(Circulation. 2000;102:88.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Brief Antecedent Ischemia Enhances Recombinant Tissue Plasminogen Activator–Induced Coronary Thrombolysis by Adenosine-Mediated Mechanism
From the Heart Institute, Good Samaritan Hospital, and the Department of Medicine, University of Southern California, Los Angeles.
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
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Clinical studies have implicated preinfarct angina (brief antecedent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clinical findings and (2) determine whether release of adenosine (a potent inhibitor of platelet aggregation via stimulation of platelet A2 receptors) during brief I/R contributes to this improved patency.
Methods and Results—To address our first objective, we compared the time required to achieve lysis with recombinant tissue plasminogen activator and patency during the first 2 hours after lysis in dogs in which 1-hour thrombotic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-minute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the I/R group versus the control group (11±1 versus 35±6 minutes, P=0.004). In addition, the duration of subsequent reocclusion was reduced (17±12 versus 30±11 minutes), and the area of the flow-time profile (normalized to baseline flowx120 minutes) was increased (64±12% versus 35±7%, P=0.04) in the I/R cohort. The protocol was then repeated, but all dogs were pretreated with the adenosine A2/A1 antagonist CGS 15943 (CGS, 1.5 mg/kg). Time to lysis (38 versus 39 minutes) and subsequent patency were comparable in the CGS+control group versus the CGS+I/R group.
Conclusions—Brief antecedent I/R enhances the efficacy of coronary thrombolysis in this canine model, which is due, at least in part, to an adenosine-mediated mechanism.
Key Words: ischemia • thrombolysis • adenosine • myocardial infarction
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Brief "preconditioning" (PC) ischemia in addition to its ability to render myocytes resistant to infarction1 2 may also have favorable effects on arterial patency.3 4 5 6 This is supported by our recent observation that 10 minutes of coronary artery occlusion attenuated the subsequent spontaneous formation/dislodgment of platelet thrombi in damaged and stenotic canine coronary arteries, which is due largely to the release of adenosine (a potent inhibitor of platelet aggregation7 8 ) during the PC stimulus.3 Clinical reports further suggest that the benefits of antecedent ischemia on coronary patency may extend to the setting of persistent thrombotic occlusion: in patients with acute myocardial infarction, preinfarct angina was associated with more rapid thrombolysis6 and lower rates of reocclusion after initial lysis.5 However, the effect of antecedent ischemia on the efficacy of coronary thrombolysis has, to date, not been rigorously assessed. By use of a canine model of occlusive coronary thrombosis, our objectives were to (1) establish whether brief PC ischemia is associated with accelerated recombinant tissue plasminogen activator (rtPA)-induced thrombolysis and better maintenance of patency after initial restoration of blood flow and (2) determine whether, as in models of recurrent platelet-mediated occlusion,3 4 adenosine receptor stimulation may play a role.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study conforms to the principles endorsed in the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, DC, 1996)
Surgical Preparation
Forty mongrel dogs (20±4 kg) were anesthetized with
sodium pentobarbital (30 mg/kg IV), intubated, and ventilated with room
air. After cannulization of the left jugular vein (for administration
of drugs and fluids) and the left carotid artery (for measurement of
systemic hemodynamics), the heart was exposed through a
left lateral thoracotomy. Two or 3 adjacent segments of the mid left
anterior descending coronary artery (LAD) were isolated. The
proximal segment served as the site of later thrombosis; the second was
instrumented with a Doppler flow probe (Transonic Systems Inc) for
monitoring of mean coronary blood flow (CBF); and in animals
enrolled in protocols 1, 2, and 3, the third segment was used as a site
of temporary occlusion during thrombus formation. In protocols 2 and 3,
a catheter was positioned in the left atrium for later injection of
radiolabeled microspheres (141Ce or
95Nb) for measurement of regional myocardial
blood flow (RMBF). Arterial pressure and CBF were
recorded throughout each experiment on a chart recorder (Gould
Inc).
