© 1997 American Heart Association, Inc.
Articles |
Oxygen Radicals Can Induce Preconditioning in Rabbit Hearts
From the Divisions of Cardiology (D.D'A., N.E., A.S., C. De S., A.V., A.E., M.C.), "Federico II" School of Medicine, Naples, Italy, and the University of Perugia School of Medicine (I.T., G.A.), Perugia, Italy.
Correspondence to Giuseppe Ambrosio, MD, PhD, Sezione di Cardiologia "R," Dipartimento di Medicina Clinica, Universita' di Perugia, Via Eugubina 42, 06122 Perugia, Italy.
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Abstract |
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Abstract Indirect evidence suggests that oxygen radicals may contribute to ischemic preconditioning. We directly investigated whether exposure to oxygen radicals per se, in the absence of ischemia, could reproduce the beneficial effects of ischemic preconditioning on infarct size and on postischemic contractile dysfunction. In one branch of the study, isolated rabbit hearts underwent 30 minutes of total global ischemia and 45 minutes of reperfusion (n=6, control group). A second group, before ischemia/reperfusion, was exposed for 5 minutes to a low flux of oxygen radicals generated by purine/xanthine oxidase (P/XO), followed by a 15-minute washout (n=6). Oxygen radical pretreatment significantly improved postischemic recovery of contractile function. We then investigated in another branch of the study whether this preconditioning effect would also reduce infarct size and whether it was mediated by protein kinase C activation. Control hearts were subjected to coronary artery occlusion for 30 minutes, followed by 2.5 hours of reperfusion (n=6). A second group, before coronary occlusion, was exposed to oxygen radicals and washout as described (n=8). A third group was subjected to oxygen radical infusion, but an inhibitor of protein kinase C (polymyxin B, 50 µmol/L) was administered throughout subsequent ischemia (n=7). A fourth group was exposed to oxygen radicals in the presence of scavengers (superoxide dismutase, 250 U/mL; catalase 500, U/mL; n=8). Pretreatment with oxygen radicals markedly reduced infarct size, from 65±19% of risk region in controls to 12±4% (P<.05). Protein kinase C inhibition significantly attenuated this effect (infarct size, 37±9% of risk region; P<.05 versus P/XO; P=NS versus controls). Oxygen radical–induced preconditioning was prevented by scavengers (infarct size, 55±14% of risk region; P<.05 versus P/XO; P=NS versus P/XO+polymyxin B). Our data show that in the absence of ischemia, exposure to low concentrations of oxygen radicals can reproduce the beneficial effects of ischemic preconditioning on infarct size and postischemic recovery of left ventricular function. Thus, oxygen radicals might be potential contributors to ischemic preconditioning.
Key Words: free radical • myocardial infarction • preconditioning • protein kinase C
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The preconditioning phenomenon was described for the first time in 1986 by Murry et al,1 who showed in dogs that the extent of necrosis following coronary artery occlusion was paradoxically reduced if a sustained ischemic period was preceded by a brief ischemic episode. A large number of studies have tried to elucidate the mechanism of preconditioning, and several different mediators have been involved in this phenomenon.2 Recently, it has been hypothesized that the common link between diverse stimuli might be represented by activation of protein kinase C induced by the brief preconditioning episode of ischemia, since many of the stimuli shown to be involved in preconditioning share the ability of activating this enzyme2 and since preconditioning can be prevented by the inhibition of protein kinase C.3 4 5
Previous studies have shown that oxidants can activate protein kinase C.6 7 8 9 In the heart, postischemic reperfusion is accompanied by the generation of oxygen radicals.10 11 Although it is known that large amounts of oxygen radicals can be toxic to cells, recent evidence also indicates that relatively low concentrations of oxidants can modulate various cell functions.12 13 14 15 16 17 Thus, it might be hypothesized that exposure to oxidants formed upon reflow after the initial brief episode(s) of ischemia might be one mechanism of preconditioning. Indeed, indirect evidence implicates oxygen radicals as potential mediators of preconditioning.18 In a canine model, Murry et al19 showed that inactivation of oxygen radicals by administration of specific scavengers during the reperfusion period following the initial brief period of ischemia could attenuate its preconditioning effects toward the subsequent longer period of ischemia. Similarly, loss of preconditioning after oxygen radical scavenger administration has been shown by Tanaka et al20 in rabbits with coronary artery occlusion/reperfusion. In addition, administration of scavengers can prevent the beneficial effects of preconditioning toward either postischemic contractile dysfunction21 or incidence of reperfusion arrhythmias.22 However, other studies that have also used oxygen radical scavengers are in contrast to those observations.23 24 Thus, there is still controversy about the role of oxygen radicals in mediating ischemic preconditioning.
