© 2000 American Heart Association, Inc.
Thrombosis |
Platelet Glycoprotein IIb/IIIa Receptor Inhibitor Preserves Coronary Flow Reserve During Progressive Coronary Arteriostenosis in Swine
From the Department of Pharmacology, Merck Research Laboratories, West Point, Pa.
Correspondence to You-Tang Shen, MD, Department of Pharmacology, Merck Research Laboratories, WP46-200, West Point, PA 19486. E-mail youtang_shen{at}merck.com
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Abstract |
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Abstract—Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95±2% (ie, nearly complete coronary artery occlusion) at 15±4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor–treated groups, resting CBF had decreased by only 21±7% at 18±3 minutes, 15±3% at 18±5 minutes, and 15±7% at 21±4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor–treated group. At a comparable level of resting CBF (
15% below baseline), the RHR was reduced more in the control
(-56±9%), heparin-treated (-49±9%), and aspirin-treated
(-61±12) groups (P<0.05) than in the GP IIb/IIIa
inhibitor–treated group (-26±6%). When the resting CBF
had decreased by 35%, the RHR still was reduced significantly more
(P<0.01) in the heparin-treated group (-64±9%) than
in the GP IIb/IIIa inhibitor–treated group (-21±6%). In
a separate group of control pigs (n=4) subjected to 2 injuries,
coronary perfusion pressure distal to the injury site was
reduced by 14±1 mm Hg from the arterial pressure,
and the RHR was 20±6%. When the distal coronary perfusion
pressure was reduced similarly (-14±1 mm Hg) in a separate
group of GP IIb/IIIa inhibitor–treated pigs (n=4) by 2
injuries and the use of a hydraulic occluder, the RHR was 130±16%
(P<0.01 versus control). Our data demonstrate for the
first time that a platelet GP IIb/IIIa receptor
inhibitor can preserve the distal coronary
vasodilatory response during progressive coronary arteriostenosis.
Key Words: coronary reactive hyperemia • coronary reserve • heparin • aspirin • coronary injury • glycoprotein IIb/IIIa
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Introduction |
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Intense vasoconstriction is often clinically observed after percutaneous transluminal coronary balloon angioplasty (PTCA),1 2 3 and it occurs both at the site of balloon dilation and distal to this site.1 It is possible that the potent vasoactive substances released during the intracoronary blood platelet adhesion and aggregation and resultant thrombosis that occur after PTCA are responsible for this vasoconstriction. Therefore, blockade of platelet aggregation may have beneficial effects on coronary vascular function. It is well known that thrombosis resulting from platelet aggregation is ultimately mediated by the activation of blood platelet glycoprotein (GP) IIb/IIIa receptors. Inhibition of these receptors with either the anti–GP IIb/IIIa antibody abciximab (ReoPro), the cyclic peptide GP IIb/IIIa antagonist eptifibatide (Integrilin), or the low-molecular-weight nonpeptide GP IIb/IIIa antagonist tirofiban (Aggrastat) has been shown to be effective in the treatment of acute coronary ischemic syndromes, such as unstable angina and PTCA.4 5 6 7 8 9 10 11 12 We hypothesized that in addition to an antithrombotic effect, inhibition of GP IIb/IIIa receptors may also affect coronary vascular dynamic function, particularly during progressive coronary arteriostenosis.
To test our hypothesis, we first examined the effects of an analogue of tirofiban, L-739,758,13 on resting coronary blood flow (CBF) during progressive coronary arteriostenosis induced by repeated injury of either the left anterior descending (LAD) or the left circumflex (LCx) coronary artery in swine. We then studied whether GP IIb/IIIa receptor inhibition alters coronary flow reserve by measuring the coronary reactive hyperemic response to a brief, complete coronary artery occlusion before and after each injury. The effects of the GP IIb/IIIa receptor inhibitor were compared with those of heparin and aspirin not only on the basis of the number of injuries necessary to cause stenosis but also at comparably reduced levels of resting CBF to determine whether a possible difference in the degree of stenosis could account for the observed differential effects. Finally, we measured coronary reactive hyperemic responses in additional control and GP IIb/IIIa receptor inhibitor–treated pigs at comparably reduced levels of coronary perfusion pressure to address whether GP IIb/IIIa receptor inhibition preserves coronary flow reserve during injury-induced coronary arteriostenosis by an effect on the coronary vasculature or simply by preventing thrombotic stenosis at the site of coronary artery injury.