Protocol 1: Thrombus Morphology
Our first aim was to document the consistent formation
of an occlusive platelet- and fibrin-rich thrombus in our model
(Figure 1
). Ten dogs received 10 minutes
of mechanically induced LAD occlusion (achieved by placing vascular
clamps at the site of later thrombotic occlusion) and 10 minutes of
reperfusion (PC group, n=5) or 20 minutes of uninterrupted perfusion
(control group, n=5). Coronary thrombosis was then initiated by
compressing the proximal LAD segment with hemostats to remove the
endothelium, tear the tunica media, and expose the
underlying (and highly thrombogenic) tunica
adventitia.3 9 10 A micromanometer
constrictor was applied at the site of injury and tightened such that
CBF was reduced to 30% to 40% of its baseline value
(stenosis), thereby precipitating an immediate decline in CBF
due to adhesion and aggregation of platelets at the site of injury.
To facilitate formation of a fully occlusive thrombus, stasis was then
induced by placing a vascular clamp on the third (distal) LAD
segment.
|
Fifty-five minutes after the onset of thrombosis, the distal clamp was removed, and occlusive thrombosis was confirmed by maintenance of CBF at 0 mL/min. Five minutes later, the animals were euthanized under deep anesthesia by intracardiac injection of KCl, and the thrombotic LAD segment was excised for histological evaluation.
Protocol 2: Effect of Brief Antecedent Ischemia on
Thrombolysis
To address our primary objective (whether brief antecedent
ischemia enhances the efficacy of
thrombolysis), 14 dogs received 10 minutes of PC
occlusion followed by 10 minutes of reperfusion (n=7) or a 20-minute
control period (n=7, Figure 1
). Coronary thrombosis was
then initiated as in protocol 1.
At 50 minutes after the onset of thrombosis, the distal clamp was removed. After confirming thrombotic occlusion, RMBF (ie, collateral perfusion to the ischemic territory) was assessed by injection of radiolabeled microspheres.1 11 At 1 hour after occlusion, all dogs received rtPA (1.3 mg/kg IV infused over 1 hour, a gift from Genentech Inc (South San Francisco, Calif)),9 11 and the time required to achieve reperfusion (defined below) was noted. CBF was then monitored for 2 hours after the initial reflow.
To confirm that 10 minutes of antecedent ischemia was also effective in eliciting cardioprotection, infarct size was measured by use of routine methods.1 2 11 At the end of the protocol, the LAD was ligated at the site of thrombotic occlusion, Unisperse Blue pigment (CIBA; 0.5 mL/kg) was injected via the left atrial catheter to delineate the area of myocardium at risk of infarction (AR), and the dogs were euthanized as in protocol 1. The hearts were then excised, cut into 5 to 8 transverse slices (10- to 12-mm thickness), and photographed. The slices were incubated in triphenyltetrazolium chloride (10 minutes at 37°C) to delineate necrotic from viable myocardium and photographed again.
Protocol 3: Effect of Adenosine Receptor
Antagonist on Thrombolysis
To evaluate our second hypothesis (whether improvements in the
efficacy of thrombolysis with PC are mediated by
adenosine), protocol 2 was repeated in 13 dogs. In this case,
however, all animals received the adenosine
A2/A1 receptor
antagonist CGS 159434 12 13 (CGS, 1.5 mg/kg IV
bolus, a gift from Novartis Inc, Summit, New Jersey) 10 minutes
before the PC (n=6) or control period (n=7, Figure 1). Time to
lysis, LAD patency during the 2 hours after lysis, and infarct size
were quantified as in protocol 2.
Protocol 4: Effect of Adenosine Receptor
Antagonist on Platelet Aggregation
To confirm in vitro findings that CGS has no intrinsic
effect on platelet aggregation,12 13 3 dogs underwent
LAD injury plus stenosis. However, rather than causing deep
arterial injury, we damaged the tunica media without
adventitial exposure by compressing the LAD with cushioned hemostats,
thereby initiating cyclic variations in coronary flow (CFVs)
caused by formation/dislodgment of platelet
thrombi3 11 14 rather than persistent thrombotic
occlusion.