To elucidate this issue, in the present yes followed a direct approach, similar to that used by Downey and colleagues25 26 to demonstrate the importance of adenosine in preconditioning. Instead of brief ischemia, these authors used a short adenosine infusion as the preconditioning stimulus; adenosine administration reproduced the beneficial effects of ischemic preconditioning episode on infarct size, thus directly confirming that this substance could mediate preconditioning. In a similar fashion, in the present study we evaluated whether a short exposure to a burst of oxygen radicals per se (ie, without preconditioning ischemia) could reproduce the beneficial effects of preconditioning on a subsequent prolonged ischemic period. This approach has the potential advantage of ruling out other mechanisms triggered by preconditioning ischemia and avoiding the limitations of scavengers, such as adequacy of type, dosage, and timing of administration. More important, it avoids any direct effect of scavengers on ischemia/reperfusion injury, which in this case would cloud the picture. In the first set of experiments of the study, we submitted rabbit hearts to total global ischemia and reflow to evaluate whether oxygen radical pretreatment could exert a protective effect on postischemic contractile dysfunction. In the second set of experiments, hearts were subjected to regional ischemia/reflow to determine whether oxygen radical pretreatment could also exert a beneficial effect on infarct size and whether this effect was mediated by protein kinase C activation.
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Materials and Methods |
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Functional Recovery Study
Isolated Heart Preparation
All procedures followed were in accordance with institutional guidelines. Female New Zealand White rabbits (1.2 to 1.7 kg) were anesthetized with intravenous pentobarbital (50 mg). After performing a tracheotomy, rabbits were intubated and ventilated with room air with a positive-pressure ventilator (Harvard Apparatus). They were heparinized, and the heart was quickly removed and perfused under a constant pressure of 80 mm Hg with Krebs-Ringer bicarbonate buffer, as previously described.27 Hearts were paced at 180 bpm through a stimulator electrode connected to a Harvard Research stimulator (Harvard Apparatus). Coronary flow was continuously monitored by a Transonics T101 electromagnetic flowmeter (Transonics Systems Inc). A latex balloon was inserted into the left ventricle to measure left ventricular hemodynamic parameters. The balloon was connected to a Statham P23Db transducer, and left ventricular pressures and coronary flow were recorded with a Gould 2400S recorder (Gould Electronics). During stabilization, the balloon was inflated with saline to an end-diastolic pressure of 10 mm Hg, which corresponds to the plateau of the Starling curve for this preparation. All subsequent measurements of left ventricular pressures were made at this same end-diastolic volume.
Experimental Protocol
After stabilization, control hearts were subjected to 30 minutes
of standard perfusion. The intraventricular balloon
was then deflated, the stimulator was turned off, and hearts were
subjected to 30 minutes of total global ischemia at 37°C,
followed by 45 minutes of reperfusion (n=6) (Fig 1
, top). Pacing was restarted at the onset of reflow, and the
intraventricular balloon was reinflated after 15
minutes of reperfusion with the same amount of saline present at
baseline.
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A second group of hearts (P/XO group, n=6; Fig 1
, top), after
stabilization and baseline measurements, was exposed for 5 minutes to a
flux of oxygen radicals generated by the purine/xanthine oxidase system
(Fig 1, top). Purine was added to the perfusion buffer at a final
concentration of 2.3 mmol/L, while xanthine oxidase was
administered by a syringe pump (model 22, Harvard
Apparatus) through a sidearm in the perfusion line at a
rate 1/100 that of coronary flow to achieve an aortic
concentration of 20 mU/mL. Under our experimental conditions, this
system generates 
4 to 5 nmol of superoxide radical per
minute.28 In previous experiments, we found that this
concentration of radicals is 5 to 10 times lower than that required to
injure cells14 and that it does not affect myocardial
energy metabolism.29 Purine and its
metabolites are devoid of stimulatory effects on adenosine
receptors.30 Purine/xanthine oxidase infusion was stopped
after 5 minutes, and hearts were allowed to recover for 15 minutes of
washout and then subjected to total global ischemia and
reperfusion with the same protocol used for control hearts.
Infarct Size Study
Heart Preparation
Female New Zealand White rabbits (1.2 to 1.7 kg) were
anesthetized, ventilated, and heparinized as described in the
functional recovery study. The chest was opened, the heart was exposed,
and a snare was loosely placed around the circumflex branch of the left
coronary artery. The heart was then quickly removed, and
retrograde perfusion was started as described in the first arm of the
study. Hearts were paced at 180 bpm throughout the experiment,
including ischemia. Left ventricular balloon was
not used in this set of experiments.
