
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