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Methods |
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Animal Model
A porcine model was used in this study because the porcine coronary arterial anatomy, including the relative lack of preexisting collateral channels and anastomoses,14 15 and coronary metabolism are similar to those of the human.15 The experiments were short-term to avoid any influence from coronary artery collateral development during chronic coronary arteriostenosis.16 All of the animals used in this study were maintained in accordance with the guidelines of the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources of the National Research Council (1996), and the studies were approved by the Merck Research Laboratories Institutional Animal Care and Use Committee. The pigs were housed individually under conventional conditions, fed commercial pig ration, and allowed access to water ad libitum before surgery.
Twenty-eight Yorkshire farm pigs 4 to 6 months old and weighing 31±3 kg were sedated with a mixture of ketamine (12 mg/kg IM) and xylazine (8 mg/kg IM). After tracheal intubation, general anesthesia was maintained with isoflurane (1.0 to 3.0 vol% in O2). A left thoracotomy was performed at the fourth intercostal space. A Tygon catheter was implanted in the descending aorta for measurement of arterial pressure, and an Angiocath IV catheter was placed in an ear vein for infusion of saline and drugs. In 20 of the pigs, the LCx and LAD were isolated, and a hydraulic occluder made from Tygon tubing was placed around each of these arteries to induce a brief, complete occlusion to be able to measure the coronary reactive hyperemic response. Volume flow probes (Transonic Systems) were also placed around the LCx and LAD coronary arteries proximal to the occluders to continuously measure CBF. In the remaining 8 pigs, only the LAD was instrumented with a volume flow probe and hydraulic occluders, 2 in the treated group and 1 in the control group. The additional occluder in the treated group was used to produce partial stenosis. In addition, a catheter made of polyethylene tubing (PE-280) was implanted in one of the distal branches of the LAD to measure the coronary perfusion pressure distal to the injury site.
Experimental Protocol
A schematic of the experimental protocol used in the first set
of experiments is shown in Figure 1
.
Briefly, experiments were initiated when both the systemic
hemodynamics and the CBF were stable, which occurred 30
to 60 minutes after the animals were instrumented. The pigs were
infused intravenously and continuously at the same flow
rate (5 mL/min) with 0.9% saline (NaCl in H2O)
(n=7), L-739,758 (an analogue of the GP IIb/IIIa receptor
inhibitor tirofiban) at a dose of 100 µg ·
kg-1 ·
h-1 (n=5), heparin at a
dose of 1 U ·
kg-1 ·
min-1 after a bolus dose
of 350 U/kg (n=5), or aspirin at a dose of 10 mg/kg (n=3). The GP
IIb/IIIa inhibitor was prepared as a 5-mg/mL solution in
100 mmol/L NaOH, then diluted to 0.1 mg/mL in 0.9% saline
buffered with 10 mmol/L
Na2HPO4. Activated
clotting time was measured periodically throughout the heparin
experiments and was always 15 minutes greater than the pretreatment
level. Baseline measurements of mean arterial pressure,
resting phasic and resting mean CBF, heart rate, and reactive
hyperemic response, which was induced by coronary
artery occlusion for 15 seconds, were made 30 minutes after the
administration of the saline, GP IIb/IIIa inhibitor,
heparin, or aspirin was begun. Then, either the LCx or the LAD was
clamped with a hemostat at a site proximal to the flow probe for
15-second periods at 30-minute intervals until resting CBF had
fallen to almost zero or until the artery had been clamped a minimum of
6 times. The unclamped artery served as a control.
