© 1995 American Heart Association, Inc.
Articles |
Effect of Adenosine on Myocardial `Stunning' in the Dog
From the Experimental Research Laboratory, Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Tex.
Correspondence to Roberto Bolli, MD, Section of Cardiology, Baylor College of Medicine, 6535 Fannin, MS F-905, Houston, TX 77030.
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Abstract |
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Abstract Recent evidence suggests a cardioprotective effect of adenosine in myocardial ischemia and reperfusion. The present study was undertaken to determine (1) whether adenosine attenuates myocardial stunning, (2) if so, whether the beneficial effect of adenosine takes place during ischemia or after reperfusion, and (3) whether adenosine preconditions against myocardial stunning. A total of 93 dogs were used. In phase A of the study, open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion received an intracoronary infusion of either saline (group I [control], n=14), 2 mg/min adenosine from 30 minutes before occlusion until 1 hour after reperfusion (group II, n=10), or 2 mg/min adenosine from 2 minutes before reperfusion until 1 hour after reperfusion (group III, n=11). Regional myocardial function (assessed as systolic wall thickening) was similar in the three groups at baseline and during ischemia. After reperfusion, dogs treated with adenosine before, during, and after ischemia (group II) demonstrated a significant improvement in the recovery of function that persisted throughout the 4 hours of reperfusion. In contrast, in dogs treated only during the reperfusion period (group III), the recovery of function was not statistically different from that in control dogs. The enhanced recovery effected by adenosine in group II could not be ascribed to differences in ischemic zone size, collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase B of the study, dogs received an intracoronary infusion of either saline (group IV [control], n=6) or adenosine (4 mg/min from 40 to 10 minutes before occlusion [group V, n=6]). Despite pretreatment with adenosine, the recovery of function in group V was indistinguishable from that in the control group. This study demonstrates that (1) continuous administration of adenosine before, during, and after ischemia results in a significant and sustained attenuation of myocardial stunning; (2) this improved recovery of function cannot be attributed to nonspecific variables, such as collateral flow during coronary occlusion, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective action of adenosine; (3) the protection against stunning is lost or markedly diminished if adenosine is given only at reperfusion; and (4) administration of adenosine before ischemia does not precondition the myocardium against the stunning induced by a 15-minute occlusion. The failure of adenosine to produce a beneficial effect when given only at reperfusion indicates that in the 15-minute occlusion model, the nucleoside acts primarily by decreasing the severity of ischemic injury rather than by mitigating reperfusion injury.
Key Words: postischemic myocardial dysfunction • coronary reperfusion • preconditioning • adenosine
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although numerous studies1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 have suggested a protective effect of adenosine in various settings of myocardial ischemia and reperfusion, most of these investigations have not specifically addressed the issue of reversible postischemic dysfunction or myocardial "stunning."16 Indeed, only few experiments12 14 15 have examined the effect of adenosine in a model of "pure" myocardial stunning in vivo. Two of these studies12 15 investigated the role of endogenous adenosine by using an adenosine deaminase inhibitor with or without a nucleoside transport blocker and reported a beneficial effect. The other study14 found a salutary effect of an A1-receptor agonist in a model of multiple 5-minute ischemia/10-minute reperfusion cycles. To our knowledge, there are no reports in the literature addressing the issue of whether exogenous adenosine protects against myocardial stunning after a single brief (<20-minute) coronary occlusion in intact animals.
The beneficial effects previously observed with augmentation of endogenous adenosine12 15 do not necessarily imply that exogenous adenosine will also be protective. This is because (1) the concentration of adenosine achieved in the interstitium and myocytes with adenosine deaminase inhibitors and nucleoside transport blockers may be much higher than that which can possibly be achieved with exogenous adenosine17 (in fact, Berne18 recently demonstrated directly that only a small amount of exogenous adenosine reaches the interstitial compartment); (2) it is not known whether the beneficial effects of inhibiting adenosine catabolism and transport are due to decreased formation of free radicals via the xanthine oxidase reaction or to increased concentration of adenosine3 8 ; and (3) in contrast to adenosine deaminase inhibitors and nucleoside transport blockers, exogenous adenosine would be expected to increase oxyradical production via xanthine oxidase,17 an effect that might offset other beneficial actions. Thus, there are important differences between endogenous versus exogenous provision of adenosine, such that the effects of one mode of therapy may not apply to the other.
