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Anesthesiology Research Laboratories, Departments of 1 Anesthesiology and 2 Physiology, and 3 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226; and 4 Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Reactive oxygen species (ROS) are
believed to be involved in triggering cardiac ischemic
preconditioning (IPC). Decreased formation of ROS on reperfusion after
prolonged ischemia may in part underlie protection by IPC. In
heart models, these contentions have been based either on the effect of
ROS scavengers to abrogate IPC-induced preservation or on a measurement
of oxidation products on reperfusion. Using spectrophotofluorometry at
the left ventricular wall and the fluorescent probe dihydroethidium
(DHE), we measured intracellular ROS superoxide
(O
cardiac injury; fluorescent dyes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BRIEF EXPOSURE OF THE HEART to ischemia leads to a state of increased resistance to the effects of subsequent ischemia and reperfusion (I/R). This is termed ischemic preconditioning (IPC) (23) and has been demonstrated in all animal species studied (25); there are also reports of its occurrence in humans (20, 24). There is indirect evidence for involvement of reactive oxygen species (ROS) in the triggering mechanism of IPC because protection was abrogated when ROS scavengers were administered with preconditioning pulses of ischemia (1, 4, 11, 13, 28, 39); moreover, it was demonstrated that pharmacological generation of endogenous ROS (4) or administration of exogenous ROS (43, 52) can similarly lead to preconditioning. Thus ROS generated during brief I/R, in quantities below those that damage the heart, appear to activate mediators that trigger preconditioning and promote cardioprotection. Other studies show the effect of IPC to decrease release of ROS during index I/R in coronary effluent during reperfusion (12) or indirectly to decrease lipid peroxidation, also at the time of reperfusion (41).
It is well known that prolonged ("index") I/R leads to generation of ROS that play a central role in subsequent tissue damage and infarction (9). Therefore, it is possible that ROS generated briefly during the preconditioning phase mediate protection in part by reducing ROS generation during index I/R. Although it was previously held that ROS formation occurred primarily or solely at return of O2 supply at reperfusion (42), there is now convincing evidence that significant ROS generation occurs not only on reperfusion but also during ischemia, as shown in isolated cardiomyocytes (6) and in intact dogs with aspirates of stationary coronary perfusate (27). We recently showed that ischemic and pharmacological preconditioning attenuated changes in NADH (33) and reduced mitochondrial Ca2+ overload (34) during ischemia in isolated hearts. These studies suggest that preconditioning leads to improved mitochondrial energetics during the period of index ischemia that may determine global cardiac outcome after reperfusion.
A role for ROS in triggering IPC is implied by the effect of ROS scavengers given during the preconditioning phase to reverse protection afforded by IPC (1, 4, 11, 13, 28, 39). The principal cause of ROS formation during ischemic myocardial injury is believed to be mitochondrial electron transport chain (ETC) dysfunction (6). We hypothesized first that ROS generated during the ischemic pulses, and not during the reperfusion phases, is the initial trigger and that a threshold of ROS is necessary to elicit IPC. Second, we hypothesized that IPC is mediated in part by improved mitochondrial bioenergetics as demonstrated by less ROS generation, not only on reperfusion but also during index ischemia. To test these hypotheses, we developed a technique for measuring cellular ROS generation continuously in the left ventricle of intact hearts by spectrophotofluorometry using dihydroethidium (DHE), which is converted to fluorescent ethidium (Eth) by ROS.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Langendorff heart preparation.
The investigation conformed to the Guide for the Care and Use of
Laboratory Animals (National Institutes of Health No. 85-23, Revised 1996). Approval was obtained from the Medical College of
Wisconsin animal studies committee. Our Langendorff preparation was
described in detail previously (2, 3, 26, 33, 34, 36, 48).
Guinea pig hearts (n = 50) were perfused at constant pressure (55 mmHg) at 37°C with an oxygenated Krebs-Ringer (KR) solution of the following composition (in mM): 138 Na+, 4.5 K+, 1.2 Mg2+, 2.5 Ca2+, 134 Cl
, 14.5 HCO
PvO2/PaO2), where
PaO2 is arterial PO2 and
PvO2 is venous PO2. Myocardial O2 consumption
(M
O2) was calculated as CF/heart
weight (g) · (PaO2 PvO2) · 24 ml
O2/µl at 760 mmHg. Cardiac efficiency was calculated as
developed LVP × HR/MO2.
