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Anesth Analg 2005;101:1252-1260
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000181336.96511.32

CARDIOVASCULAR ANESTHESIA

Section Editor:
Kenneth J. Tuman

The Influence of Mitochondrial KATP-Channels in the Cardioprotection of Preconditioning and Postconditioning by Sevoflurane in the Rat In Vivo

Detlef Obal, MD, DEAA, Saskia Dettwiler, cand. MD, Christian Favoccia, MD, DEAA, Horst Scharbatke, MD, Benedikt Preckel, MD, DEAA, and Wolfgang Schlack, MD, PhD, DEAA

Klinik für Anaesthesiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

Address correspondence and reprint requests to Professor Wolfgang Schlack, DEAA, Klinik für Anaesthesiologie, Universitätsklinikum Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany. Address e-mail to schlack{at}med.uni-duesseldorf.de.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Volatile anesthetics induce myocardial preconditioning and can also protect the heart when given at the onset of reperfusion—a practice recently termed "postconditioning." We investigated the role of mitochondrial KATP (mKATP)-channels in sevoflurane-induced cardioprotection for both preconditioning and postconditioning alone and whether there is a synergistic effect of both. Rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Infarct size was determined by triphenyltetrazolium staining. The following protocols were used: 1) preconditioning (S-Pre, n = 10, achieved by 2 periods of 5 min sevoflurane administration (1 MAC) followed by 10 min of washout); 2) sevoflurane postconditioning (1 MAC of sevoflurane given for 2 min at the beginning of reperfusion; S-Post, n = 10); 3) administration before and after ischemia (S-Pre + S-Post, n = 10). Protocols 1–3 were repeated in the presence of 5-hydroxydecanoate (5HD), a specific mKATP-channel-blocker (S-Pre + S-Post + 5HD, S-Pre + 5HD: n = 10; S-Post + 5HD: n = 9). Nine rats served as untreated controls (CON) or received 5HD alone (5HD, n = 10). Both S-Pre (23% ± 13% of the area at risk, mean ± sd) and S-Post (18% ± 5%) reduced infarct size compared with CON (49% ± 11%, both P < 0.05). S-Pre + S-Post resulted in a larger reduction of infarct size (12% ± 5%, P = 0.054 versus S-Pre) compared with administration before or after ischemia alone. 5HD diminished the protection in all three sevoflurane treated groups (S-Pre + 5HD, 35% ± 12%; S-Post + 5HD, 44% ± 12%; S-Pre + S-Post + 5HD, 46% ± 14%;) but given alone had no effect on infarct size (41% ± 13%). Sevoflurane preconditioning and postconditioning protects against myocardial ischemia-reperfusion injury. The combination of preconditioning and postconditioning provides additive cardioprotection and is mediated, at least in part, by mKATP-channels.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Preconditioning describes a protective mechanism against myocardial ischemia that can be initiated by short episodes of coronary occlusion (ischemic preconditioning) or by administration of certain drugs (pharmacological preconditioning). One of these classes of drugs, volatile anesthetics, when given before ischemia, induces a cardioprotective effect similar to that of ischemic preconditioning. Whereas the end-effector of both ischemic and anesthetic preconditioning remains unknown, mitochondrial KATP (mKATP)-channels appear to play a central role in anesthetic preconditioning (1,2).

Most research in the last years has focused on interventions like preconditioning to ameliorate irreversible ischemic cell damage. However, the first minutes of reperfusion are critical, and reperfusion paradoxically worsens ischemic injury. Studies have demonstrated a protective effect of brief episodes of ischemia after prolonged coronary artery occlusion that resulted in reduced infarct size. In parallel to preconditioning this strategy was termed "postconditioning" (3).

Similar to the protection of volatile anesthetics given as preconditioning stimulus, these drugs can also protect the heart when given after ischemia during reperfusion (4–6). The protection resulting in a decrease of infarct size might be a mechanism of "anesthetic postconditioning." Although both mechanisms are effective to protect the heart against ischemia-reperfusion injury, the underlying mechanism of both strategies is still unknown. Because mKATP-channels are of such great importance in preconditioning, we hypothesized an involvement of these channels also during postconditioning. The present study also investigated if additive protection and a reduction in infarct size could be achieved by combining both preconditioning and postconditioning strategies. We further questioned whether both protection mechanisms might work additively and enhance the infarct size-limiting effect of each single intervention.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was performed in accordance with the regulations of the German Animal Protection Law and was approved by the Bioethics Committee of the District of Duesseldorf.

