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Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky 40536
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although there are
conflicting results on whether adenosine infusion during reperfusion
alters infarct size, there are several reports that indicate adenosine
A2a agonists reduce infarct size. There are also reports
that the A2a agonist CGS-21680 increases cAMP and
contractility in ventricular myocytes. The purpose of this study was to
determine whether low-dose intracoronary infusions of CGS-21680 during
reperfusion exert any beneficial effects in irreversibly and reversibly
injured myocardium. Open-chest pigs were submitted to 60 min of
coronary artery occlusion and 3 h of reperfusion. Treated pigs
were administered intracoronary CGS-21680 (0.2 µg · kg
1 · min1) for the
first 60 min of reperfusion. Pigs submitted to regional stunning (15 min ischemia) were treated with intracoronary CGS-21680 (0.15 µg · kg1 · min1) after
2 h of reperfusion. In the infarct protocol, CGS-21680 reduced
infarct size from 62 ± 2% of the region at risk to 36 ± 2%. In stunned myocardium, CGS increased load-independent regional preload recruitable stroke work and area by 
70%, but the same infusion in normal myocardium was associated with no inotropic effect.
Both beneficial effects were associated with little systemic hemodynamic effects. These findings suggest that reperfusion infusions of low doses of the A2a agonist CGS-21680 exert beneficial
effects in reversibly and irreversibly injured myocardium.
adenosine A2a receptor; myocardial stunning; preload recruitable stroke work; myocardial infarction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE BENEFICIAL EFFECTS of adenosine in reversibly and irreversibly injured myocardium are now well recognized. Adenosine infusion before ischemia attenuates myocardial stunning and reduces infarct size, effects, which based on results with adenosine receptor agonists and antagonists, appear to be mediated primarily via activation of adenosine A1 receptors (15). Furthermore, it is thought that these beneficial effects occur on the cardiac myocytes, because radioligand binding studies indicate that A1 receptors are located primarily on the cardiomyocytes (19) and because A1 agonist protection can be elicited in myocyte models of simulated ischemia (33). Although the results of some recent studies indicate the possible involvement of myocyte A3 receptors (2, 32), there is, to date, no physical evidence of myocyte A3 receptors.
Though the primary focus of the beneficial effects of adenosine has been on the modulation of myocyte signaling during ischemia, many of the initial studies on adenosine cardioprotection were designed to test whether reperfusion infusions of adenosine reduced infarct size. Studies with adenosine generally yielded conflicting results, despite the use of high doses of adenosine (9, 12, 22-24, 34). There are additional reports, however, of the beneficial effects of reperfusion treatments with adenosine A2a agonists (14, 21, 26). It is generally thought that these beneficial effects of adenosine A2a receptor activation are due to reduction of vascular injury and inhibition of neutrophil O2 free radical production (14, 38).
Despite this renewed interest in the reperfusion effects of adenosine A2a agonists in the irreversibly injured heart, there have been few, if any, studies of the effects of reperfusion administration of A2a agonists in stunned myocardium. In fact the few studies on the effects of adenosine administration on postischemic function in stunned myocardium, including a previous study from our laboratory (25), have demonstrated little, if any, beneficial effects of reperfusion adenosine treatments in stunned myocardium (25, 28). However, there is now evidence that cardiac myocytes express adenosine A2a receptors (17), and there are reports that adenosine A2a receptor agonists exert a positive inotropic effect in ventricular myocytes (5, 37). Therefore, the purpose of this study was to determine whether low-dose reperfusion treatment with the selective adenosine A2a receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS-21680) reduces infarct size and enhances postischemic function in an in vivo porcine regional ischemia preparation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All animals in this study received humane care according to the guidelines set forth in The Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, Revised 1996). In addition, animals were used in accordance with the guidelines of the University of Kentucky Institutional Animal Care and Use Protocol.
Animal preparation.
