(Circulation. 1999;100:843-848.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Brief Myocardial Ischemia Attenuates Platelet Thrombosis in Remote, Damaged, and Stenotic Carotid Arteries
Presented in part at the 47th Annual Scientific Sessions of the American College of Cardiology, Atlanta, Ga, March 30, 1998, and published in abstract form (J Am Coll Cardiol. 1998;31:168A).
From the Heart Institute, Good Samaritan Hospital and Department of Medicine (Section of Cardiology), University of Southern California, Los Angeles, Calif.
Correspondence to Karin Przyklenk, PhD, Heart Institute/Research, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017-2395. E-mail karinp{at}dnamail.com
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Abstract |
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Background—Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation—circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery—remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A2 receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency.
Methods and Results—In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary—but not carotid—occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A2/A1 antagonist CGS 15943.
Conclusions—Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.
Key Words: adenosine • platelets • thrombosis • ischemia • cerebrovascular circulation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recent evidence from our laboratory revealed that the favorable effects of brief "preconditioning" ischemia extend beyond myocyte protection and reduction of infarct size1 ; brief antecedent coronary artery occlusion also resulted in better maintenance of subsequent blood flow in damaged and stenotic canine coronary arteries.2 Stimulation of adenosine receptors (presumably by adenosine released from the heart during brief ischemia/reflow)3 4 5 was identified as a crucial component of this improved vessel patency.2 However, the site of receptor stimulation—ie, adenosine receptors on blood-borne elements (most probably platelets) versus local vessel-wall components (such as vascular smooth muscle of the culprit coronary artery)—was not discerned.
We proposed2 that the superior coronary patency seen with brief antecedent coronary occlusion was due to inhibition of platelet aggregation via stimulation of adenosine receptors on circulating platelets.6 7 8 9 If so, then 3 corollaries should hold true: (1) transient coronary occlusion should provide a systemic benefit and attenuate platelet-mediated thrombosis at a remote, peripheral site; (2) because A2 receptors are the subtype present on platelets, administration of an adenosine A2 receptor antagonist should attenuate this effect; and (3) brief vascular occlusion per se, not associated with substantive adenosine release, should be ineffective in eliciting protection. To test these concepts, we first exploited the fact that in the rabbit, brief carotid artery occlusion causes negligible cerebral ischemia due to the well-developed circle of Willis in this species,10 11 12 and we evaluated the effect of brief antecedent coronary versus carotid artery occlusion on subsequent spontaneous, platelet-mediated thrombosis in damaged and stenotic carotid arteries. We then used the canine model to document, in a second species, the consequences of brief coronary occlusion on the patency of injured and stenotic carotid arteries. Finally, in the canine preparation, we determined whether the benefits of brief coronary artery occlusion on remote, platelet-mediated thrombosis were blocked by administration of the adenosine A2/A1 antagonist CGS 15943.
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Methods |
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These protocols were approved by the Institutional Animal Care and Use Committee of Good Samaritan Hospital and conform with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington DC, 1996).
Protocol 1: Rabbit Model
Surgical Preparation
New Zealand White rabbits (weight 2.2 to 3.2 kg; n=26) were
anesthetized with ketamine and xylazine (130 and 30
mg/kg IM) followed by intraperitoneal injections of
sodium pentobarbital (
50 mg/h), intubated, and ventilated with room
air. The right femoral artery was cannulated for measurement of heart
rate and arterial pressure. Both the left and right common
carotid arteries were isolated, and the left carotid was instrumented
with a Doppler flow probe. The heart was exposed through a left
thoracotomy, and the left circumflex artery (or a large anterolateral
branch) was encircled with a snare. Continuous tracings of
arterial pressure and mean carotid blood flow were obtained
on a chart recorder.
Study Design
After stabilization, each rabbit was assigned to undergo one of
the following procedures (Figure 1A
):
brief coronary occlusion (5 minutes of coronary artery
occlusion followed by 5 minutes of reperfusion, accomplished by
tightening/releasing the coronary snare; n=8); brief carotid
occlusion (5 minutes of bilateral carotid occlusion and 5 minutes of
reflow, achieved by applying/removing atraumatic vascular clamps on
both carotid arteries and, importantly, purported to cause a negligible
deficit in cerebral blood flow10 11 12 ; n=6); or a 10-minute
control period (n=12).