CBF was monitored for 2 hours after injury plus stenosis. All dogs then received CGS (1.5 mg/kg IV bolus), and LAD patency was monitored for an additional 2 hours. The dogs were then euthanized, and the damaged LAD segment was excised for histological assessment.
Analysis
Histological evaluation of LAD segments (all
protocols) was conducted from cross sections (5-µm thickness, 4 to 10
per sample) stained with hematoxylin-eosin and picrosirius red (to
visualize adventitial collagen) and viewed at magnifications of x10 to
x25.3 9 All samples were evaluated by using bright-field
illumination to confirm the expected loss of
endothelium and tearing of the tunica media and to
document the presence or absence of adventitial exposure.
Identification of thrombotic components was facilitated by viewing
picrosirius red–stained sections with polarized light; fibrin fibers
are birefringent and appear green when this method is used, whereas
platelets and erythrocytes are not birefringent and thus
appear dark.
Heart rate and arterial pressure (all protocols) were
measured and averaged over 5 cardiac cycles for each sample period.
Mean CBF (all protocols) was determined at discrete time points during
which coronary flow was stable, ie, at baseline, after CGS
treatment (protocol 3), after the PC/control period (protocols 1, 2,
and 3), and immediately after application of the stenosis. Time
to lysis (protocols 2 and 3) was defined as the time from the onset of
rtPA infusion until CBF was restored to its stenotic value.
Coronary patency after lysis (protocols 2 and 3) and after
injury plus stenosis (protocol 4) was assessed by measuring the
duration (in minutes) of reocclusion (CBF=0) and percent flow-time area
(defined as the area of the flow-time profile throughout each 2-hour
observation period) and normalized for each dog to the baseline
flowx120 minutes.3 4 9 Total duration of thrombotic
occlusion (protocols 2 and 3) was calculated as 
(1-hour test
occlusion+time to achieve reperfusion+duration of reocclusion after
initial lysis). RMBF (protocols 2 and 3) was measured in subendocardial
and subepicardial tissue blocks cut from the center of the LAD
territory with the use of routine methods.1 11 Risk region
and infarct size (protocols 2 and 3) were measured from photographic
images of the heart slices traced at magnifications of x2 to x4. AR
and area of necrosis (AN) in each slice were quantified by computerized
planimetry, corrected for tissue weight, expressed in grams, and summed
for each heart.11
Statistics
CBF and hemodynamics (protocols 1, 2, and
3) were compared by 2-factor ANOVA with replication, followed by the
Tukey test. For protocols 2 and 3, the time to lysis, patency after
lysis, total duration of LAD occlusion, RMBF, and risk region were
compared between matched control and PC groups by t test.
Infarct size was compared by t test and by incorporating
RMBF and the duration of occlusion as covariates in the
analysis. For protocol 4, hemodynamics and
coronary patency were qualitatively compared before versus
after CGS treatment. All data are reported as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Protocol 1
CBF and Hemodynamics
Baseline CBF was 10.0±0.9 and 12.0±1.9 mL/min in the control and PC cohorts, respectively, and was reduced to 3.7±0.4 and 3.7±0.3 mL/min on application of the stenosis. Heart rate and arterial pressure did not differ between groups at any time (not shown).
Arterial Injury and Thrombus Morphology
Histological evaluation revealed (1) the absence
of endothelium, tearing of the tunica media, and
exposure of the adventitia and (2) platelet- and fibrin-rich
thrombus within the lumen, with no differences in the severity of
arterial injury or thrombus composition between groups
(Figure 2).
|
Protocol 2
CBF and Hemodynamics
CBF was comparable between control and PC groups at
baseline, before application of the stenosis (after the
transient hyperemia in the PC group), and immediately after the
stenosis (flow reduced to 3.3 to 3.5 mL/min, or 39% to 45% of
baseline). There were no significant group differences in heart rate or
arterial pressure during the protocol (Table 1).
|
Efficacy of Thrombolysis
The time required to achieve thrombolysis was
35±6 minutes in the control group versus 11±1 minutes in the PC group
(P=0.004, Figure 3A).
|
All controls exhibited multiple episodes of reocclusion/reperfusion
(CFVs) after initial lysis, with the duration of reocclusion and
flow-time area averaging 30±11 minutes and 35±7%, respectively.