Farm pigs weighing 22-27 kg were used. Pigs were premedicated with
ketamine (30 mg/kg im) and pentobarbital sodium (15-20 mg/kg iv)
and maintained with additional pentobarbital sodium (1.5-2 mg/kg
iv) every 15 min. A tracheotomy was performed, and the animals were
mechanically ventilated with a mixture of room air and 100%
O2. Tidal volume, respiratory rate, and fraction of
O2 in inspired air were adjusted to maintain normal
arterial blood gas and pH values. Core body temperature was monitored
with an esophageal temperature probe and maintained with a heating pad
between 37.5 and 38.0°C. Lactated Ringer solution was administered via an ear vein or femoral vein at 5-7
ml · kg1 · h1, after an
initial bolus administration of 300-400 ml. A femoral artery catheter was used to monitor arterial blood pressure and to
obtain samples for blood-gas analysis.
Experimental protocols.
The preparation was allowed to stabilize for 30 min after all
instrumentation was complete before the experimental protocols were
initiated. In the infarct studies, pigs were submitted to 60 min of LAD
occlusion and 3 h of reperfusion. Before ischemia, phosphate-buffered saline (PBS) was infused through the intracoronary cannula in all pigs. At the onset of reperfusion, control pigs (n = 6) received intracoronary saline for the full 3-h
reperfusion period. Treated animals (n = 6) received
intracoronary CGS-21680 (0.2 µg · kg1 · min1) for the
first hour of reperfusion, after which intracoronary PBS was infused
for the last 2 h of reperfusion. In the stunning protocol, pigs in
both groups received intracoronary PBS before ischemia and for
the first 2 h of reperfusion following 15 min of LAD occlusion.
After 2 h of reperfusion, pigs in the treatment group received
CGS-21680 (0.150 µg · kg1 · min1
intracoronary) for the final hour of reperfusion, whereas the PBS
infusion was continued in the control pigs.
Regional ventricular function and load-insensitive contractility.
In the stunning experiments, pigs were instrumented with piezoelectric
crystals (Crystal Biotech; Houston, TX) to measure regional segment
shortening via sonomicrometry. Pairs of crystals were placed in the LAD
and left circumflex coronary artery-perfused beds. Crystals were placed
in the midmyocardium (~4-6 mm deep) 5-15 mm apart and
aligned in a manner such that the intercrystal axis was parallel to the
direction of myocardial fiber shortening. End diastole was defined as
the onset of pressure increase over time (+dP/dt), and end
systole was defined as 20 ms before peak pressure decrease over time
(
dP/dt). Segment shortening was defined as
end-diastolic length (EDL) minus end-systolic length (ESL), and percent
segment shortening (%SS) was calculated as (EDL ESL/EDL) × 100%. All hemodynamic and sonomicrometry signals were fed through a
32-bit analog-digital converter into an online data acquisition
computer with customized software (Augury, Coyote Bay Instruments;
Manchester, NH). All hemodynamic data were continuously displayed on a
computer monitor. Stroke work (SW) was calculated by quantifying the
area within the pressure-segment length loops generated during each
cardiac cycle.
Lw), where Msw is the
slope of PRSW and Lw is the x-axis
intercept. PRSWA was determined by the formula PRSWA = Msw/2 (1.2Lw,max Lw)2, where
Lw,max is the maximum x-axis
intercept during the entire experiment. Baseline and caval occlusion
data were saved at specific time points in the protocol for offline
analysis. On average 9-11 beats were used in each calculation.
Area at risk and infarct size measurement. The isolated left ventricles were cut into four slices of equal thickness in a plane parallel to the atrioventricular groove. Each slice was weighed and compressed between two transparent Plexiglas plates separated by a distance of 8 mm to achieve uniform thickness. The cross-sectional surface and ischemic areas of each slice were traced onto a transparency sheet. The slices were then incubated in a 1% triphenyltetrazolium chloride solution in PBS, at 37°C for 15 min. The presence of a brick red stain indicated viable tissue, whereas nonviable tissue (infarcted) remained pale. If any infarct was present, the tissue slices were again compressed between the Plexiglas plates and retraced. The areas on the tracings were quantified with a digitizer (Mustek 1200 III, parallel port scanner at 200 dpi) and graphic analysis software (Sigma Scan Pro Automated Image Analysis Software, Jandel Scientific, SPSS; San Rafael, CA). The percent area at risk was calculated for each slice by dividing the area at risk by the total slice area. The sum of the areas at risk of all slices was divided by the sum of the areas of all slices to obtain the percentage of the LV that was ischemic.