Furthermore, although it is well established that adenosine A1-receptor activation preconditions the heart against infarction and that the magnitude of this protection is dramatic,11 13 19 it is controversial whether A1-receptor activation can also precondition against stunning. Studies using multiple 5-minute coronary occlusions interspersed with 10 minutes of reperfusion have yielded conflicting results, with one study20 suggesting that adenosine receptor blockade prevents the preconditioning effect of the first occlusion and another14 suggesting that it does not. Studies using brief ischemic episodes followed by a longer ischemic episode have also yielded conflicting results. A recent report21 concluded that a 1-minute coronary occlusion attenuated the stunning induced by a subsequent 10-minute occlusion and that this effect was abolished by adenosine receptor blockade. In contrast, other studies22 23 found that brief (2- to 5-minute) ischemia did not precondition against the stunning induced by a 15-minute coronary occlusion. However, since the preconditioning protocols known to be most effective against infarction (ie, a 5-minute occlusion) induced stunning in themselves,22 23 the possibility remains that a preconditioning effect of these protocols did not become manifest because there was a cumulative effect between the dysfunction induced by the preconditioning 5-minute ischemia and the dysfunction induced by the 15-minute occlusion. A 2.5-minute and a 2-minute occlusion also failed to precondition against stunning22 23 ; although these short occlusions did not induce overt depression of contractility,22 23 it is nevertheless possible that they may have "sensitized" the myocardium to the dysfunction caused by the subsequent 15-minute occlusion.24 In an effort to overcome these problems, in the present investigation we substituted adenosine for ischemia as a preconditioning protocol, so that any protective effect of A1-receptor stimulation could be evaluated without impairing baseline contractile function.
The present study was undertaken to address three fundamental questions. First, what effect, if any, does exogenous adenosine have on myocardial stunning in intact animals? Second, if a beneficial effect does exist, is it due to attenuation of cellular perturbations that occur during ischemia (ischemic injury) or cellular perturbations that occur after reperfusion ("reperfusion injury")? This is an important issue in view of the numerous reports2 4 6 10 indicating a reduction in infarct size when adenosine was administered at the time of reperfusion. Finally, does adenosine precondition against myocardial stunning?
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Materials and Methods |
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A total of 93 dogs were used. Since the experimental preparation and techniques have been previously described in detail,15 25 26 27 28 29 30 31 32 they will not be detailed here.
Experimental Preparation and General Protocol
Pentobarbital-anesthetized dogs of either sex (13 to 34 kg) were
instrumented with a snare and a Doppler flow probe around the mid left
anterior descending coronary artery (LAD), a 27-gauge intracoronary
needle just distal to the snare occluder, Doppler wall thickening
probes, catheters in the aorta and left atrium, and a high-fidelity
Millar pressure transducer in the left ventricular (LV) cavity. To
prevent clotting, heparin was given immediately after insertion of the
needle (3000 U IV) and thereafter (500 U/h). All dogs underwent a
15-minute LAD occlusion followed by 4 hours of reperfusion. Regional
myocardial blood flow was determined by injecting radioactive
microspheres, as previously described,25 before coronary
occlusion (baseline), 8 to 10 minutes after occlusion, 25 minutes after
reperfusion (during adenosine infusion), and 4 hours after reperfusion.
Systolic thickening fraction was assessed by using the pulsed Doppler
epicardial probe.15 25 26 27 28 29 30 31 32 The total deficit of wall
thickening after reperfusion was calculated by measuring the area
between the wall thickening–time line and the baseline (100% line)
during the first 4 hours of reflow.30 31 The size of the
occluded coronary vascular bed was determined by a postmortem
dual-perfusion technique.15
Adenosine Treatment
In phase A, dogs were assigned to one of three intracoronary
treatments. Group I (control group) received vehicle (heparinized
normal saline) at a rate of 2 mL/min beginning 30 minutes before
occlusion and ending 60 minutes after reperfusion, whereas groups II
and III received adenosine. Adenosine (Sigma Chemical Co) was dissolved
in heparinized saline at a final concentration of 1 mg/mL; the pH of
the solution (which was 
2.8) was adjusted to 7.4 by using 0.1 mol/L
NaOH. In group II, the infusion of adenosine was started 30 minutes
before coronary occlusion and ended 60 minutes after reperfusion. In
group III, the infusion of adenosine was started 2 minutes before
reperfusion and ended 60 minutes after reperfusion. In both groups,
adenosine was infused at a rate of 2 mL/min, corresponding to a dose of
2 mg/min. In pilot studies, this was found to be the highest dose that
could be given intracoronarily without producing hemodynamic effects
(ie, arterial hypotension). During the first 13 minutes of LAD
occlusion, the rate of infusion was reduced to 10% of preocclusion
values (0.2 mL/min) in all three groups to avoid washout of catabolites
and in group II to prevent the local concentration of adenosine in the
ischemic tissue from achieving very high levels.
In phase B, dogs were assigned to one of two intracoronary treatments: (1) group IV (control group) received vehicle for a duration of 30 minutes at a rate of 2 mL/min beginning 40 minutes before coronary occlusion and ending 10 minutes before occlusion, and (2) group V received a 4-mg/min infusion of adenosine for a duration of 30 minutes starting 40 minutes before coronary occlusion and ending 10 minutes before occlusion. Adenosine was dissolved as in phase A, except that the final concentration was 2 mg/mL.