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In a separate set of experiments, the reactive hyperemic response was measured in an additional 8 pigs, 4 control and 4 GP IIb/IIIa inhibitor–treated, in which the LADs were clamped twice for 15-second periods 15 minutes apart. In the GP IIb/IIIa inhibitor–treated group, a hydraulic occluder placed around the LAD was used to partially occlude the vessel so that the coronary perfusion pressure distal to the site of injury could be reduced by a similar degree to that resulting from the 2 injuries alone in the control group. Saline or L-739,758 was infused into the control or the treated pigs, respectively, at the same rates as those used in the first set of experiments.
Data Analysis
Hemodynamic recordings were made with a
data tape recorder and a multiple-channel oscillograph.
Arterial pressure was measured with a strain-gauge
manometer connected to a fluid-filled aortic catheter. LAD and LCx
blood flows were measured with a volume flowmeter (Transonic Systems).
A cardiotachometer, triggered by the phasic arterial
pressure signal, provided instantaneous and continuous measurements of
heart rate. Coronary vascular resistance was calculated as the
quotient of mean arterial pressure and mean CBF. Total CBF
during reactive hyperemia was measured with a planimeter to
integrate the area of the mean CBF recording. Blood flow debt,
reactive hyperemic flow, and blood flow debt repayment were
calculated as described previously.17 18 The equations
used were as follows:
Blood flow debt (mL)=control blood flow rate (mL/s)xduration of occlusion (seconds).
Reactive hyperemic flow (mL)=total blood flow during reactive hyperemia (mL)-[control blood flow rate (mL/s)xduration of reactive hyperemia (seconds)].
Blood flow debt repayment (%)=[reactive hyperemic flow (mL)/blood flow debt (mL)]x100.
The coronary reactive hyperemic response was not examined in 2 of the 7 control animals in the first set of experiments because the first one was not instrumented with hydraulic occluders and there were technical problems with another one. The data from the GP IIb/IIIa receptor antagonist (L-739,758), heparin, aspirin, and control groups were compared by 1-way ANOVA with the Student-Newman-Keuls test. The probability values were corrected with the Bonferroni procedure. All values are expressed as the mean±SEM. Statistical significance was accepted at the P<0.05 level.
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Results |
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There was no significant difference in mean arterial pressure, heart rate, or resting CBF at baseline (ie, immediately before coronary artery injury) between the control, GP IIb/IIIa inhibitor, heparin, and aspirin groups (Table
). The changes in resting
CBF after mechanically induced coronary artery injury are shown
in Figure 2. In the control pigs, resting
CBF had fallen to nearly zero after 3 injuries, whereas in the pigs
treated with the GP IIb/IIIa inhibitor and heparin, resting
CBF was reduced by only 16±6% and 17±8% after 5 injuries,
respectively.
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Because the number of injuries that were necessary to affect resting
CBF varied within the groups as well as between the groups (ie,
2.4±0.4, 4.6±0.4, and 3.0±0.4 injuries for the control, GP IIb/IIIa
inhibitor, and heparin groups, respectively), the plot of
the time course of the change in resting CBF for these groups begins
after the injury that resulted in a prolonged reduction in resting CBF
(Figure 3). The resting CBF fell by
93±2% at 14±2.7 minutes in the control group, whereas in the GP
IIb/IIIa inhibitor group, the decrease in resting CBF was
delayed and then CBF was maintained between 70% and 80% of the
baseline, ie, preinjury level, despite additional injuries performed at
30-minute intervals. The time course of the reduction in resting CBF in
the heparin group was similar to that in the GP IIb/IIIa
inhibitor group, indicating that the GP IIb/IIIa
inhibitor and heparin each prevented the proximal
thrombotic coronary occlusion that occurred after multiple
mechanically induced injuries in the control group. Also shown in
Figure 3 are the changes in resting CBF in the uninjured
vessels, ie, the contralateral coronary arteries, for each of
the groups. The resting CBF in the uninjured arteries was unchanged in
the GP IIb/IIIa inhibitor and heparin groups. In the
control group, however, the resting CBF through the uninjured artery
was reduced by 15% when the resting CBF through the injured artery
was reduced by 95% from the baseline level. This decrease in blood
flow in the uninjured artery was most likely due to a decrease in left
ventricular pump function and consequently coronary
perfusion pressure because of the marked and rapid reduction in blood
flow in the injured artery.