Statistical analysis. Results are expressed as means ± SE. Differences between groups were determined by two-way analysis of variance for treatment and time (ANOVA) followed by Duncan's post hoc test. Differences within each group were determined by repeated-measures ANOVA followed by Duncan's post hoc test. A P value < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Infarction protocol.
The systemic and cardiac hemodynamic data in the infarction protocol
are shown in Table 1. There were no
differences in mean arterial blood pressure (MAP), heart rate, or LAD
CBF in either group before or during ischemia. During the first
hour of reperfusion, the CGS-21680-treated group exhibited a higher
heart rate than the control group, which persisted after
discontinuation of the CGS 21680 treatment. The intracoronary infusion
of CGS-21680 did not significantly alter CBF with the exception that at
60 min of reperfusion CBF was greater than preischemic
CBF. There were no significant differences in reperfusion MAP
or CBF values between the groups.
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Stunning protocol.
As shown in Table 2, there were no
differences in any hemodynamic parameters between the groups before
ischemia. Regional ischemia was associated with segment
lengthening, but there were no differences in any hemodynamic parameter
between the groups. After 2 h of reperfusion, MAP tended to be
lower than preischemia values within each group, but again
there were no differences between the groups. The intracoronary
infusion of CGS-21680 was associated with reflex tachycardia as heart
rate increased by ~20 beats/min (P < 0.05 vs.
pre-CGS), and, as expected, CBF during CGS-21680 infusion was
significantly increased.
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1 (P < 0.05). In contrast in the control group, PRSW values at 3 h of
reperfusion (73 ± 6 mmHg · mm · mm1) were not significantly
different from 2-h values (60 ± 9 mmHg · mm · mm1). The x-axis
intercept of the PRSW relationship tended to shift rightward from
preischemic values in both groups, but there were no
differences between the groups. %SS in control pigs decreased from
preischemic values of 20.3 ± 2.8 to 8.0 ± 1.7 and
8.5 ± 1.5% after 2 and 3 h reperfusion, respectively. In
the CGS-21680-treated pigs, %SS decreased from 19.3 ± 2.4%
before LAD occlusion to 6.0 ± 1.0% after 2 h of
reperfusion. At the end of the 60-min CGS-21680 infusion, %SS
increased to 9.0 ± 1.6% (P < 0.05 vs. pre-CGS). There was no evidence of necrosis (based on TTC-positive staining) in
any of the pigs.
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1
(P < 0.05). This increase was maintained throughout
the remainder of the intracoronary CGS-21680 infusion (PRSWA at 60 min
treatment was 466 ± 73 mmHg · mm3 · mm1). In
contrast, PRSWA in the control stunned pigs increased only slightly
over the final hour of reperfusion (from 242 ± 31 to 275 ± 42 mmHg · mm3 · mm1). The
PRSWA values in the nonstunned left circumflex artery bed in both
control and A2a agonist-treated pigs remained stable
throughout the experiment, and the LAD infusion had no effect on PRSWA
in this bed (Fig. 3B).
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1 · min1) was
started and maintained for 60 min. As shown in Fig.
5 papaverine increased LAD CBF
approximately threefold in both pigs, but PRSWA was only marginally
increased.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study indicate that low-dose reperfusion treatment with the adenosine A2a receptor agonist CGS-21680 not only reduces infarct size following prolonged ischemia but also exerts a positive inotropic effect in regionally stunned myocardium. The inotropic effect of CGS appeared to be independent of CBF, because it was not mimicked by the smooth muscle dilator papaverine. In addition the inotropic effect of CGS-21680 was evident only in stunned myocardium. The beneficial effects of CGS-21680 in both reversibly and irreversibly injured myocardium were associated with little hemodynamic effects. These results suggest that cardiac adenosine A2a receptor stimulation exerts beneficial effects in both stunned and infarcted myocardium independent of systemic hemodynamic effects.