Experimental Protocol
After stabilization, control hearts were perfused for 30
minutes and then subjected to 30 minutes of regional ischemia,
induced by tightening the coronary snare; at the end of
ischemia, the snare was released, and hearts were reperfused
for 2.5 hours (n=6) (Fig 1, bottom). A second group of hearts (P/XO
group, n=8; Fig 1, bottom), after stabilization and baseline
measurements, was exposed for 5 minutes to oxygen radicals with the
same protocol used in the functional recovery study; hearts were
allowed to recover for 15 minutes and then subjected to regional
ischemia and reperfusion with the same protocol used for the
control hearts. A third group of hearts (P/XO+PolyB group, n=7; Fig 1, bottom) was subjected to the same protocol used for the second group,
but an inhibitor of protein kinase C (polymyxin B, 50
µmol/L) was administered, starting 5 minutes before coronary
occlusion and continuing throughout ischemia. We chose this
drug and this administration protocol because it has been shown to
prevent ischemic preconditioning in the same rabbit model,
without having any other effect on infarct size.4 In
addition, in pilot experiments we checked that this dose of polymyxin B
prevented the hemodynamic effects of protein kinase C
activation by 10 µmol/L 1,2-dioctanoyl-sn-glycerol on
isolated rabbit hearts. A fourth group of hearts (P/XO+SOD/CAT group,
n=8; Fig 1, bottom) was subjected to the same protocol used for the
second group, but the oxygen radical scavengers (superoxide dismutase,
250 U/mL; catalase, 500 U/mL) were administered throughout oxygen
radical exposure and for an additional minute into washout.
Measurement of Risk Region and Infarct Size
To delineate risk region, at the end of reperfusion,
hearts were arrested by aortic infusion of cold KCl solution (50
mmol/L); the snare placed around the coronary artery was then
reoccluded; and fluorescent polystyrene microspheres
(10-µm diameter, Fluoresbrite, Polysciences Inc) were injected into
the aorta until complete embolization of the heart. Hearts were then
removed from the perfusion apparatus, and the left
ventricle was isolated, frozen, and cut in sections parallel to the
atrioventricular groove. Tissue slices were then
exposed to UV light to delineate risk region. Infarct size was then
calculated by planimetry on tissue slices incubated for 30 minutes in a
1% solution of 2,3,5-triphenyltetrazolium
chloride in phosphate buffer at 37°C.
Chemicals
Xanthine oxidase (salicylate free, from bovine milk;
specific activity, 1 U/mg of protein), from Boehringer-Mannheim
GmbH, was dialyzed for 24 hours at 4°C against perfusion buffer to
remove ammonium sulfate and EDTA contained as preservatives. Purine
(7H-imidazo[4,5-d]pyrimidine), superoxide
dismutase, and catalase were purchased from Sigma Chemical Co.
2,3,5-Triphenyltetrazolium chloride was
purchased from Merck. All other chemicals were purchased from
Carlo Erba.
Statistical Analysis
Data are expressed as mean±SEM. Differences in the recovery of
hemodynamic parameters were tested using a
repeated-measures ANOVA. Comparisons between individual time points
were performed by Student's t test for unpaired values.
Overall statistical significance for differences in infarct size and
risk region across the various groups was tested by ANOVA. Comparisons
between groups were then made by Bonferroni-corrected t
test.
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Results |
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Functional Recovery Study
Heart weights were similar between the two groups, averaging 5.0±0.5 g in the control group and 5.0±0.3 g in the P/XO group.
In our experimental conditions, exposure of hearts to oxygen
radicals had only minimal hemodynamic effects, which
completely reverted during washout (Fig 2). Thus, at the
onset of ischemia, hemodynamic
parameters were similar in the two groups. In control
hearts, ischemia/reperfusion resulted in marked impairment of
function; coronary flow was also impaired (Fig 3). In contrast, recovery of left
ventricular developed pressure was significantly greater in
oxygen radical–treated hearts than in control hearts (Fig 3).
Preservation of systolic performance was also
accompanied by improved diastolic function
(end-diastolic pressure was lower in the treated group
compared with the control group) throughout recovery (Fig 3).
Coronary flow tended to be higher in treated hearts compared
with control hearts, although this trend did not reach statistical
significance (Fig 3). Heart rate never increased above 180 bpm, and it
did not decline because of pacing.