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The baseline and percent change from baseline values for
coronary vascular resistance, blood flow deficit, and repayment
of CBF deficit after injury in the control, GP IIb/IIIa
inhibitor, heparin, and aspirin groups are shown in the
Table
. There were no differences between the groups in any of
the parameters at the baseline level, suggesting that
neither agent affected the resting coronary vasomotor tone. The
repayment of CBF deficit was reduced significantly compared with
baseline after the second injury in the untreated control group
(-57±3%) and after the third injury in the heparin (-52±12%) and
aspirin (-54±16%) groups (Figure 4).
In contrast, the repayment of CBF deficit was reduced significantly
(P<0.01) less, even after the fourth injury, in the GP
IIb/IIIa inhibitor group (-15±4%) compared with the
heparin (-66±4%) and aspirin (-60±4%) groups.
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To determine whether the difference in the repayment of CBF deficit
between the GP IIb/IIIa inhibitor, heparin, and aspirin
groups was due to a difference in the degree of coronary
arteriostenosis, the data from the different groups also were
compared at similarly reduced levels of resting CBF. Figure 5 shows the relationship between the
repayment of CBF deficit and resting CBF for the 3 groups. At a
comparable level of resting CBF (15% below baseline), the repayment
of flow deficit was reduced more (P<0.05) in the control
(-56±9%), heparin (-49±9%), and aspirin (-61±12%) groups than
in the GP IIb/IIIa inhibitor group (-26±6%). When the
resting CBF had decreased by 35%, the repayment of CBF deficit was
reduced significantly (P<0.01) more in the heparin group
(-64±9%) than in the GP IIb/IIIa inhibitor group
(-21±6%).
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To determine the site of the beneficial effect of the GP IIb/IIIa
inhibitor on coronary flow reserve, the reactive
hyperemic response was measured in control and GP IIb/IIIa
inhibitor–treated pigs subjected to coronary
artery injury while coronary perfusion pressure was measured
simultaneously distal to the injury site. The repayment of
CBF deficit was inversely correlated with the reduction in the distal
coronary perfusion pressure in both groups (Figure 6). When the distal coronary
perfusion pressure was reduced by similar amounts, however, the
repayment of CBF deficit in the control group was significantly
attenuated (P<0.01) compared with that observed in the GP
IIb/IIIa inhibitor–treated group. For example, when the
distal coronary perfusion pressure fell by 14±1 and 20±1
mm Hg, the repayments of CBF deficit in the control group were 20±6%
and 12±7%, respectively, whereas in the GP IIb/IIIa
inhibitor–treated group they were 130±16% and 65±14%,
respectively, which were significantly different (P<0.01)
from the control values in both cases.
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Discussion |
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The major finding of the present study was that although an analogue (L-739,758) of the GP IIb/IIIa receptor inhibitor tirofiban, heparin, and aspirin each effectively prevented acute proximal coronary thrombosis induced by repeated injury of coronary arteries in swine, the reactive hyperemic response after injury was clearly preserved by the GP IIb/IIIa receptor inhibitor but not by heparin or aspirin. This suggests that in addition to or because of its antithrombotic effect, the GP IIb/IIIa receptor inhibitor was able to maintain the distal coronary artery vasodilatory response. To the best of our knowledge, this is the first study of the effect of a GP IIb/IIIa receptor inhibitor on coronary flow reserve during progressive coronary arteriostenosis.