The overwhelming majority of the studies on the cardioprotective
effects of adenosine have focused on beneficial effects of adenosine
when administered before ischemia and its role in
ischemic preconditioning. This is in contrast to original
studies on adenosine cardioprotection in which the primary focus was
whether adenosine infusion during reperfusion reduced myocardial
infarct size. The results of several of these initial studies indicated
that adenosine could reduce infarct size in dogs if administered at the
onset of reperfusion (22-24). Several subsequent
studies in both dogs and rabbits failed to replicate these positive
results, although one such study indicated that the combination of
lidocaine and adenosine did reduce infarct size in canines (9,
12, 34). However, in the two canine studies (12,
34) neither intracoronary nor intravenous adenosine at a dose of
150 µg · kg1 · min1
increased CBF. Goto et al. (9) reported that intravenous
adenosine infusion (370 µg · kg1 · min1) during
reperfusion following regional ischemia in the rabbit was
associated with coronary steal. Thus the results of these studies
indicate that high doses of adenosine may mask any beneficial effects
of selective A2a receptor activation.
There are previous reports that adenosine A2a receptor activation during reperfusion can reduce infarct size (14, 21, 26). However, in two of these studies (21, 26) the infarct sizes in the control animals were only 29% of the region at risk. In the present study control infarct size was 62% and was decreased 42% by CGS-21680. This is the first report documenting the ability of reperfusion treatment with a selective adenosine A2a agonist to reduce infarct size in porcine myocardium. Furthermore, this beneficial effect was associated with little, if any, systemic hemodynamic side effects. Adenosine and A2a agonist-induced decreases in infarct size are reported to be associated with reduced neutrophil infiltration (14, 22), consistent with the ability of CGS-21680 to reduce neutrophil adherence to endothelium in vitro and inhibit neutrophil production of superoxide radical (14, 38). These observations are consistent with the presence of adenosine A2a receptors on endothelial cells and neutrophils, and all of these effects would be expected to be beneficial in reperfused myocardium. Because there appears to be a large receptor reserve for coronary adenosine A2a receptors (29), activation of only a small percentage of these receptors should exert significant cardiac effects without the deleterious effects caused by high doses of adenosine or adenosine agonists.
The novel finding in the present study was the ability of a reperfusion infusion of the A2a agonist CGS-21680 to increase contractility in in vivo stunned myocardium. Within 30 min of the commencement of an intracoronary infusion of this agent, PRSW and PRSWA exhibited significant increases from the 2-h reperfusion values, and contractility in the stunned bed remained elevated during the infusion. The A2a agonist infusion was associated with a small decrease in arterial blood pressure and reflex tachycardia; however, PRSW and PRSWA are relatively load-insensitive parameters of regional contractility. Glower et al. (8) reported that PRSWA was one of the most sensitive load-independent parameters of contractility in stunned myocardium. We (13) recently used this measurement to verify that ischemic preconditioning does not improve contractility in stunned porcine myocardium. Treatment with CGS-21680 also improved the recovery of regional segment shortening; however, this measurement of regional ventricular function is load dependent. Given the changes in arterial blood pressure and heart rate during the agonist infusion, this means of assessing regional contractility is not as reliable as PRSW and PRSWA.
Previous studies on the effects of adenosine during reperfusion in stunned myocardium have indicated little, if any, beneficial effects. Sekili et al. (28) reported that intracoronary adenosine infusion for the first hour of reperfusion did not attenuate regional myocardial stunning in dogs. These same authors also observed that a transient adenosine infusion during reperfusion, which increased regional CBF fourfold, did not increase systolic wall thickening. In contrast, our laboratory previously reported that a brief (10 min) intracoronary infusion of adenosine in stunned canine myocardium (after 60 min reperfusion) did increase systolic wall thickening (25). This effect was associated with a five- to sixfold increase in CBF, and when the adenosine infusion was terminated, regional wall thickening decreased in parallel with blood flow. Our laboratory's previous findings with adenosine are thus consistent with a previous report that increasing blood flow in stunned myocardium can increase regional ventricular function (30).
In the present study, the A2a agonist increased regional CBF twofold, but several observations suggest that the increased inotropy was not merely due to increased flow. First, in a subset of animals in which the infusion was terminated after 1 h, CBF returned to basal levels within 15 min, but regional PRSWA remained elevated. Furthermore, an intracoronary infusion of the smooth muscle dilator papaverine, titrated to increase CBF approximately threefold, did not exert any beneficial effect on PRSWA in stunned myocardium. These observations provide evidence that the effect of CGS-21680 in stunned porcine myocardium was independent of changes in CBF. Rather these data are consistent with the hypothesis that CGS-21680 exerted a positive inotropic effect in stunned myocardium.