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indicates control hearts; 
,
oxygen radical–treated hearts; and P/XO, 2.3 mmol/L purine+20
mU/mL xanthine oxidase.
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Infarct Size Study
There were no statistically significant differences in heart
weights among groups (control, 5.1±0.2 g; P/XO, 4.0±0.3 g;
P/XO+PolyB, 4.4±0.2 g; and P/XO+SOD/CAT, 4.7±0.4 g).
In control hearts, purine/xanthine oxidase infusion induced a small
decrease in coronary flow that completely reverted during
recovery, similar to what was observed in the functional recovery study
(Table); this change was prevented by administration of
the scavengers superoxide dismutase and catalase (Table). Polymyxin B
infusion did not influence coronary flow.
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Heart rate did not decline because of pacing, and none of the treatments increased heart rate above 180 bpm.
The extent of risk region after coronary artery occlusion
was similar in all groups (54±5% of left ventricle in the control
group, 54±5% in the P/XO group, 52±2% in the P/XO+PolyB group, and
48±5% in the P/XO+SOD/CAT group; P=NS). In control hearts,
regional ischemia/reperfusion resulted in a large infarct size,
involving 34±10% of left ventricle; thus, necrosis involved 65±19%
of the risk region (Fig 4). Pretreatment of hearts with
oxygen radicals resulted in substantial protection against myocardial
necrosis induced by ischemia/reperfusion, as infarct size was
markedly reduced in these hearts compared with control hearts (12±4%
of risk region; P<.05) (Fig 4). This effect was
significantly attenuated by protein kinase C inhibition, since in the
P/XO+SOD/CAT group infarct size averaged 37±9% of the risk region
(P<.05 versus the P/XO group; P=NS versus the
control group) (Fig 4). The beneficial effect of oxygen radicals was
also completely prevented by oxygen radical removal, since in the
P/XO+SOD/CAT group infarct size averaged 55±14% of the risk region
(P<.05 versus the P/XO group; P=NS versus the
P/XO+PolyB group) (Fig 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, exposure to a low dose of oxygen radicals, in the absence of ischemia, was capable of mimicking the beneficial effects of ischemic preconditioning. Pretreatment with purine/xanthine oxidase reduced the extent of myocardial necrosis in rabbit hearts subjected to coronary artery occlusion and reperfusion. Furthermore, oxygen radical pretreatment exerted a protective effect also in an experimental model of postischemic contractile dysfunction. The beneficial effect of purine/xanthine oxidase infusion was completely prevented by scavenger administration, thus confirming that the preconditioning effect was secondary to oxygen radical generation and not to other consequences of drug infusion.
Previous studies had shown that the administration of oxygen radical scavengers, such as mercaptopropionyl-glycine or superoxide dismutase, was able to blunt the protective effect of ischemic preconditioning on infarct size and postischemic recovery of contractile function.19 20 21 Similarly, the beneficial effects of preconditioning on reperfusion-induced arrhythmias was prevented by superoxide dismutase administration during the preconditioning ischemia.22 In contrast, other studies do not support the potential role of oxygen radicals in preconditioning.23 24 However, all previous studies are based on results obtained through removal of oxygen radicals by the administration of scavengers during preconditioning ischemia; therefore, they may provide only indirect evidence about the possible role of oxygen radicals in preconditioning. We chose to directly test the ability of oxygen radicals, in the absence of ischemia, to reproduce the beneficial effects of ischemic preconditioning. This approach allowed us to eliminate confounding factors related to the use of scavengers, such as adequacy and efficacy of drug or persistence of its effects also during the reperfusion period. This latter phenomenon might protect the heart from toxic effects of oxygen radicals generated at reflow; therefore, it would make prevention of preconditioning less evident. Thus, our data directly demonstrate that oxygen radicals are capable of preconditioning the ischemic myocardium. Independent support for this conclusion comes from preliminary observations by Baines et al,31 who have very recently described reduction in infarct size by pretreatment with an oxygen radical–generating system in a rabbit model. Preliminary data from Pathak et al32 have also suggested that infusion of hydrogen peroxide can precondition rabbit hearts in vivo. Finally, it has recently been shown that oxygen radicals may also play an important role in the induction of "late" preconditioning against myocardial stunning in pigs.33
The beneficial effects of oxygen radicals, while seemingly paradoxical, could be explained by several mechanisms. It has recently become appreciated that in addition to their well-established toxic role when formed in large amounts, oxygen radicals at relatively low concentrations can influence several cellular activities in the absence of cell damage, but these effects are secondary to changes in the activity of various enzymes.12 13 14 15 16 17 Thus, it could be hypothesized that reperfusion after the "preconditioning" short ischemic episode results in the generation of relatively low amounts of oxygen radicals, insufficient to determine cell necrosis, but which nevertheless could modify cellular activities and thus induce preconditioning.18
Activation of protein kinase C is currently held as a central mediator of ischemic preconditioning.2 Oxygen radicals might represent a possible inducer of preconditioning via protein kinase C activation. In fact, studies in various cell types demonstrate that mild oxidative conditions activate protein kinase C.6 7 8 9 This effect is linked to an increase of the Ca2+/phospholipid-independent form of protein kinase C6 and is accompanied by translocation of the inactive form of the enzyme from the cytoplasm to the cell membrane, where protein kinase C exerts its activity.7 Taken together, these data support the hypothesis that protein kinase C activation and/or translocation might be a possible mechanism of action of oxygen radicals in preconditioning.