Statistical Analysis
Data are reported as mean±SEM. Continuous variables were
analyzed by a two-way repeated-measures ANOVA to determine whether
there was a main effect of group, a main effect of time, or a time by
group interaction. If the global tests showed a significant main effect
or interaction, post hoc contrasts between groups at various time
points or between time points within one group were performed with
Student's t tests for unpaired or paired data, as
appropriate, and the resulting P values were adjusted
according to the Bonferroni correction.33 All analyses
were performed using the SAS software system.34 Two-way
ANOVA was performed by using the SAS procedure
GLM.34 The correlation between thickening
fraction at 1 and 4 hours of reperfusion and transmural collateral
blood flow was examined by using linear regression analysis, and
comparisons between groups were made by ANCOVA, in which collateral
flow was the covariate.
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Results |
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Phase A: Effect of Adenosine on Myocardial Stunning
Of the 72 dogs initially anesthetized in phase A, 37 (51%) were excluded for the reasons outlined in Table 1
. The final
analysis included 14 dogs in group I (control), 10 dogs in group
II, and 11 dogs in group III. Postmortem triphenyltetrazolium chloride
(TTC) staining confirmed the absence of infarction in all animals.
Among the dogs that underwent coronary occlusion, the incidence of
ventricular fibrillation tended to be higher in group II (6 [38%] of
16) than in group I (3 [18%] of 17) and group III (2 [15%] of
13), but the differences were not statistically significant
(P=.37 versus group I and P=.36 versus group III
[
2 test with continuity correction]). It is important
to point out that among the dogs that survived, there was no evidence
that the severity of ischemia was less in group II than in groups I and
III, since collateral flow and occluded bed size were similar in all
three groups and the rate-pressure product during occlusion was
actually higher in group II (see below).
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Arterial Blood Gases, Hematocrit, and Temperature
As illustrated in Tables 2 and 3,
the arterial pH, PO2, hematocrit, and the
esophageal temperature were within physiological limits in all three
groups throughout the experimental protocol (the hematocrit tended to
decrease at 2 hours of reperfusion in group II but was not
significantly different from baseline values).
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Hemodynamic Variables
Table 4 shows hemodynamic variables for phase A.
The intracoronary administration of adenosine at a dose of 2 mg/min did
not produce any substantial hemodynamic alteration other than a
fourfold to fivefold increase in LAD blood flow. In groups II and III,
LAD flow remained elevated until 1 hour after reperfusion (ie, until
the end of adenosine infusion); however, by 2 hours of reperfusion, LAD
flow had returned to baseline levels in both groups. Peak flow after
reperfusion was similar in groups I, II, and III (76.7±6.7,
77.2±11.3, and 89.7±11.9 mL/min, respectively), and minimal vascular
resistance was also similar (data not shown), indicating that adenosine
did not increase the hyperemic response after reflow. Throughout the
protocol, all measured variables (heart rate, systolic arterial
pressure, rate-pressure product, left atrial pressure, LAD blood flow,
and peak positive and negative LV dP/dt) were similar in the control
and treated groups, with few exceptions. Compared with the control
group (group I), group II exhibited a greater heart rate at baseline
and a greater rate-pressure product at baseline and during coronary
occlusion, two differences that, if anything, would be expected to
exacerbate the severity of myocardial stunning. Peak positive LV dP/dt
at 4 hours of reperfusion was greater in groups II and III than in the
control group. However, none of these differences could account for the
enhanced recovery of wall thickening observed in group II at 2 and 3
hours of reperfusion.
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Occluded Bed Size
The size of the occluded vascular bed in the three groups was
comparable, averaging 17.4±1.0 g (20.9± 1.1% of LV weight) in
control dogs, 22.7±2.2 g (23.8 ±1.0%) in group II, and 18.1±1.8 g
(20.9±1.7%) in group III.
Regional Myocardial Blood Flow
Table 5 shows regional myocardial blood flow for
phase A. At baseline, blood flow to both the ischemic and the
nonischemic zone was significantly (P<.05) greater in
groups II and III than in the control group, possibly because of the
higher oxygen demands associated with the higher heart rate-pressure
product (Table 4
). This difference persisted at 4 hours of reperfusion
(P<.05); however, when blood flow to the postischemic
region at 4 hours of reperfusion was expressed as a percentage of
nonischemic zone flow, no difference was observed among the three
groups, indicating that the higher flows noted in the stunned
myocardium in groups II and III were a consequence of the baseline flow
differences rather than the manifestation of a protective effect of
adenosine on the postischemic vasculature. During coronary occlusion,
the average blood flow to the ischemic region was similar in control
and treated groups, both in absolute terms (milliliters per minute per
gram) and as a percentage of nonischemic zone flow. As expected, at 25
minutes after reperfusion (during adenosine infusion), mean transmural
blood flow to the previously ischemic region was markedly elevated in
both groups II and III (3.7 and 5.6 times baseline flow, respectively).