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After the intervention phase, the segment of the left carotid artery
located immediately proximal (ie, upstream, toward the heart) to the
flow probe was gently compressed with a hemostat to induce
endothelial denudation and medial injury, thereby
exposing the highly thrombogenic tunica media and tunica adventitia
(confirmed histologically in all rabbits; data not
shown). A micromanometer constrictor was then
tightened around the site of trauma such that carotid flow was reduced
to 75% of its baseline value. This, as
expected,2 13 14 15 16 triggered the development of cyclic
variations in carotid blood flow (CFVs) caused by repeated spontaneous
formation/dislodgement of platelet-rich thrombi at the site of
injury plus stenosis. Carotid patency was then monitored
without additional intervention for 2 hours after stenosis.
At the end of each experiment, the coronary snare was briefly retightened, and blue pigment was injected into the coronary circulation via the left atrium to confirm the presence of a perfusion defect. All rabbits were killed under deep anesthesia by intracardiac injection of KCl.
Protocol 2: Canine Model
Surgical Preparation
Mongrel dogs (weight 16 to 23 kg; n=13) were
anesthetized with sodium pentobarbital (30 mg/kg IV),
intubated, and ventilated with room air. The left jugular vein was
cannulated for administration of drugs and fluids, and a long segment
of the left carotid artery was isolated and instrumented with a
Doppler flow probe. The heart was exposed through a left lateral
thoracotomy and suspended in a pericardial cradle. Two adjacent
segments of the mid to distal left anterior descending coronary
artery (LAD) were then isolated: a second Doppler flow probe was
positioned on the distal segment for measurement of LAD flow, whereas
the proximal segment served as the site of later LAD occlusion. In
addition, a small fluid-filled cannula was positioned in the left
ventricular (LV) cavity via the left atrial appendage for
continuous monitoring of heart rate and LV pressures. Carotid flow and
LV pressures were recorded continuously, whereas coronary
flow was monitored before, during, and after LAD occlusion.
Study Design
After stabilization, the segment of the left carotid artery
proximal to the carotid flow probe was clamped with hemostats to induce
endothelial denudation and medial injury (confirmed
histologically in all dogs; data not shown). CFVs were
initiated by tightening a micromanometer
constrictor around the site of injury such that carotid flow was
reduced to 15% of baseline. Carotid patency was then monitored for
1 hour after injury plus stenosis (Figure 1B
).
After 1 hour of observation, 11 animals were randomly assigned to
receive an intravenous bolus of CGS 15943 (Sigma
RBI; 1.5 mg/kg suspended in 2 mL of polyethylene glycol and 0.1
mL of 1N NaOH, sonicated until clear, and diluted in saline to a final
volume of 20 mL; n=5) or vehicle (n=6). CGS 15943 is a potent
adenosine A2/A1
antagonist with no intrinsic effect on platelet
aggregation per se.17 18 Ten minutes later, all 11 dogs
underwent 10 minutes of LAD occlusion (achieved by placement of
atraumatic vascular clamps) and 10 minutes of reperfusion. Carotid
patency was then monitored for an additional 2 hours after this
30-minute "treatment" period (Figure 1B). To document the
stability of the preparation, the 2 remaining dogs served as
time-matched shams, ie, they received vehicle but did not undergo LAD
occlusion. At the end of the protocol, all dogs were killed under deep
anesthesia by intracardiac injection of KCl.
End Points
Heart rate and arterial/LV pressure were averaged
over 5 cardiac cycles. In each protocol, hemodynamics
were tabulated at baseline and at multiple time points throughout the
experiments.
In protocol 1 (rabbits), mean carotid blood flow was measured at baseline, immediately on relief of brief carotid/coronary occlusion, before stenosis, and immediately after stenosis (before the onset of CFVs). In Protocol 2 (canine model), mean carotid flow was determined at baseline and immediately after carotid injury plus stenosis (before the onset of CFVs).