Although reocclusion was not prevented in the PC group, the duration of
reocclusion tended to be reduced (17±12 minutes, Figure 3B) and
flow-time area was increased (64±12%, P=0.04; Figure 3C) compared with control values. As a result, the total
duration of thrombotic occlusion was 1.5±0.2 versus 2.1±0.2 hours in
the PC versus control groups (P=0.07, Figure 3D).
RMBF and Infarct Size
Both RMBF and AR were comparable between groups (Table 2).
However, infarct size was smaller in PC dogs versus controls, with
AN/AR averaging 16±5% versus 47±8% (P=0.02; Table 2).
|
Protocol 3
CBF and Hemodynamics
CBF did not differ between groups at baseline and showed the same
temporal profile during the PC/control period and after
stenosis as described for protocol 2. CGS had no effect on
hemodynamics, and there were no significant group
differences in heart rate or arterial pressure (Table 1).
Efficacy of Thrombolysis
Time required to achieve thrombolysis was similar
in both CGS+control and CGS+PC groups, averaging 38±4 and 39±4
minutes, respectively (Figure 4A), and
there were no differences in subsequent patency or total duration of
thrombotic occlusion between the 2 cohorts (Figures 4B to
4D).
|
RMBF and Infarct Size
RMBF and infarct size did not differ between CGS+control and
CGS+PC groups: AN/AR averaged 48±8% and 49±7% (Table 2).
Protocol 4
CBF and Hemodynamics
CBF averaged 13.2±3.1 mL/min at baseline and was reduced to
4.6±0.2 mL/min (39% of baseline) on application of the
stenosis. Hemodynamics remained stable
throughout the protocol and were not altered by CGS treatment (not
shown).
Arterial Injury and Thrombus Morphology
All arteries exhibited endothelial denudation and
medial damage, without adventitial exposure (Figure 5A). Remnants of platelet-rich
(rather than fibrin-containing) thrombus were present in the
lumen.
|
Coronary Patency
All dogs developed CFVs on application of the
stenosis. Neither the duration of total thrombotic occlusion
nor flow-time area deteriorated after CGS treatment (Figures 5B and 5C).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Antecedent Ischemia Enhances Thrombolysis
We report a significant improvement in the efficacy of rtPA-induced thrombolysis in dogs in which thrombotic occlusion was preceded by a brief 10-minute episode of PC ischemia. These results are consistent with clinical observations of accelerated reperfusion6 and lower rates of reocclusion5 in patients with versus patients without preinfarct angina. Moreover, these benefits of antecedent ischemia on vessel patency may, together with the well-described protective effects of PC on the myocardium, contribute to the favorable association between preinfarct angina and outcome after infarction reported in patients receiving thrombolytic therapy.2 5 6 15
Role of Adenosine
We further found that pretreatment with CGS abrogated the effects
of antecedent ischemia on rtPA-induced
thrombolysis. These results implicate adenosine
released during the PC stimulus and adenosine receptor
stimulation in eliciting the more rapid reflow and better
maintenance of subsequent patency seen in the PC group.
How might adenosine improve the efficacy of thrombolysis? Numerous studies have documented massive release of adenosine from myocytes after relief of a brief ischemic episode.2 16 Moreover, adenosine, despite its highly labile nature,4 16 initiates a potent and sustained (>3-hour3 ) inhibition of platelet aggregation via A2 receptor–mediated signaling.7 8 Thus, the improved patency observed in the PC group after thrombolysis may reflect an adenosine-mediated attenuation of recurrent platelet-mediated thrombosis analogous to that seen in models of CFVs.3 4
The mechanisms by which PC ischemia accelerated thrombolysis are unclear. One possibility is that PC ischemia, by attenuating initial platelet aggregation, impaired the formation of a fully occlusive thrombus. However, protocol 1 revealed that PC ischemia did not impair the evolution of a persistent platelet- and fibrin-containing clot.