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Regional Myocardial Function
The systolic thickening fraction in the nonischemic (control)
region did not differ significantly among the three groups at any time
point during the protocol (Table 4). Baseline systolic thickening
fraction in the region to be rendered ischemic was 23.7±2.0%,
25.5±2.0%, and 28.3±2.1% in groups I, II, and III, respectively
(P=NS). In group II, the thickening fraction decreased
significantly during infusion of adenosine (to 84.1±3.6% of baseline,
P<.01), indicating a negative inotropic effect of the
nucleoside. During coronary occlusion, the extent of paradoxical
systolic thinning in the ischemic region was similar in all three
groups (Fig 1). After reperfusion, control dogs (group
I) exhibited little recovery of contractile function, and 4 hours after
restoration of flow, the previously ischemic region was still
dyskinetic, indicating severe myocardial stunning. Two-way ANOVA
demonstrated that after reperfusion there was a significant
time-by-group interaction, indicating that the changes in thickening
fraction over time were different in the three groups. As Fig 1
illustrates, in group II the recovery of function was enhanced
throughout the 4-hour observation period; post hoc Student's
t tests with the Bonferroni correction confirmed that the
thickening fraction was significantly greater than in the control group
at 30 minutes after reflow and at all subsequent time points. In
contrast, in group III post hoc tests demonstrated that the
postischemic recovery of function did not differ significantly from
that in the control group (Fig 1). In comparison with the control
group, the total deficit of wall thickening during the entire 4-hour
period of reperfusion (an integrative assessment of postischemic
dysfunction30 31 was reduced by 38% in group II
(P<.01) and by only 14% in group III (P=NS).
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As shown in Fig 2, in control dogs wall thickening at 1
and 4 hours after reperfusion was directly related to collateral flow
during coronary occlusion (r=.59 and r=.53,
respectively). ANCOVA demonstrated that in group II this relation was
altered, so that for the same level of collateral flow, thickening
fraction after reperfusion was greater than in the control group by an
average of 43% at 1 hour (P<.01) and 69% at 4 hours
(P<.01) after reperfusion. ANCOVA demonstrated that the
wall thickening–collateral flow relation was also significantly
(P<.05) different between group II and group III. These
results indicate that the enhanced recovery of wall thickening effected
by adenosine infusion in group II was independent of any differences in
blood flow during ischemia.
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To determine whether adenosine-induced hyperemia increases
systolic wall thickening in the stunned myocardium (and thus may
account for the increased wall thickening observed in group II at 30
minutes and 1 hour), at 4 hours of reperfusion adenosine was infused
intracoronarily for 10 minutes at a rate of 2 mg/min, which did not
produce any systemic hemodynamic effects, in nine dogs from groups I or
III (Fig 3). Despite an average 4.4-fold increase in LAD
flow, the thickening fraction did not change significantly
(-29.8±11.7% of baseline before adenosine versus -14.7±12.0%
during adenosine, P=.14 [Fig 3]).
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Power Analysis
A statistical analysis was performed to measure the
probability that an improvement of wall thickening by adenosine given
at reperfusion (group III) was missed because of insufficient sample
size (type II error). Since in group II adenosine infused before,
during, and after ischemia increased wall thickening at 4 hours of
reperfusion by an average of 72% of baseline values compared with the
control group (group I) and decreased the total postischemic deficit of
wall thickening during the entire 4-hour period of reperfusion by an
average of 38% compared with the control group, we measured the power
of our experiment to demonstrate similar effects in group III. All
power calculations were made at 
=.05. The calculations revealed that
there was a 94% probability of demonstrating a 
72% (of baseline
values) improvement of wall thickening in group III dogs versus control
dogs at 4 hours of reperfusion, if this was the true effect of
adenosine in group III. The chance of demonstrating a 38% reduction
in the total deficit of wall thickening in group III dogs compared with
control dogs was 84%.
On the other hand, the demonstration of smaller beneficial effects of adenosine given at reperfusion would have been difficult. For example, if the true increase in wall thickening effected by adenosine given at reperfusion was the same as that observed in our study in group III (ie, an increase of 15% of baseline values over the control group) and assuming that the variance of the samples was the same as that observed in our study, >120 dogs would have had to be studied in both groups I and III (total of >240 dogs) for this difference to be significant at P<.05. If the true decrease in the total postischemic deficit of wall thickening effected by adenosine given at reperfusion was the same as that observed in our study in group III (ie, a 14% decrease versus the control group) and assuming that the variance of the samples was the same as that observed in our experiment, 72 dogs would have had to be studied in both groups III and I (total of 144 dogs) for this difference to be statistically significant. In conclusion, if adenosine given at reperfusion exerted beneficial effects comparable to those produced by adenosine given before, during, and after ischemia, it is unlikely that such effects would have remained undetected in the present experiment; detection of smaller effects would have required prohibitively large sample sizes.
Phase B: Effect of Adenosine on Preconditioning Against Myocardial
Stunning
Of the 21 dogs initially anesthetized in phase B, 9 (43%) were
excluded for the reasons outlined in Table 1. Thus, the final
analysis included 6 control dogs (group IV) and 6 dogs pretreated
with adenosine (group V). As in phase A, postmortem TTC staining
confirmed the absence of infarction in all animals.
Arterial Blood Gases, Hematocrit, and Temperature
As shown in Tables 2 and 3, the arterial pH,
PO2, hematocrit, and the esophageal temperature
were within physiological limits in both groups.