Global ischemia was achieved by clamping the aortic inflow
line. If ventricular fibrillation occurred on reperfusion a bolus of
lidocaine (250 µg) was given immediately. At the end of 120-min reperfusion, hearts were removed, cut into six transverse sections, and
stained with 1% 2,3,5-triphenyltetrazolium chloride in 0.1 M
KH2PO4 buffer (pH 7.4, 38°C) for 10 min.
Infarct size was expressed as a percentage of total ventricular weight
(2, 26).
Eth fluorescence to assess ROS in intact hearts.
Oxidation of the fluorescent dye DHE (Molecular Probes, Eugene, OR) to
Eth was used to measure ROS formation. DHE enters cells and, when
oxidized by ROS, with a relative selectivity for
O
1 · min1.
Brief pharmacological arrest induced with adenosine or lidocaine had no
effect on FI. Endogenous generation of OProtocol.
There were four experimental groups (n = 8 animals/group) and one time-control group (n = 6) (Fig.
1). Each experiment lasted 190 min after
a 30-min equilibration period, a 25-min DHE loading period, and a
15-min washout period. The untreated (time control) group was not
subject to ischemia; the ischemia-control group underwent only 30-min index ischemia and 120-min reperfusion. Cardiac preconditioning consisted of two 5-min pulses of global ischemia with an intervening 5-min perfusion period and a
20-min perfusion period before the index ischemia. In the
IPC+manganese(III) tetrakis (4-benzoic acid) porphyrin chloride
(MnTBAP) group, the ROS scavenger MnTBAP (20 µM; OxisResearch,
Portland, OR) was given from 5 min before the first IPC pulse, during
the intervening perfusion period, and for 5 min after the conclusion of
the second IPC pulse before the index ischemia. In the MnTBAP
group, MnTBAP was given continuously for 25 min without IPC before the
index ischemia. Eth FI was sampled for 100 ms every 12 s
during the entire experimental protocol for a total fluorescence
recording time of 95 s. At restitution of flow after
ischemia, increases in the extracellular-to-intracellular
volume ratio were hypothesized to alter FI, introducing a potential
source of artifact. Eth FI in this preparation reflects an aggregate of
intracellular O
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Statistical analysis. All data are expressed as means ± SE. Among-group data were compared with two-way analysis of variance at the following time points: baseline (0 min), during and after the preconditioning stimuli, during ischemia at 5-min intervals, during reperfusion at 5-min intervals to 15 min of reperfusion, and at 60 and 120 min of reperfusion. Post hoc Student-Newman-Keuls tests were utilized where differences were found (Prisma version 3.0a; GraphPad Software, San Diego, CA). The groups compared were IPC+ MnTBAP, MnTBAP, and IPC vs. ischemia-control and all ischemia groups vs. time control. Differences among means were considered statistically significant when P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Changes in mechanical function and infarct size after IPC.
Baseline values (0 min) and values immediately before index
ischemia (40 min) were similar for each group. Figures
2 and 3 and
Table 1 show that IPC was manifested
by improved developed and diastolic LVP, CF, and
MO2 on reperfusion, and reduced
infarct size. These effects of IPC were blocked completely by
MnTBAP. MnTBAP alone before ischemia did not produce values
different from those in the ischemia control group for any of
these variables.
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Changes in ROS generation during and after IPC.
Figure 4 shows ROS generation, primarily
O
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This is the first study in the intact, beating heart to directly assess intracellular ROS formation continuously during IPC pulses and to examine the effects of IPC on ROS formation throughout index I/R. It was demonstrated previously that IPC (12, 41) and pharmacological preconditioning (26) cause a reduction in ROS release during reperfusion after index ischemia. We show additionally in isolated hearts that reduced ROS formation also occurs during ischemia and that the preconditioning effect is likely triggered by the burst of ROS formed during the brief ischemic pulses rather than during the reperfusion phases. Moreover, we show the effects of an ROS scavenger to attenuate, but not block, the rise in ROS during preconditioning ischemic pulses, suggesting that a threshold level of ROS is necessary for preconditioning.