Although thrombus morphology appeared comparable between groups, we speculate that 3 factors might contribute to the more rapid lysis. First, the porosity of the thrombus (determined by the architecture of the fibrin fibers17 ) might differ, such that penetration of rtPA might be facilitated in the PC cohort. Second, accretion of platelets onto the evolving thrombus may have been inhibited in the PC group, thereby altering thrombus stability, an explanation invoked previously to explain the accelerated reflow reported with administration of platelet glycoprotein IIb/IIIa receptor inhibitors.18 Finally, thrombus stability might be compromised in the PC cohort via adenosine-mediated inhibition of platelet adhesion molecule expression, possibly P-selectin.8
Deleterious Effect of CGS on Coronary Patency?
In protocol 3, the time required to achieve
thrombolysis and patency after reflow were comparable
in the CGS+PC and CGS+control groups. However, qualitative comparison
of protocols 2 and 3 suggests that reocclusion after
thrombolysis was exacerbated by CGS treatment,
suggesting that CGS may have had a direct proaggregatory effect.
To address this issue, vessel patency was assessed before versus after CGS treatment in a model of CFVs (protocol 4). We observed no deleterious changes in patency, consistent with ex vivo evidence showing CGS to be devoid of intrinsic effects on platelet aggregation.12 13
An explanation for the poor patency in CGS-treated dogs may be derived from evidence from a canine model of hypoperfusion, which showed that maintenance of stable coronary blood flow is dependent on endogenous adenosine; ie, infusion of a nonselective adenosine receptor antagonist initiated a progressive deterioration in coronary perfusion that was due to the formation of platelet thrombi.7 8 Thus, even in non-PC controls, adenosine may participate in the regulation of platelet activity and coronary patency.
Infarct Size Reduction With Antecedent Ischemia: PC or
Accelerated Lysis?
In addition to the enhanced efficacy of
thrombolysis, we also observed, in protocol 2, a
significant reduction in infarct size in dogs that received antecedent
ischemia. Does this represent cardioprotection
conferred by brief PC ischemia,1 2 or is it a
secondary consequence of the more rapid reflow in the PC group?
To resolve this issue, infarct size was compared between control
and PC groups by incorporating, as covariates, the 2 major determinants
of infarction in the dog: total duration of occlusion and collateral
perfusion (severity of ischemia)1 11 (Figure 6). Multiple regression analysis
confirmed a significant correlation between these variables and
infarct size for both control and PC cohorts
(r2
0.85, P
0.02).
However, there was a significant downward shift in the regression plane
for the PC group versus controls with respect to both collateral
perfusion and occlusion time (P=0.003 and P=0.05
by ANCOVA), indicating that dogs in the PC group developed smaller
infarcts over the range of collateral flow values and total occlusion
times obtained in the present study. Similar results were obtained
when the duration of persistent occlusion (1-hour thrombotic
occlusion+time to lysis) rather than the total occlusion time was used
as the covariate (not shown). Thus, although the shorter
ischemic duration was a contributing factor, the smaller
infarct sizes in the PC group were not uniquely due to differences in
the duration of ischemia. Rather, classic
ischemia-induced cardioprotection was manifest in the PC
cohort.
|
Loss of Cardioprotection With CGS: Poor Patency or
A1 Inhibition?
The efficacy of infarct size reduction with PC is dependent on
ischemic duration and, in the canine model, wanes with
occlusions >90 minutes.1 2 As a result, we propose that
the absence of protection seen in PC dogs treated with CGS is a
consequence of poor patency (prolonged duration of ischemia)
that is due to the inhibition of platelet A2
receptors. However, this conclusion is confounded by the fact that
PC-induced cardioprotection is initiated by stimulation of
adenosine A1/A3
receptors on myocyte membranes,2 and CGS, despite its
nanomolar affinity for the A2 receptor, is not
subtype specific12 13 ; ie, the loss of protection seen in
PC dogs that received CGS could be due in part to residual
A1 receptor antagonism on myocytes.