The surgical procedures were described in detail previously (5). In brief, {alpha}-chloralose-anesthetized male Wistar rats (mean body weight, 397 ± 46 g) were artificially ventilated after orotracheal intubation (rodent ventilator Rhema-Labortechnikâv®, Type 10 mL, Class 34931, Germany) with a Fio2 ~0.4 and a positive end-expiratory pressure of 3–5 cm H2O for maintaining arterial pH, Pco2, and Po2 within normal physiological limits. Body temperature was maintained at 38°C by the use of a heating pad. The rats were instrumented for measurement of mean aortic pressure (AOP, catheter in the left femoral artery), left ventricular (LV) pressure (LVP, tip manometer introduced through the right carotid artery, Millar Instruments®), and cardiac output (CO, ultrasonic flowprobe (6S) around the pulmonary artery; T 208; Transonic Systems Inc., Ithaca, NY). A ligature snare was looped around a major coronary artery supplying the anterior wall of the LV for later occlusion. Myocardial ischemia was verified by the appearance of epicardial cyanosis and changes in surface electrocardiogram. Successful reperfusion was evidenced later by disappearance of epicardial cyanosis, as described previously (6).

Hemodynamic variables were recorded after a 15-min stabilization period. All rats underwent 25 min of regional myocardial ischemia by tightening the snare around the prepared coronary artery, followed by 120 min of reperfusion. Successful reperfusion was evidenced by the disappearance of epicardial cyanosis. After 120 min of reperfusion, the hearts were quickly excised and infarct size was measured by triphenyltetrazoliumchloride (TTC) staining. Therefore, the hearts were perfused on a modified Langendorff apparatus with normal saline at 80 mm Hg perfusion pressure to washout the remaining blood. The coronary artery was then reoccluded and 5–10 mL of 0.2% Evans Blue dye in 1% Dextran was infused via the aortic root into the coronary system. This maneuver identifies the area at risk as the part of the myocardium that remains unstained. The heart was then frozen and cut into approximately 10 transverse slices of equal thickness (1 mm). The slices were incubated (37°C) for 15 min in buffered 1% TTC adjusted to pH 7.4 and then incubated for 2 days in 4% formaldehyde. Viable myocardium was then identified as red stained by TTC, whereas necrotic myocardium appears pale gray. The area at risk and the infarcted area were determined by planimetry using Sigma Scan Pro 5 computer software (SPSS Science Software, Chicago, IL) and corrected for dry weight (5).

All rats were randomly assigned to one of the following groups (Fig. 1):



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  		Figure 1. Experimental protocol. CON = control group; 5HD = 5-hydroxydecanoate; S-Pre = group preconditioned by two episodes of sevoflurane administration interspersed with 10 min of washout; arrows mark the time of continuous 5HD administration (5 µg · kg–1 · min–1); S-Post = group which received sevoflurane at the beginning of reperfusion (anesthetic postconditioning); all rats underwent 25 min of coronary artery occlusion followed by 2 h of reperfusion.

 

Control (CON, n = 9): After a stabilization period of 45 min, rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion (ischemia and reperfusion period similar in all other groups).

5-Hydroxydecanoate (5HD, n = 10): IV administration of 5HD (5 µg · kg–1 · min–1 in saline aqueous solution) starting 40 min before ischemia until the beginning of reperfusion.

Sevoflurane preconditioning (S-Pre, n = 10): Rats received sevoflurane 2.0 vol.% (corresponding to one minimal alveolar concentration (MAC) in rats (7) for 2 5-min periods interspersed by 10 min of washout 10 min before coronary artery occlusion.

Sevoflurane preconditioning + 5HD (S-Pre + 5HD, n = 10): Rats underwent the S-Pre protocol with additional administration of 5HD starting 10 min before the preconditioning protocol until the occlusion of the coronary artery.

Sevoflurane during reperfusion ("postconditioning") (S-Post, n = 10): Rats received one MAC sevoflurane for 2 min starting at the beginning of reperfusion.

Sevoflurane during reperfusion + 5HD (S-Post + 5HD, n = 9): Rats received 5HD starting 10 min before ischemia until the end of sevoflurane administration during reperfusion.

Sevoflurane during preconditioning and postconditioning (S-Pre + S-Post, n = 10): Both, the S-Pre and S-Post protocol were combined and rats received one MAC of sevoflurane before and after myocardial ischemia.

Sevoflurane preconditioning and postconditioning + 5HD (S-Pre + S-Post + 5HD, n = 10): Rats received sevoflurane before and after myocardial ischemia and 5HD 10 min before preconditioning until the end of sevoflurane administration during reperfusion.