Mean LAD flow (protocol 2 only) was tabulated at 1 hour after carotid injury plus stenosis (at the onset of the 30-minute treatment period, immediately before administration of vehicle/CGS 15943), immediately before LAD occlusion, and at 1, 3, and 10 minutes after reflow.
We analyzed CFVs for all observation periods in both protocols
by measuring both their frequency and mean nadir.2 13 14 15 16
In both protocols, a CFV was defined as a slow decrease followed by an
abrupt (within 
1 minute) increase in carotid flow, with an amplitude
20% of the poststenotic flow value.
Carotid patency throughout all observation periods was assessed by measurement of the area of the flow-time profile.2 In protocol 1 (rabbits), the area of the flow-time tracing throughout the 2 hours after carotid injury plus stenosis was measured by computerized planimetry and normalized for each animal to the baseline flow x120 minutes. In protocol 2 (dogs), flow-time area was planimetered: (1) over the first hour of observation (before LAD occlusion) and normalized to baseline flow x60 minutes and (2) over the final 2 hours of observation (after LAD occlusion) and normalized to baseline flow x120 minutes.
Statistics
In protocol 1 (rabbits), the primary end points of the study
(ie, the nadir and frequency of the CFVs and percent flow-time area)
were compared among all groups by ANOVA. In protocol 2 (dogs), indexes
of patency were compared before versus after the 30-minute treatment
period (ie, before versus after LAD occlusion) in vehicle- and
CGS-treated animals by 2-factor ANOVA (for group and time) with
repeated measures. Data from the 2 time-matched shams are reported but
were not included in the statistical analyses. In both
protocols, hemodynamic parameters, carotid
blood flow, and LAD flow (dogs only) were assessed by 2-factor ANOVA
with replication. All post hoc comparisons were made by Tukey test. All
results are reported as mean±SEM, and probability values <0.05 were
considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Protocol 1 (Rabbit Model)
Hemodynamics
All groups showed a modest but significant decrease in heart rate at the end of the 2-hour observation period (Table 1
). However, there were no
differences in heart rate or arterial pressure among the 3
groups at any time during the protocol.
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Carotid Flow
Carotid blood flow was comparable among all rabbits at baseline,
averaging 5 to 6 mL/min (Table 2).
Immediately on relief of bilateral carotid occlusion, maximal
hyperemic carotid flow was increased to 132% of baseline
(P=0.05 versus baseline) but did not differ significantly
from time-matched measurements obtained in the control and
coronary occlusion groups (104% and 113%, respectively). In
all groups, carotid flow was significantly reduced to 76% to 78% of
baseline (P<0.05) on application of the
stenosis.
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CFVs and Carotid Patency
All groups exhibited 4 CFVs during the 2 hours of observation
(P=NS). In control rabbits, the nadir of the CFVs was
1.5±0.3 mL/min, and percent flow-time area averaged 44±8%. Similar
results were obtained in the cohort that received antecedent carotid
occlusion, ie, nadir of the CFVs averaged 1.6±0.3 mL/min, and percent
flow-time area was 38±6%. In contrast, in rabbits that received brief
antecedent coronary occlusion, the nadir of the CFVs was
greater (3.0±0.5 mL/min; P=0.01; Figure 2A) and percent flow-time area was
improved (69±5%; P=0.03; Figure 2B) versus
controls.
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Protocol 2 (Dog Model)
Hemodynamics
Both heart rate and peak LV pressure increased modestly but
significantly during the protocol, with no differences between vehicle-
and CGS-treated cohorts that underwent LAD occlusion (Table 3). A similar temporal profile was
observed in time-matched shams.
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Carotid Flow
Baseline values of carotid flow averaged 94±13 mL/min in the
vehicle control group, 86±4 mL/min in dogs later randomized to receive
CGS, and 90±9 mL/min in the shams. Immediately after injury plus
stenosis, carotid flow was reduced to 14±2, 12±1, and 11±1
mL/min (ie, 12% to 15% of baseline) in the 3 cohorts, respectively
(P=NS).