Hemodynamic Variables
Table 6 shows hemodynamic variables for phase B. In
group V, the intracoronary administration of adenosine at a dose of 4
mg/min resulted in a 3.7-fold increase in LAD blood flow (as measured
by Doppler flow probe) and in a 15-mm Hg drop in diastolic arterial
pressure (95±8 mm Hg at baseline versus 80±10 mm Hg during
adenosine, P<.05). Both the LAD flow and the diastolic
pressure returned to baseline values during the 10-minute interval
between adenosine administration and coronary occlusion. Throughout the
protocol, all measured variables (heart rate, systolic arterial
pressure, rate-pressure product, left atrial pressure, LAD blood flow,
and peak positive and negative LV dP/dt) were similar in the control
and treated groups, with the exception of left atrial pressure, which
was greater in group V than in the control group at baseline, before
occlusion, and at several time points after reperfusion.
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Occluded Bed Size
The size of the occluded vascular bed did not differ in the
two groups (16.6±1.1 g [22.9±1.9% of LV weight] in the control
group and 19.8±2.6 g [20.2±1.9%] in group V).
Regional Myocardial Blood Flow
Table 7 shows regional myocardial blood flow
for phase B. There were no significant differences between the two
groups with respect to regional myocardial blood flow at baseline,
during LAD occlusion, and 4 hours after reperfusion. In group V, the
mean transmural blood flow to the soon-to-be-ischemic zone increased
4.2-fold during infusion of adenosine. At the same time, flow to the
nonischemic zone increased 2.4-fold (P<.05), as a result of
recirculation of adenosine. In both groups, flow to the postischemic
subendocardium at 4 hours of reperfusion was significantly decreased
compared with baseline values (P<.01 in group IV and
P<.05 in group V).
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Regional Myocardial Function
Systolic thickening fraction in the nonischemic (control) region
did not differ significantly between the two groups (Table 6). Baseline
systolic thickening fraction in the region to be rendered ischemic was
23.6±2.8% in the control group and 24.5±2.1% in group V
(P=NS). In group V, thickening fraction decreased
transiently during the infusion of adenosine (81.4±4.8% of baseline
values, P<.01) (Fig 4), in analogy with the
results obtained in group II. After discontinuation of adenosine
(immediately before coronary occlusion), however, thickening fraction
returned to values not significantly different from baseline
(91.2±4.5% of baseline). During coronary occlusion, the degree of
paradoxical systolic wall thinning was comparable in groups IV and V
(Fig 4). After reperfusion, there was no appreciable difference in the
recovery of contractile function between the two groups, both of which
exhibited severe stunning (Fig 4). Two-way ANOVA failed to show a
significant main effect for group or a group by time interaction. Fig 5 illustrates the relation between postischemic wall
thickening and collateral flow for these two groups. Note that there is
overlap between groups IV and V at all levels of collateral flow.
ANCOVA failed to reveal any difference between the two groups.
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Power Analysis
As in phase A, we measured the probability that a beneficial
effect of adenosine pretreatment was missed in group V (type II error).
Because infusion of adenosine in group II increased wall thickening at
4 hours of reperfusion by an average of 72% of baseline values
compared with the control group, we measured the power of our
experiment to demonstrate a similar effect in group V. Power
calculations revealed that there was an 81% probability of
demonstrating a 72% (of baseline values) improvement of wall
thickening in group V compared with the control group at 4 hours of
reperfusion, if this was the true effect of adenosine pretreatment.
Thus, if pretreatment with adenosine produces an appreciable beneficial
effect on myocardial stunning, it is unlikely that such an effect would
have remained undetected in the present study. On the other hand,
if the true increase in wall thickening effected by adenosine
pretreatment was the same as that observed in group V (ie, only an
increase of 13% of baseline values compared with the control group)
and assuming that the variance of the samples was the same as that
observed in our study, it would have been necessary to study >120 dogs
in both groups IV and V (total of >240 dogs) for this difference to
become significant at P<.05. Thus, the demonstration of
minor beneficial effects of adenosine pretreatment would have required
prohibitively large sample sizes.
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Discussion |
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To our knowledge, this is the first study to demonstrate that (1) exogenous adenosine mitigates the severity of postischemic myocardial dysfunction after a single brief ischemic insult in the intact animal; (2) this improved recovery of function cannot be ascribed to nonspecific variables, such as collateral blood flow during coronary occlusion, ischemic zone size, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective effect of adenosine; (3) the primary mechanism of the beneficial action of adenosine in myocardial stunning is a decrease in the severity of ischemic injury rather than reperfusion injury; and (4) administration of intracoronary adenosine does not precondition the myocardium against the stunning associated with a 15-minute coronary occlusion. Each of these points requires further discussion and will be addressed below.