After 2 coronary artery injuries in the control pigs, resting CBF was unchanged, whereas the reactive hyperemic response was markedly reduced, indicating that these injuries were sufficient to cause stenosis. When the coronary arteries in the control pigs were subjected to further injury, the resting CBF fell steeply to almost zero, indicating nearly complete occlusion of the coronary artery. In contrast, the resting CBF was only slightly changed in the GP IIb/IIIa inhibitor–treated, heparin-treated, and aspirin-treated pigs. Thus, it appears that the GP IIb/IIIa inhibitor, heparin, and aspirin each delayed the onset of stenosis and prevented the complete coronary artery occlusion that had occurred in the control pigs as a result of repeated coronary artery injury. After 3 coronary artery injuries, however, the reactive hyperemic response was reduced more in the heparin-treated and aspirin-treated groups than in the GP IIb/IIIa inhibitor–treated group, suggesting that the coronary vasodilatory response was preserved by inhibiting the GP IIb/IIIa receptor.
One of our concerns in the present study was that the greater
reactive hyperemic response observed in the GP IIb/IIIa
inhibitor–treated group compared with that observed in the
heparin- and aspirin-treated groups after the same number of injuries
could have been attributable partly to a difference in the degree of
stenosis because of a variable degree of mechanically
induced injury or because of differences in the antithrombotic efficacy
of heparin, aspirin, and the GP IIb/IIIa inhibitor, as
evidenced by the fact that the number of injuries necessary to reduce
the resting CBF was different for these groups. In an attempt to
account for these factors, the reactive hyperemic responses of
the groups were compared at similarly reduced levels of resting CBF,
when the degrees of stenosis should have been similar. When
resting CBF was reduced 15% or 35%, the reactive hyperemic
responses in the pigs treated with the GP IIb/IIIa
inhibitor were still greater than those in the pigs treated
with either heparin or aspirin, suggesting that GP IIb/IIIa receptor
inhibitors are more efficacious in preserving
coronary flow reserve during progressive coronary
arteriostenosis, possibly because of their greater ability to
inhibit platelet function.
To determine the site of this effect of the GP IIb/IIIa receptor
inhibitor, the reactive hyperemic response was
measured while the coronary perfusion pressure distal to the
injury site was also measured in 2 additional groups of control and GP
IIb/IIIa inhibitor–treated pigs. After 2 injuries in the
GP IIb/IIIa inhibitor–treated pigs, a hydraulic occluder
was used to reduce the coronary perfusion pressure by amounts
similar to those resulting from injury alone in the control pigs. As
expected, the coronary flow reserve was negatively correlated
with the reduction in distal coronary perfusion pressure. When
the distal coronary perfusion pressure was reduced by >20
mm Hg, the reactive hyperemic response was basically exhausted
in both groups. When the coronary perfusion pressure was
reduced by lesser but comparable amounts, however, the reactive
hyperemic responses in the GP IIb/IIIa
inhibitor–treated pigs were significantly greater than
those in the control pigs, indicating that the effect of the GP
IIb/IIIa receptor inhibitor was in the coronary
vasculature distal to the injury site. Although the precise area within
the distal vasculature is unknown, it is likely that this effect was
occurring at vessels located in the epicardial and midmyocardial layers
rather than in the endomyocardial layer. It has
been shown previously that when the resting CBF was reduced by 40%,
the epicardial blood flow was unchanged, whereas the endocardial blood
flow fell by 70%,19 suggesting that coronary
vasodilatory reserve was reduced considerably in the endocardial region
but not in the epicardial region. Thus, it is conceivable that the
reactive hyperemic response observed in the present study
would not have occurred in the subendocardial microcirculation.