Although the beneficial action of CGS-21680 on load-independent contractility in stunned myocardium was unexpected, there are two possible explanations for this effect. The first is that coronary A2a receptor activation may have stimulated the release of nitric oxide (NO) via endothelial NO synthase. There are several reports that adenosine, via A2a receptor activation, stimulates coronary NO release (1, 7, 10). Gao et al. (10) recently reported that infusion of CGS-21680 in postischemic isolated rat hearts increased recovery of LV function, an effect that was associated with increased NO release. Although there is a report that NO donors exert no effects on contractility in isolated papillary muscles (36), there are additional reports that NO donors exert biphasic effects on contractility in ventricular myocardium, with low concentrations producing a positive inotropic effect (21, 35). However, all of these studies have been performed in normal myocardium, and NO may exert different effects in stunned myocardium.
A second possibility for the positive inotropic effect of CGS-21680 in stunned myocardium is the stimulation of cardiac myocyte A2a receptors. There is pharmacological (3, 5, 31, 37) and immunological (18) evidence that ventricular myocytes express adenosine A2a receptors. Although in two of the above studies the A2a-induced increases in cAMP were associated with increased myocyte contractility (5, 37), A2a agonists and adenosine do not increase contractility in normal intact ventricular myocardium (16, 25). In the present study CGS-21680 did not alter load-independent PRSW or PRSWA in normal myocardium. Compartmentation of signal transduction may explain the different effects of CGS-21680 on contractility in normal and stunned myocardium. Boknik et al. (3), who reported that CGS-21680 increased guinea pig myocyte cAMP levels, but did not increase contractility, first suggested that A2a receptor-mediated increases in cAMP may be compartmentalized. These same authors (3) also provided evidence that CGS-21680 inhibited cAMP phosphodiesterase activity in guinea pig isolated ventricular myocytes. It is now well recognized that increases in cardiomyocyte contractility correlate to a much greater degree with increases in particulate, as opposed to total intracellular, cAMP levels (4, 11). There are additional reports that adenylyl cyclase subcellular localization is altered during myocardial ischemia (27), and myocardial cAMP levels are reported to be decreased in in vivo stunned myocardium (17). Finally, it is reported (6) that the phosphodiesterase inhibitor milrinone exerted no effects on regional function in normal myocardium, but significantly improved contractility in stunned myocardium, a finding similar to what was observed with CGS-21680 in the present study.
It is unlikely that A2a receptor activation altered some aspect of reperfusion injury, because this treatment was not initiated until 2 h of reperfusion, a time point at which both groups exhibited similar degrees of stunning, and long after the release of potential mediators of reperfusion injury would have subsided. It is also not very likely that the positive inotropic effect of CGS-21680 was due primarily to a reflex mechanism, because this intracoronary infusion was associated with little hemodynamic effects, and similar hemodynamic effects in the nonstunned animals were associated with no inotropic effect.
In conclusion the results of the present study indicate that low doses of the adenosine A2a agonist CGS-21680 administered during reperfusion can reduce infarct size and increase contractility in stunned myocardium. These effects can be achieved with low-dose intracoronary infusions that exert only very minor hemodynamic effects. Although the current hypothesis is that this beneficial effect in irreversibly injured myocardium is mediated via effects on the vasculature and blood cells, it is possible that the effects of A2a agonists in stunned myocardium may be mediated via by ventricular myocyte A2a receptor activation.
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ACKNOWLEDGEMENTS |
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The authors thank Jennifer Wixson for technical assistance in the animal preparation.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-34579.
Address for reprint requests and other correspondence: R. D. Lasley, Dept. of Surgery, Univ. of Kentucky College of Medicine, MN 276 Chandler Medical Center, 800 Rose St., Lexington, KY 40536-0298 (E-mail: rlasley{at}pop.uky.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5 October 2000; accepted in final form 22 November 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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