Effect of Adenosine on Myocardial Stunning
When adenosine was given continuously before, during, and after
ischemia (group II), a significant and sustained attenuation of
stunning was observed, which persisted throughout 4 hours of
reperfusion despite the fact that adenosine infusion was discontinued
after 1 hour of reperfusion. Since LAD blood flow returned to baseline
values within minutes after stopping the infusion of adenosine, the
improved recovery of function observed at 2, 3, and 4 hours of
reperfusion cannot be attributed to increased myocardial perfusion (ie,
to a Gregg phenomenon35 ). Although at 30 minutes and 1
hour of reperfusion LAD flow was approximately fourfold higher in group
II compared with group I (Table 4), several considerations make it
unlikely that this hyperemia accounted for the difference in wall
thickening observed at these time points. First, in group II we found
that when LAD flow returned to baseline values (10 minutes after
adenosine was discontinued), the thickening fraction did not decrease
significantly compared with the 1-hour values measured during hyperemia
(
= -7.4±12.9%, P=NS). Second, if the enhanced wall
thickening observed at 30 minutes and 1 hour in group II was due to the
hyperemia, one would have expected a similar beneficial effect in group
III, which exhibited a similar hyperemia at 30 minutes and 1 hour
(Table 4). Finally, infusion of adenosine at 4 hours failed to increase
thickening fraction in the stunned myocardium despite a 4.4-fold
increase in LAD flow (Fig 3).
There were no other differences that could have accounted for
the enhanced recovery in group II. This group was similar to groups I
and III with respect to collateral flow, ischemic zone size, and most
of the hemodynamic variables. For reasons that are unclear, group II
had a higher heart rate and rate-pressure product at baseline and a
higher rate-pressure product during occlusion (Table 4), but these
differences, if anything, should have exacerbated the severity of
ischemia and thus should have led to an underestimation of the
beneficial effects of adenosine. It should be noted that at 3 and 4
hours of reperfusion, the heart rate and rate-pressure product were
similar in groups II and III (Table 4), yet the recovery of function
was significantly enhanced only in group II. Thus, we conclude that
continuous infusion of adenosine before, during, and after ischemia
reduces the severity of myocardial stunning by a mechanism that is
independent of nonspecific factors, such as coronary flow or systemic
hemodynamics.
Does Adenosine Attenuate Ischemic Injury or Reperfusion Injury?
In contrast to group II, group III exhibited no statistically
significant improvement in the recovery of function when compared with
the control group. The dose of adenosine used in group III (2 mg/min)
was the same as that used in group II, and the fact that the infusion
was started intracoronarily 2 minutes before the release of occlusion
ensured that high local levels of adenosine were present in the LAD
region at the very onset of reperfusion. Power analysis showed that
there was a >90% probability that if adenosine given at reperfusion
(group III) improved recovery of function to the same extent as
adenosine given before, during, and after ischemia (group II), such an
effect would have been detected in our study. With our sample sizes, we
cannot rule out the possibility that adenosine given at reperfusion
could exert a small protective effect (eg, an improvement of wall
thickening of 15% of baseline values), but the physiological
significance of such an effect would be questionable.
Thus, our results indicate that in the 15-minute occlusion model, administration of adenosine only during the reperfusion phase is either ineffective or much less effective than continuous administration of adenosine before ischemia, during ischemia, and during reperfusion. This implies that adenosine does not act primarily to decrease the component of "reperfusion injury" that contributes to the development of myocardial stunning.36 (Such a component may still be decreased indirectly, however, as a result of the ability of adenosine to attenuate ischemic injury, since the severity of reperfusion injury in stunned myocardium appears to be modulated by the severity of the antecedent ischemic injury.26 27 28 29 31 36 On the other hand, the results of phase B clearly demonstrate that administration of adenosine only before ischemia fails to enhance the postischemic recovery of function, implying that the beneficial effects observed in group II were not due to the 30-minute infusion of adenosine given before coronary occlusion in this group. Taken together, the results of phases A and B indicate that in the 15-minute coronary occlusion model, the attenuation of myocardial stunning by adenosine is due to a beneficial effect that takes place mainly during the period of ischemia, not before ischemia or after reperfusion; ie, the primary mechanism of action of adenosine appears to be a reduction in the severity of the cellular perturbations that occur during ischemia (ischemic injury).
Does Adenosine Precondition Against Stunning?