Expiratory sevoflurane concentration was measured at the end of the endotracheal tube (Datex Capnomac Ultima, Division of Instrumentarium Corp., Helsinki, Finland) at a sampling rate of 200 mL/min. By using a high inspiratory flow of 12 L/min, rapid changes of sevoflurane concentrations could be achieved as evidenced by a very rapid decrease in expiratory sevoflurane concentration during the experimental course (0.0 vol. % within 15 s) and by rapid changes in hemodynamics during the first seconds of sevoflurane administration (5,6).

LVP, its first derivative dP/dt, AOP and CO were recorded continuously on a polygraph (Hellige 120 710 94; Freiburg, Germany) and were digitized using an analog-to-digital converter (Data Translation, Marlboro, MA) at a sampling rate of 500 Hz and processed later on a personal computer.

Global myocardial function was measured in terms of LV peak systolic pressure (LVPSP). Global LV end-systole was defined as the point of minimum dP/dt (dP/dtmin) and LV end-diastole as the beginning of the sharp upslope of the LV dP/dt tracing. Systemic vascular resistance (SVR) was estimated from AOP and CO, assuming a right atrial pressure of 0 mm Hg in the open-chest preparation.

Results are expressed as mean ± sd. Statistical analysis was performed by a two-way analysis of variance for time and treatment (preconditioning versus protection against reperfusion) effects. Time effects (changes from baseline value) during the experiments were analyzed using Dunnett’s post hoc test. If an overall significance among groups was found, Student’s t-test with Bonferroni correction for multiple comparisons was performed for each time point. The same analysis was used for detection of differences in infarct size. Changes within and between groups were considered statistically significant with P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
A total of 80 rats were used. Two rats died from untreatable arrhythmia during ischemia and reperfusion. In the remaining 78 animals, complete data sets were obtained.

Differences in hemodynamics were not observed among the groups at the beginning of the experiments; data are summarized in Tables 1 and 2 and Fig. 2. Preconditioning with sevoflurane resulted in a reduction of global (LV) function (LVPSP, 94 ± 18 mm Hg and rate pressure product [RPP], 35 ± 9 mm Hg · min–1 · 1000–1 summarized for all groups which received sevoflurane, values after second exposure to sevoflurane; P < 0.05 versus CON or 5HD). Sevoflurane also decreased SVR (189 ± 54 mm Hg · min–1 · 1000–1) and AOP (56 ± 19 mm Hg). After 10 min of washout, recovery was similar in all groups and hemodynamics did not differ among the groups before coronary artery occlusion (Tables 1 and 2 and Fig. 2).


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  		Table 1. Hemodynamic Data

 


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  		Figure 2. Line plot showing the time course of left ventricular peak systolic pressure (LVPSP) during the experiments. Dots express mean ± sd.

 


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  		Table 2. Hemodynamic Data

 

During reperfusion, LVPSP remained nearly constant in CON (129 ± 17 mm Hg) and 5HD (123 ± 21 mm Hg, both at 15 min of reperfusion) groups. Although global hemodynamics were reduced (at least due to metabolic depression) in all groups during initial reperfusion, sevoflurane treatment was followed by stronger reduction of global hemodynamic variables (LVPSP, 93 ± 13 mm Hg; RPP, 36 ± 8 mm Hg · min–1 · 1000–1; all data at 2 min of reperfusion, all P < 0.05 versus baseline); SVR (167 ± 46 mm Hg · min · L–1) and AOP (52 ± 13 mm Hg, both P < 0.05) were also reduced, whereas CO remained nearly constant (32 ± 8 mL/min). LVPSP (94 ± 14 mm Hg) and AOP (57 ± 12 mm Hg) decreased similarly in S-Post and S-Pre + S-Post at the beginning of reperfusion.

After sevoflurane was discontinued the cardiodepressive effect in all groups was rapidly abrogated (LVPSP, 119 ± 19 mm Hg; RPP, 48 ± 11 mm Hg · min–1 · 1000–1; all data after 5 min of reperfusion). SVR (251 ± 76 mm Hg · min · L–1) and AOP (86 ± 20 mm Hg) returned to values similar to those of the groups that did not receive sevoflurane at beginning of reperfusion. No further differences among the groups were observed until the end of reperfusion.