To distinguish between these possibilities, we conducted
supplemental experiments using ZM 241385 (ZM, Tocris-Cookson Inc), a
potent and highly selective (1000-fold) A2
antagonist. Five dogs received ZM (1.5 mg/kg IV bolus) and,
10 minutes after treatment, underwent 10-minute PC ischemia
plus 10-minute reflow followed by 1 hour of thrombotic occlusion (same
design as protocol 3). The time required to achieve
thrombolysis (35±3 minutes) and patency after initial
lysis (flow-time area 16±9%, mean duration of reocclusion 75 minutes,
and total duration of occlusion 2.8±0.4 hours) seen in ZM-treated dogs
were comparable to results obtained in CGS+control and CGS+PC groups in
protocol 3. Moreover, the infarct size in PC dogs that received ZM
(AN/AR=46±9%) was also similar to the value of 49% obtained in the
PC+CGS group. These data support the hypothesis that the improved
efficacy of thrombolysis achieved with PC
ischemia is mediated by an A2 mechanism.
Furthermore, although residual A1 effects remain
possible, the results suggest that the large infarct sizes seen in
antagonist-treated PC dogs are due predominantly to
A2 receptor inhibition (presumably on
platelets) and the resultant prolonged duration of ischemia
rather than to A1 receptor inhibition on
myocytes.
Finally, it is perhaps surprising that infarct size was not increased in the CGS+control group of protocol 3 versus the control group of protocol 2, given that the duration of total thrombotic occlusion was 2.9 versus 2.1 hours. This increase in total ischemic burden was due to exacerbated reocclusion after initial lysis (68 versus 30 minutes) rather than differences in the time to achieve reflow (38 versus 35 minutes), suggesting that "stuttering" flow (ie, CFVs with short individual episodes of recurrent ischemia) does not exacerbate necrosis.19
Summary
Brief antecedent ischemia, in addition to protecting
myocytes and limiting infarct size, significantly accelerates
rtPA-induced thrombolysis and improves patency during
the first 2 hours after reflow in the canine model. Pretreatment with
CGS and ZM rendered PC ineffective in augmenting the efficacy of
thrombolysis, thereby implicating adenosine
release during the PC stimulus and the resultant adenosine
receptor stimulation as important contributors to this
ischemia-induced improvement in patency.
Our results suggest that stimulation of platelet A2 receptors "triggers" the improved patency achieved with PC ischemia. However, local vasodilation via A2 and/or A1 receptor stimulation on the coronary vasculature or A2/A1 stimulation on neutrophils and attenuation of neutrophil "plugging" may also play a role.20 21 Moreover, platelet adhesion and aggregation are complex, and other metabolites liberated from ischemic myocardium (eg, nitric oxide and prostaglandins) might also be involved. Finally, the time course of PC-induced adenosine release on vessel patency and the downstream mechanism(s) by which adenosine receptor stimulation elicits an increase in the efficacy of thrombolysis remain to be elucidated.
Received October 20, 1999; revision received January 28, 2000; accepted February 7, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.
2. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis. 1998;40:517–547.[Medline] [Order article via Infotrieve]
3.
Hata K, Whittaker P, Kloner RA, et al.
Brief antecedent ischemia attenuates platelet-mediated
thrombosis in damaged and stenotic canine coronary
arteries: role of adenosine. Circulation. 1998;97:692–702.
4.
Hata K, Whittaker P, Kloner RA, et al. Brief
myocardial ischemia attenuates platelet thrombosis in
remote, damaged, and stenotic carotid arteries.
Circulation. 1999;100:843–848.
5. Muller DWM, Topol EJ, Califf RM, et al. Relationship between antecedent angina pectoris and short-term prognosis after thrombolytic therapy for acute myocardial infarction. Am Heart J. 1990;119:224–231.[Medline] [Order article via Infotrieve]
6.