In phase B, we sought to determine whether adenosine can
precondition against stunning. The impetus to test this idea was
provided by the demonstration that activation of adenosine
A1-receptors preconditions the myocardium against
infarction11 13 19 and by recent reports20 21
suggesting that brief ischemia preconditions against stunning via an
adenosine receptor–mediated mechanism. Our results clearly demonstrate
that pretreatment with adenosine failed to protect the myocardium
against subsequent stunning, despite the fact that adenosine was given
for a relatively long time (30 minutes) and at a dose (4 mg/min)
twofold greater than the dose (2 mg/min) found to be protective in
group II. Thus, although adenosine preconditions against
infarction,11 13 19 it does not precondition against the
stunning induced by a 15-minute coronary occlusion. This finding
further corroborates the concept that the pathogenesis and
pathophysiology of myocardial stunning (a reversible form of injury)
differ importantly from those of irreversible cellular injury (ie,
myocardial infarction).36
We elected to use a higher infusion rate in group V than in group II (4 versus 2 mg/min, respectively) to maximize the chances of detecting a preconditioning effect, if one truly existed. Since exogenous adenosine is rapidly taken up by red blood cells and endothelial cells, we reasoned that a higher infusion rate would be more likely to produce sufficient myocardial A1-receptor activation to induce a preconditioning effect. The failure of the 4-mg/min infusion to precondition against stunning is unlikely to be due to toxicity because (1) the hemodynamic effects were very mild (only a transient decrease in diastolic arterial pressure with no change in systolic pressure or heart rate); (2) these effects resolved promptly after the infusion of adenosine was stopped, ie, before coronary occlusion; and (3) similar doses of adenosine (3.75 mg/min IC) have been shown to be protective in models of infarction.2 4
Previous Studies of Whether Adenosine Treatment Attenuates
Myocardial Stunning
In a previous study,37 a bolus of adenosine given at
the time of reperfusion was found to accelerate the rate of early
contractile recovery (without affecting the final recovery) in stored
or heterotopically transplanted rat hearts studied in vitro; this
beneficial effect was associated with a sustained improvement in
coronary flow. The difference between these findings and our
present results may reflect differences in experimental
preparations, species, and/or severity of ischemic injury.
Although many studies have suggested a beneficial effect of adenosine on postischemic myocardial dysfunction in a variety of experimental models,1 2 3 4 5 8 9 10 12 14 15 extrapolation of these results to the setting of regional myocardial stunning after reversible ischemia would be problematic. Many of these studies3 5 8 9 12 15 examined the effects of inhibitors of adenosine catabolism and transport, not the effect of exogenous adenosine. Some studies1 5 9 were conducted in isolated hearts, so that the results cannot necessarily be extrapolated to intact animals. Other studies2 4 10 involved models of prolonged (90- to 120-minute) ischemia resulting in subendocardial infarction, which differ from models of "pure" stunning caused by a brief (<20-minute), completely reversible ischemic insult.36 Since the amelioration of postischemic dysfunction noted in these studies2 4 10 was associated with a decrease in infarct size, one cannot comment on the specific effects on myocardial stunning. Finally, two studies3 8 used a model of prolonged global ischemia with cardioplegic arrest and cardiopulmonary bypass, which again differs importantly from brief, regional ischemia.36
To our knowledge, only three full-length reports12 14 15 have addressed the role of adenosine on myocardial stunning after reversible ischemia in vivo. Using an open-chest canine model of 15 minutes of coronary occlusion followed by 1 hour of reperfusion, Dorheim et al12 observed a modest attenuation of postischemic dysfunction in dogs treated with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of adenosine deaminase. Zughaib et al15 demonstrated that augmentation of endogenous adenosine with EHNA plus 6-(4-nitrobenzyl)mercaptopurine ribonucleoside (NBMPR), a nucleoside transport inhibitor, resulted in attenuation of myocardial stunning in dogs subjected to a 15-minute coronary occlusion followed by 4 hours of reperfusion. Unlike the present study, the purpose of these previous studies12 15 was to examine the effects of increasing the levels of endogenous adenosine by inhibiting its metabolism and transport. However, inhibitors of adenosine catabolism and transport may act not only by augmenting adenosine levels but also by preventing the generation of oxygen radicals from xanthine and hypoxanthine; therefore, it is not possible to discern whether the protective effects of EHNA and NBMPR in these studies12 15 were due to the former or to the latter mechanism. In open-chest dogs subjected to six 5-minute occlusion/10-minute reperfusion cycles followed by 2 hours of reperfusion, Yao and Gross14 found a significant beneficial effect when a selective adenosine A1-receptor agonist was infused continuously before and during the six cycles and a significant exacerbation of stunning when the animals were pretreated with an A1-receptor antagonist. Unlike the present investigation, their study14 examined a model of stunning induced by repetitive ischemia, which differs in several respects from models of stunning induced by a single coronary occlusion.36 Our results expand the findings of Dorheim et al,12 Zughaib et al,15 and Yao and Gross14 by demonstrating that (1) exogenous adenosine ameliorates myocardial stunning after a single ischemic insult, (2) this beneficial effect is sustained for 4 hours after reperfusion, (3) it requires the administration of adenosine during ischemia, and (4) adenosine does not precondition against the stunning induced by a 15-minute coronary occlusion. Since exogenous adenosine should, if anything, increase oxyradical production through the xanthine oxidase reaction, our results imply that the salutary effects observed with EHNA alone12 and EHNA+NBMPR15 were indeed mediated, at least in part, by augmentation of adenosine.
Previous Studies of Whether A1-Receptor Activation
Preconditions Against Stunning
In a preliminary report in isolated working rat hearts, Cave et
al38 found that a 5-minute period of perfusion with
adenosine (10, 50, and 100 µmol/L) followed by a 5-minute
adenosine-free perfusion period failed to increase the recovery
of function after a subsequent 20-minute period of global ischemia.
Although it is unclear whether the dysfunction observed in this model
represents solely stunning, the results of Cave et al are in
agreement with our conclusion that adenosine pretreatment does not
mitigate myocardial stunning.