ROS scavenging abrogated IPC-protective effects on cardiac function and infarction and restored ROS formation during index I/R to the ischemia control (unpreconditioned) values. Our study indicates that IPC delays the onset of irreversible myocardial dysfunction as evidenced by the delayed and reduced rise in ROS formation during the last 10 min of ischemia. In concert with our other studies using the same preparation (33, 34), this study suggests a primary role of IPC in preserving mitochondrial bioenergetics during ischemia.
Evidence for role of ROS in IPC. Existing studies in isolated hearts or intact animals have either deduced a role for ROS in IPC from the observed effects of ROS scavengers to abrogate improvement in cardiac functional and structural variables induced by IPC (1, 4, 11, 13, 28, 39) or have used techniques that allow for measurement of ROS only during reperfusion (12, 41). In the latter measurement, however, it was not possible to know whether collected samples represented ROS generated during reperfusion only or included a flushout of the ROS probe accumulated during the ischemic period. The latter possibility was supported by the work of Zweier and Kuppusamy (53). They used electron paramagnetic resonance spectroscopy in isolated rat hearts to provide evidence that the time constant of enzymatic clearance of administered ROS (a nitroxide) during ischemia was unaltered during ischemia but that a slower clearance of the nitroxide occurred because of loss of the washout effect present in the perfused heart. This suggested that ROS accumulation in the ischemic heart was due both to increased production and to reduced clearance of ROS. Thus measurement of ROS in coronary effluent at reperfusion may include ROS accumulated in the cells and interstitium during ischemia and ROS formed at reperfusion and therefore may overestimate ROS formed on reperfusion.
Our method of continuous ROS measurement in the intact heart permits the study of ROS formation synchronous with global cardiac function and metabolism throughout I/R. We found an increase in ROS production in hearts during brief ischemia (the preconditioning pulses) and during the 30-min index ischemia. These findings are supported by reports that oxidant injury occurs in cardiac tissue during ischemia without reperfusion (10) and by work in isolated cardiomyocytes that indicates significant ROS production during simulated ischemia (6, 46). The latter group reported an approximately twofold increase in Eth oxidation at the end of 30-min ischemia (6). O'Neill et al. (27) used an intact feline model in which samples of coronary venous blood were taken at intervals during ischemia. They reported a severalfold increase in ·OH formation estimated by hydroxylation of phenylalanine. Using a similar measurement technique, Sun et al. (38) reported a large increase in ·OH within 1 min of ischemia in open-chest dogs. Importantly, with regard to possible mechanistic insights into the triggering of IPC, we found that brief ischemia caused an increase in ROS formation whereas reperfusion after brief ischemia did not cause an increase in ROS. This agrees with findings in isolated cardiomyocytes subjected to IPC (44). Our observations, moreover, suggest that ROS released during the ischemic pulses, and not on reperfusion, leads to activation of cardioprotective pathways during the intervening perfusion period. Nonetheless, it is possible that OUse of ROS scavengers in IPC.
MnTBAP is a cell-permeant superoxide dismutase mimetic that is reported
to dismutate O
Mechanisms of ROS in IPC. An essential role for ROS in the triggering mechanism of preconditioning, especially IPC, appears to be accepted. Exogenous administration of H2O2 can induce a preconditioned state in cardiomyocytes (44) and intact hearts (43), and a similar effect can be achieved by endogenous ROS formation by the xanthine/xanthine oxidase reaction (4, 52) or by using the ETC inhibitor menadione (49). Furthermore, scavenging of ROS has been shown to abrogate IPC in most (4, 11, 13, 28, 39), but not all (32) studies. Although there is evidence to link ROS with other factors involved in IPC, the mechanism by which ROS induce preconditioning is unknown. ROS have been shown to activate transcription factors (13), ATP-sensitive potassium (KATP) channels (40, 50), protein kinase C (50), and mitogen-activated protein kinases (8), each of which has been implicated in preconditioning (5, 13, 18). Nonetheless, neither the signaling sequence nor the mechanism by which proposed mediators lead to a state of protection has been elucidated.