Andreotti F, Pasceri V, Hackett DR, et al.
Preinfarction angina is a predictor of more rapid coronary
thrombolysis in patients with acute myocardial
infarction. N Engl J Med. 1996;334:7–12.
7.
Kitakaze M, Hori M, Sato H, et al.
Endogenous adenosine inhibits platelet
aggregation during myocardial ischemia in dogs. Circ
Res. 1991;69:1402–1408.
8. Minamino T, Kitakaze M, Asanuma H, et al. Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs. J Clin Invest. 1998;101:1643–1653.[Medline] [Order article via Infotrieve]
9. Przyklenk K, Hutsell TC, Hata K, et al. Targeted coronary thrombolysis via "pericardial" administration of lytic agents? J Thromb Thrombolysis.. 1998;6:83–88.[Medline] [Order article via Infotrieve]
10.
Steele PM, Chesebro JH, Stanson AW, et al. Balloon
angioplasty: natural history of the
pathophysiological response to injury in a pig
model. Circ Res. 1985;57:105–112.
11.
Przyklenk K, Kloner RA. Oxygen radical scavenging
agents as adjuvant therapy with tissue plasminogen
activator in a canine model of coronary thrombosis.
Cardiovasc Res. 1993;27:925–934.
12.
Zocchi C, Ongini E, Conti A, et al. The non-xanthine
heterocyclic compound SCH 58261 is a new potent and selective
A2a adenosine receptor
antagonist. J Pharmacol Exp Ther. 1996;276:398–404.
13. Dionisotti S, Conti A, Sandoli D, et al. Effects of the new A2 adenosine receptor antagonist 8FB-PTP, an 8-substituted pyrazolo-triazolo-pyrimidine, on in vitro functional models. Br J Pharmacol. 1994;112:659–665.[Medline] [Order article via Infotrieve]
14. Folts JD. An in vivo model of experimental arterial stenosis, initial damage, and periodic thrombosis. Circulation. 1991;83(suppl IV):IV-3–IV-14.
15.
Kloner RA, Shook T, Przyklenk K, et al. Previous angina
alters in-hospital outcome in TIMI-4: a clinical correlate to
preconditioning? Circulation. 1995;91:37–47.
16.
Lasley RD, Konyn PJ, Hegge JO, et al. Effects of
ischemia and adenosine preconditioning on
interstitial fluid adenosine and myocardial infarct
size. Am J Physiol. 1995;269:H1460–H1466.
17. Becker RC. Hemodynamic, mechanical and metabolic determinants of thrombolytic efficacy: a theoretical framework for assessing the limitations of thrombolysis in patients with cardiogenic shock. Am Heart J. 1993;125:919–929.[Medline] [Order article via Infotrieve]
18.
Madan M, Berkowitz SD, Tcheng JE.
Glycoprotein IIb/IIIa integrin blockade.
Circulation. 1998;98:2629–2653.
19. Alker KJ, Bellows SD, Kloner RA. Stuttering reperfusion of ischemic myocardium does not exacerbate myocardial infarction: evidence against lethal cell reperfusion injury in the rabbit. J Thromb Thrombolysis. 1996;3:185–188.[Medline] [Order article via Infotrieve]
20. Abebe W, Marala RB, Mustafa SJ. Adenosine and coronary vascular pharmacology. In: Abd-Elfattah AA, Wechsler AS, eds. Purines and Myocardial Protection. Norwell, Mass: Kluwer Academic Publishers; 1996:95–104.
21. Cronstein BN, Daguma L, Nichols D, et al. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2- generation, respectively. J Clin Invest. 1990;85:1150–1157.
This article has been cited by other articles:
 |
|
 |
|
  E. A. Amsterdam and S. Schaefer Ischemic preconditioning in coronary heart disease: a therapeutic golden fleece? J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1515 - 1516. [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A Kloner, M. T Speakman, and K. Przyklenk Ischemic preconditioning: a plea for rationally targeted clinical trials Cardiovasc Res, August 15, 2002; 55(3): 526 - 533. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||