LAD Flow
LAD coronary flow at the onset of the 30-minute treatment
period averaged 16 to 18 mL/min in dogs assigned to receive vehicle
or CGS plus LAD occlusion and was not altered by vehicle or CGS
treatment (Table 4). All dogs subjected
to coronary occlusion displayed cyanosis and dyskinesis, and
all were hyperemic on reperfusion; ie, mean coronary
flow at 1 minute after relief of ischemia was 500% of
baseline, with no difference between vehicle- or CGS-treated groups.
Time-matched sham animals, as expected, showed no evidence of
hyperemia.
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CFVs and Carotid Patency
During the initial hour after carotid injury plus
stenosis, all groups exhibited 4 CFVs per 30-minute
interval, and all groups were comparable with respect to both the nadir
of the CFVs (Figure 3A) and percent
flow-time area (Figure 3B). No temporal changes in carotid
patency were observed in time-matched shams.
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Both the vehicle-treated and CGS plus LAD occlusion groups continued to
develop CFVs at a frequency of 4 per 30-minute interval during the
final 2 hours of observation (P=NS). However, in dogs that
received vehicle plus LAD occlusion, both the nadir of the CFVs (Figure 3A)
and area of the flow-time profile (Figure 3B) were
significantly increased after the 30-minute treatment period, ie,
8.4±2.4 versus 5.8±2.3 mL/min (P=0.04) and 16±3% versus
11±3% (P=0.01) after versus before LAD occlusion,
respectively. In contrast, dogs treated with CGS 15943 showed no
improvement in either the nadir of the CFVs (4.6±2.1 versus 5.6±1.8
mL/min) or flow-time area (8±2% versus 10±2%) after versus before
LAD occlusion.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we make the novel observation that in both rabbit and dog models, brief antecedent coronary artery occlusion enhances subsequent vessel patency in remote, damaged, and stenotic carotid arteries. In contrast, brief antecedent bilateral carotid occlusion in rabbit, known to cause negligible cerebral ischemia and thus minimal release of adenosine, fails to evoke a benefit on subsequent carotid patency. Moreover, administration of the adenosine receptor antagonist CGS 15943 abrogates the improvement in carotid patency seen after coronary artery occlusion in the canine preparation. These latter results implicate release of adenosine from ischemic myocardium and resultant stimulation of adenosine receptors on circulating blood-borne elements (presumably platelets) as an important mediator of the enhanced carotid patency seen after coronary artery occlusion.
Background and Rationale
We previously demonstrated that a brief (10 minute) episode of
antecedent coronary artery occlusion elicited a significant and
sustained subsequent improvement in blood flow in damaged and
stenotic canine coronary arteries. Moreover, we found
that the benefits of brief antecedent coronary occlusion were
mimicked by brief intracoronary adenosine infusion and
blocked by the nonselective adenosine receptor
antagonist PD 115,199.2 These results suggest
that release of adenosine from ischemic/reperfused
myocardium and resultant adenosine receptor
stimulation contributed significantly to this enhanced coronary
patency.2 However, the data did not reveal whether the
improved coronary patency seen with antecedent coronary
occlusion was specifically due to attenuated platelet aggregation
via stimulation of adenosine receptors on circulating
platelets6 7 8 9 or whether local vasodilation or relief
of vasospasm via stimulation of adenosine receptors in the
media of the culprit coronary artery6 also played
a role.
It is well recognized that adenosine is generated in ischemic myocardium via the catabolism of ATP and liberated during the initial minutes after reperfusion.3 4 5 This transient release of adenosine, together with its highly labile nature (plasma half-life on the order of seconds to minutes),19 essentially precludes the sustained transport of adenosine from the heart to a peripheral location, and thus provides the rationale for evaluating the effect of brief coronary artery occlusion on vessel patency in damaged and stenotic carotid arteries. Specifically, if local adenosine receptor stimulation is required to achieve the improvement in flow, then a short-lived release of adenosine from the heart would not be expected to elicit an improvement in arterial patency at a peripheral site. In contrast, if, as we propose,2 the improved patency was due to stimulation/binding of adenosine receptors on circulating blood-borne elements exposed to adenosine (ie, platelets traversing the ischemic/reperfused myocardium), then logic would dictate that brief coronary occlusion should effectively attenuate subsequent platelet thrombosis at a site remote from the source of adenosine production. Our current results demonstrating, in both rabbit and dog, a sustained improvement in the patency of damaged and stenotic carotid arteries after brief coronary artery occlusion appear consistent with this hypothesis.