In the present study, inhibition of protein kinase C by polymyxin B significantly reduced the beneficial effects of oxygen radicals, consistent with the hypothesis that the beneficial effects of oxygen radicals can be mediated by protein kinase C. However, the effect was not complete. It is unlikely that timing and dosage of polymyxin B were not adequate to completely block protein kinase C, since we determined that the dose of polymyxin B we used completely blocked the hemodynamic effects of protein kinase C activation in isolated rabbit hearts and since this same protocol of drug administration completely prevented ischemic preconditioning in the same animal model.4 An alternative explanation is that oxygen radicals might also activate other cardioprotective mechanisms. In this regard, recent studies have shown that oxidants can open the ATP-dependent K+ channels in patch-clamp myocytes34 35 and other cell types36 and in isolated hearts.29 Opening of the ATP-dependent K+ channels exerts a strong cardioprotective effect, and some studies have suggested that it might play a major role in the pathogenesis of preconditioning.37 38 This possibility is supported by the preliminary observation that the preconditioning effect of hydrogen peroxide can be prevented by glybenclamide, an inhibitor of ATP-dependent K+ channels.32 Another possibility is that oxygen radicals were acting by modifying cell redox potential. Numerous studies have documented that small changes in redox potential can exert signaling functions.15 16 17 Interestingly, Chen et al21 have shown that ischemic preconditioning is associated with changes in myocardial redox status and that administration of N-acetyl-cysteine, an oxygen radical scavenger, can prevent this effect. They speculated that a redox-sensitive mechanism can play a role in the protective effect of ischemic preconditioning in the heart. Thus, it is possible that in our study exposure to oxygen radicals might have exerted some effects secondary to direct changes in the redox status of myocytes, in addition to its effects on protein kinase C. In this regard, very recent observations have suggested that tyrosine kinase, which is activated by changes in the redox potential, might be involved in the pathogenesis of preconditioning.39 40
In interpreting the present results, the possibility should
be considered that oxygen radicals were merely acting by inducing
myocardial ischemia. However, this possibility seems unlikely.
For one thing, the reduction in coronary flow during
purine/xanthine oxidase infusion was modest (ie, <15%; Fig 2 and
Table). In addition, we have recently shown in this model that exposure
to a much higher dose of oxygen radicals is not accompanied by
metabolic indices of ischemia, such as decrease in
myocardial concentrations of ATP and phosphocreatine or in
pHi, as directly measured by nuclear magnetic resonance
spectroscopy.29
The extent of risk region that underwent necrosis in the present study was larger than what has been previously reported by other investigators using a similar experimental model.4 31 Although we have no immediate explanations for this finding, it should be noted that our protocol differs from that of previous studies with respect to pacing protocol, buffer composition, use of intraventricular balloon, and length of reperfusion. It is possible that one or more of these variables, as well as other unidentified factors, might have contributed to the observed difference.
In conclusion, the present data demonstrate that exposure to a low dose of oxygen radicals in the absence of ischemia can reproduce the beneficial effects of ischemic preconditioning, both on infarct size and on postischemic recovery of myocardial function. Oxygen radical formation might therefore be an important contributor to preconditioning induced by brief ischemia.
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Acknowledgments |
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This study was supported in part by grant 96.03489.CT04 from Consiglio Nazionale delle Ricerche, Italy.
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Footnotes |
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Presented in part at the 65th Scientific Sessions of the American Heart Association, New Orleans, La, November 16-19, 1992, and at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995.
Received October 22, 1996; accepted January 22, 1997.
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