Our reperfusion results are consistent with those of Park et al. (30), who reported that IPC attenuated ROS production by isolated mitochondria, and those of Crestanello et al. (12) and our laboratory (26), in which IPC and pharmacological preconditioning, respectively, attenuated ROS release in isolated hearts at reperfusion. Most important is our observation that IPC decreased ROS production during the index ischemia as well as during reperfusion. This supports and extends the results of Vanden Hoek et al. (45), who showed reduced DCF fluorescence intensity in isolated cardiomyocytes after hypoxic preconditioning and subsequent simulated ischemia and reoxygenation. In light of our finding of reduced ROS formation during the latter period of 30-min ischemia after IPC, it is noteworthy that we found, using a similar model, more normalized NADH levels during the latter period of 30-min ischemia after IPC (33) and reduced mitochondrial Ca2+ loading during 30-min ischemia after pharmacological preconditioning (34). Together, these results indicate that mitochondrial bioenergetics are better preserved during ischemia after preconditioning and suggest that this is responsible for improved global cardiac function and reduced infarction at reperfusion. In addition, our studies suggest that decreased production of mitochondrial ROS, rather than increased antioxidant systems, is primarily responsible for decreased ROS formation after IPC. The mechanism by which IPC leads to improved mitochondrial function during I/R requires further study. The mitochondrial (m)KATP channel is a regulator of mitochondrial bioenergetics and may have a role in preconditioning (18). Activation of the mKATP channel may partially uncouple the mitochondrion; this has been proposed to optimize ETC function (37) and may be a mechanism to reduce ROS formation. It has been suggested that the mKATP channel regulates mitochondrial ROS production to effect preconditioning (17, 29, 45). In one study, the mKATP channel opener nicorandil enhanced postischemic supply of high-energy phosphates and decreased oxidant injury (35); both factors are consistent with improved ETC function and with evidence that the mitochondrion is the most likely source of ROS during ischemia (44, 47). Interestingly, although the mKATP channel may regulate ROS production by the ETC, there is also evidence that ROS directly activate the mKATP channel (50, 51), suggesting a model for IPC that includes a positive-feedback mechanism involving ROS.Possible limitations. Certain limitations to our method of ROS measurement must be considered. This model lacks blood-borne sources of ROS, particularly neutrophils, that could contribute to either IPC or I/R injury in the heart (15). Furthermore, the area of the probe on the surface of the left ventricular free wall is small and we cannot distinguish ROS produced by cardiomyocytes from those produced by other cells underlying the probe, including vascular cells and occasional macrophages. Cardiomyocytes exist in vast excess over other cell types, however. During late reperfusion, infarction of cells will lead to loss of nuclei (in which Eth is contained), and therefore the fluorescent signal might decrease. Nonetheless, infarction occurred less in the IPC group so that the real difference between this and the other groups could be greater than reported here.
It is important to note that Benov et al. (7) demonstrated that although DHE is oxidized by O| |
ACKNOWLEDGEMENTS |
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The authors thank the following for valuable contributions to this study: James Heisner, Dr. Ming Tao Jiang, Samhita S. Rhodes, Peter Katz, Jeff Fitzgerald, and Anita Tredeau.
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FOOTNOTES |
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The study was supported in part by National Institutes of Health Grants HL-58691 and GM-8204-06, by American Heart Association Grant 0020503Z, and by the Department of Veterans Affairs.
Portions of this work have appeared in abstract form (Kevin LG, Riess ML, Chen Q, and Stowe DF. Anesthesiology 96: A80, 2002).
Address for reprint requests and other correspondence: D. F. Stowe, M4280, 8701 Watertown Plank Rd., Medical College of Wisconsin, Milwaukee Regional Medical Center, Milwaukee, WI 53226 (E-mail: dfstowe{at}mcw.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.
First published October 31, 2002;10.1152/ajpheart.00711.2002
Received 13 August 2002; accepted in final form 15 October 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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