The preconditioning effects of adenosine A1-receptors against stunning in vivo are controversial. In a rabbit model of stunning induced by a 10-minute coronary occlusion, Urabe et al21 found that a prior 1-minute occlusion resulted in enhanced recovery of wall thickening and that the adenosine receptor antagonist 8-phenyltheophylline blocked this beneficial effect. However, other studies in dogs22 and pigs23 have failed to demonstrate a preconditioning effect of brief (2- to 5- minute) coronary occlusions against the stunning induced by a subsequent 15-minute occlusion. In a rabbit model of stunning induced by four cycles of 5-minute coronary occlusion/10-minute reperfusion, Bunch et al20 found that the adenosine receptor antagonist PD 115199 caused a progressive deterioration of function after each cycle, suggesting that the adenosine produced during the first ischemic episode preconditioned against the subsequent episodes. In contrast, using a canine model of stunning induced by six 5-minute occlusion/10-minute reperfusion cycles, Yao and Gross14 found that the adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine decreased the recovery of function after the first cycle but caused no additional deterioration after the next five cycles, suggesting that the adenosine released during the first ischemic episode was protective during that episode but did not precondition against the stunning induced by subsequent episodes.
The reason(s) for the apparent discrepancy among these previous studies14 20 21 22 23 is unclear but may relate to differences in experimental models and/or species. It should be noted that no previous study has examined the ability of adenosine (or adenosine agonists) to precondition against the stunning induced by a 15-minute coronary occlusion in the dog.
Mechanism of Adenosine-Mediated Protection
Adenosine exerts a number of actions that could beneficially
affect myocardial stunning (reviewed in References 17, 39, and 4017 39 40 ).
Theoretically, adenosine may reduce free radical formation by
inhibiting lipolysis (and thus decreasing lipid peroxidation) and/or by
decreasing auto-oxidation of catecholamines as a result of the
inhibition of norepinephrine release.17 39 Adenosine may
also protect against the effects of oxygen metabolites.41
However, our results clearly demonstrate that the primary mechanism of
action of adenosine in this model of stunning is a decrease in the
severity of ischemic injury, not reperfusion injury. Mitigation of
ischemic injury by adenosine may take place via various mechanisms. For
example, adenosine may attenuate calcium overload during ischemia by
inhibiting calcium influx through the L-type calcium
channel.17 40 42 Adenosine may also improve energy balance
during ischemia by stimulating glycolysis,43 by inhibiting
the release of norepinephrine from nerve endings,44 and/or
by antagonizing the effect of catecholamines on
contractility.39 45 46 In this regard, in the present
study adenosine exerted a negative inotropic effect, as evidenced by a
15% to 20% decrease in wall thickening before coronary occlusion in
both groups II and V (Figs 1 and 4), which is consistent with previous
observations.47 48 49 50 51 Therefore, it is possible that the
protection afforded by adenosine in group II was due in part to its
antiadrenergic effects reflected by the decrease in ventricular
contractility. Interestingly, adenosine failed to enhance recovery in
group V, in which ischemia was initiated 10 minutes after
discontinuation of the adenosine infusion, when the negative inotropic
effect had largely dissipated (Fig 4).
Our finding that adenosine acts primarily by mitigating ischemic injury is not in conflict with the notion that a free radical–mediated reperfusion injury plays a prominent role in the pathogenesis of myocardial stunning. First, it has been pointed out32 36 52 that free radicals are not the sole factor contributing to the pathogenesis of myocardial stunning. Second, and most important, since the magnitude of free radical generation after reperfusion in the stunned myocardium is directly related to the severity of the antecedent ischemic insult,26 27 28 29 31 36 any intervention that alleviates the injury incurred during ischemia would be expected to indirectly attenuate the radical-mediated injury inflicted after reperfusion.
Conclusions
In summary, the present study demonstrates that
infusion of adenosine before, during, and after a 15-minute coronary
occlusion results in a significant and sustained improvement in the
recovery of myocardial function, which reflects a direct
cardioprotective action of adenosine. This beneficial effect cannot be
reproduced when adenosine is infused solely at reperfusion, indicating
that in the 15-minute occlusion model, the purine acts primarily by
decreasing the severity of ischemic injury. Intracoronary adenosine
fails to precondition against myocardial stunning, a finding that
emphasizes the differences between the pathophysiology of stunning and
that of infarction. Although adenosine itself would not be a practical
clinical therapy, adenosine receptor agonists or adenosine modulators
may be useful in the management of myocardial stunning in patients.
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Acknowledgments |
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This study was supported in part by National Institutes of Health (NIH) grant HL-43151 and SCOR grant HL-42267 (Dr Bolli) and by the Veterans Affairs Research Advisory Group Program (Dr Jeroudi). We thank Jennifer S. Pocius and Alejandro Tumang for excellent technical assistance and Valerie R. Price for expert secretarial assistance. Ultrasonic probes were provided by Dr Craig J. Hartley with the support of NIH grant HL-22512.
Received April 12, 1994; accepted October 3, 1994.
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References |
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