Coronary driving pressure and resting coronary
vasomotor tone are known to affect the coronary reactive
hyperemic response. The peak CBF rate after a brief occlusion
has been shown to depend on the arterial
pressure.20 Although our data show that after 5 injuries,
mean arterial pressure had decreased slightly more in the
heparin-treated group than in the GP IIb/IIIa
inhibitor–treated group, it was 70 mm Hg, which
should have been sufficient to not affect the coronary driving
pressure and, consequently, the reactive hyperemic response.
Furthermore, mean arterial pressure was reduced comparably
in the heparin- and GP IIb/IIIa inhibitor–treated groups
after 4 coronary artery injuries. Therefore, a difference in
the coronary driving pressure is unlikely to have accounted for
the observed difference in the reactive hyperemic response
between the 2 groups. It has also been shown that the coronary
reactive hyperemic response is inversely related to the degree
of coronary vasodilation.21 In our study, neither
the baseline levels of coronary resistance nor the
coronary resistance after repeated injuries were different
among the GP IIb/IIIa inhibitor, heparin, and aspirin
groups, suggesting that the difference in the reactive
hyperemic response between the groups cannot be attributed to a
difference in the resting coronary vasomotor tone.
Many local metabolically linked substances have been proposed to be responsible for the modulation of coronary reactive hyperemia, including bradykinin, histamine, potassium, prostaglandin, serotonin, and endothelium-derived relaxing factor,22 23 24 with adenosine being the most likely substance.20 21 It is possible that platelet GP IIb/IIIa receptors indirectly affect either a metabolic mediator or the release of a vasoconstrictive substance via their role in platelet aggregation and thrombus formation, because it has been shown that both activated platelets and thrombus formation control several vasoactive mediators.1 2 3 25 26 27 Thus, inhibition of the platelet GP IIb/IIIa receptor may prevent the release of some vasoconstrictive substances and, as a result, help to maintain the coronary reactive hyperemic response. It is unlikely that simply reducing thrombus formation accounts for these results, because heparin had similar effects on resting coronary flow but did not maintain coronary flow reserve.
In summary, heparin, aspirin, and the GP IIb/IIIa receptor inhibitor each prevented the reduction in resting CBF induced by coronary artery injury. At similarly reduced levels of CBF, however, only the GP IIb/IIIa receptor inhibitor preserved the coronary vasodilatory response to a brief coronary artery occlusion. In addition, this response was maintained in the GP IIb/IIIa receptor inhibitor group better than in the control group when coronary arterial perfusion pressure distal to the injury site was reduced by similar amounts. These results suggest that the beneficial effects of a GP IIb/IIIa receptor inhibitor on myocardial infarction and unstable angina may result from its enhanced ability to inhibit blood platelet function and are manifested in the distal coronary vasculature. Further investigation is necessary, however, to determine whether the effect of GP IIb/IIIa receptor inhibition observed in the present study using healthy animals would be altered in an arteriosclerotic model.
Received January 12, 2000; accepted June 13, 2000.
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 T. Heitzer, I. Ollmann, K. Koke, T. Meinertz, and T. Munzel Platelet Glycoprotein IIb/IIIa Receptor Blockade Improves Vascular Nitric Oxide Bioavailability in Patients With Coronary Artery Disease Circulation, August 5, 2003; 108(5): 536 - 541. [Abstract] [Full Text] [PDF]
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J. A. Barrabes, D. Garcia-Dorado, M. Mirabet, R.-M. Lidon, B. Soriano, M. Ruiz-Meana, P. Pizcueta, J. Blanco, Y. Puigfel, and J. Soler-Soler Lack of effect of glycoprotein IIb/IIIa blockade on myocardial platelet or polymorphonuclear leukocyte accumulation and on infarct size after transient coronary occlusion in pigs J. Am. Coll. Cardiol., January 2, 2002; 39(1): 157 - 165. [Abstract] [Full Text] [PDF]
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