We further reasoned that if adenosine plays an important role,
then no benefit should be seen in response to local brief vascular
occlusion not accompanied by appreciable adenosine release. To
test this corollary, we used the rabbit model to evaluate the effects
of brief antecedent bilateral carotid artery occlusion on later carotid
patency. Although there is no question that as in heart, profound
cerebral ischemia results in ATP catabolism and
adenosine production,10 it is equally well
established that the rabbit possesses a highly redundant blood supply
to the brain such that shunting of blood via the circle of Willis can
compensate for even prolonged periods of bilateral carotid artery
obstruction.10 11 12 20 21 In fact, occlusion of multiple
cerebral arteries,22 sometimes combined with systemic
hypotension,10 is needed to induce a significant perfusion
deficit. Our measurements of carotid blood flow in the rabbit
corroborate this concept: maximum hyperemia immediately after
brief bilateral carotid occlusion was only 130% of baseline (Table 2), in marked contrast to the 5-fold increase in
coronary flow seen on reperfusion of acutely ischemic
myocardium (Table 4), thereby implying that cerebral
adenosine release was indeed negligible in rabbits that
underwent antecedent carotid occlusion. Our results obtained in
protocol 1 with bilateral carotid occlusion reveal that
arterial occlusion per se does not ensure a favorable
influence on the subsequent patency of that same artery after injury
plus stenosis. Rather, arterial occlusion resulting
in ischemia appears to be required.
Data obtained in protocol 1 implied, but failed to establish, that adenosine (and subsequent binding to adenosine receptors) is the metabolite primarily responsible for the sustained benefit of coronary artery occlusion on "remote" vessel patency. Thus, as a final test of our hypothesis, we reasoned that administration of an adenosine receptor antagonist should attenuate the improved carotid patency seen after coronary artery occlusion. Indeed, in protocol 2, we found that brief coronary occlusion was ineffective in triggering an improvement in carotid patency in dogs that had received CGS 15943, an A2/A1 antagonist devoid of intrinsic platelet effects.17 18 Platelet adhesion and aggregation is a complex process,23 and we cannot exclude the possibility that other metabolites liberated from ischemic myocardium (including NO, prostaglandins, and bradykinin), acting alone or in concert with adenosine, might also play a role. In this regard, it is interesting to note that synthesis of NO, which is also a potent inhibitor of platelet aggregation,23 24 25 26 may be initiated as a secondary consequence of adenosine A2 receptor stimulation.27 However, our observation that CGS 15943 abolished the benefits of brief coronary occlusion suggest that the improved vessel patency manifest "at a distance" is due in large part to adenosine.
Limitations and Unanswered Questions
We acknowledge that despite the implicit involvement of
adenosine, we did not measure adenosine concentrations
in heart or blood; rather, we rely on previous studies by our group and
others unequivocally documenting massive release of adenosine
from rabbit and dog hearts in response to brief coronary
occlusion/reperfusion.3 4 5 Second, although we infer from
our data that the benefits of brief coronary occlusion on
carotid patency are in all likelihood due to binding to and stimulation
of adenosine A2 receptors on circulating
platelets, it must be recognized that CGS 15943, despite its high
affinity for the A2 receptor,17 is
not subtype specific. Direct documentation of increased activity of
platelet A2 receptors in response to brief
coronary occlusion will be required to definitively resolve
this issue. Finally, although carotid blood flow was significantly
enhanced, brief coronary artery occlusion clearly did not
prevent subsequent platelet-mediated thrombosis at the
peripheral site. It is, however, noteworthy that even under
the severe conditions required to elicit CFVs in the large, muscular,
and high-flow carotid arteries of the dog (ie, medial injury plus
tightening of the stenosis to reduce carotid flow to 15% of
baseline), brief coronary occlusion nonetheless elicited a
significant improvement in carotid patency.
Received February 23, 1999; revision received May 21, 1999; accepted May 26, 1999.
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