Mean LV dry weight was 0.15 ± 0.05 g with no differences among groups (data for the individual groups are given in Table 3). The ischemic-reperfused area (area at risk) constituted 39% ± 16% of the LV. In CON, infarct size was 49% ± 11% of the area at risk, which was not affected by administration of 5HD alone (41% ± 13%) (Fig. 3). Sevoflurane preconditioning reduced infarct size to 23% ± 13% of the area at risk (P < 0.001 versus CON). The cardioprotective effect of sevoflurane was greater in the group that received sevoflurane during reperfusion alone (S-Post: 18% ± 5%) and further increased by administration of sevoflurane before and after ischemia (S-Pre + S-Post: 12% ± 5%; P = 0.054 versus S-Pre). Administration of the specific mKATP-channel blocker 5HD abolished the protection. (S-Pre + 5HD: 35% ± 12%; P = 0.08 versus S-Pre; S-Post + 5HD: 44% ± 12%, P < 0.05 versus S-Post; S-Pre + S-Post + 5HD: 46% ± 14%, P < 0.05 versus S-Pre + S-Post).


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  		Table 3. Weights and Size of Area at Risk

 


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  		Figure 3. Infarct size expressed as percent of the area at risk. Bars present mean ± sd. CON = control group; 5HD = 5-hydroxydecanoate; S-Pre = group preconditioned by 2 episodes of sevoflurane administration interspersed by 10 min of washout; S-Post = group received sevoflurane at the beginning of reperfusion; S-Pre + S-Post = group received sevoflurane before ischemia (preconditioning) and at the beginning of reperfusion (anesthetic postconditioning). *P < 0.05 versus CON or 5HD; #P < 0.05 versus S-Post; °P < 0.05 versus S-Pre + S-Post.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that mKATP-channels are also involved in sevoflurane-induced cardioprotection during reperfusion, i.e., in anesthetic postconditioning. Thus, anesthetic preconditioning and anesthetic postconditioning may share opening of mKATP-channels during cardioprotection. Sevoflurane postconditioning further enhanced the cardioprotection of sevoflurane preconditioning.

In the present study we used two 5-minute periods of sevoflurane exposure to induce anesthetic preconditioning. This was similar to a study of An et al. (8) in isolated guinea pig hearts. From studies of ischemic preconditioning and anesthetic preconditioning (9) it is known that repeated transient ischemic episodes are more effective in reducing infarct size than one single ischemic period (10). Sevoflurane was given at only one concentration (1 MAC) because we had demonstrated previously that a maximal cardioprotective effect can be achieved by using this concentration of sevoflurane for 2 minutes of reperfusion (5,6). Recently published data confirmed those findings for isoflurane (11).

Besides the anti-ischemic properties (12), volatile anesthetics given before myocardial ischemia induce anesthetic preconditioning, characterized by an application period separated from the subsequent ischemia by a memory period (13–15). The administration of volatile anesthetics at the beginning of reperfusion also protects against a lethal cell injury (5,6,16) and the term "postconditioning" was recently introduced for interventions after ischemia (17).

Initially, mKATP-channels were thought only to be the end-effectors of preconditioning. Direct openers of mKATP-channels (i.e., diaxozide) given before a sustained ischemia significantly prolonged the time to ischemic contracture in isolated hearts (18) and reduced the cell damage (19). These effects could be abolished by previous administration of the mKATP-blocker 5HD without having any specific effect on infarct size (20). Nevertheless, Pain et al. (21) demonstrated that mKATP-channels are only one part of the signal cascade of preconditioning. They demonstrated that release of reactive oxygen species (ROS) might be involved in the protection mediated by ischemic preconditioning cascade, which was also shown for anesthetic preconditioning (22–24). In contrast to large amounts of ROS that might be harmful, small concentrations of ROS seem to act as a trigger of preconditioning. Different ROS species seem to have protective properties. One possible way to initiate preconditioning might be the generation of free radicals or reactive nitrogen species, which may, in turn, activate the intracellular protein kinase C (PKC) or tyrosine kinase pathway, resulting in a lower threshold for mKATP-channels opening. Opening of mKATP-channels causes a small decrease in mitochondrial membrane potential, which would slow the electron transport chain and oxidative phosphorylation during ischemia and reperfusion (25).

Maintenance of mitochondrial bioenergetics might decrease generation of damaging ROS and so produce better function and reduced cell damage after ischemia. However, there are still many questions about the protective effect of preconditioning induced by ROS (26,27).

Although the mKATP-channels appear to be involved in anesthetic preconditioning, so does enhanced ROS production (24). With normal cellular adenosine triphosphate (ATP) levels volatile anesthetics did not activate the mKATP-channels as shown in patch clamp experiments (28) but sensitized the mKATP-channels to reduced ATP levels (29,30). Anesthetic preconditioning also modifies the phosphorylation state of different kinases (31). Therefore, activated and translocated PKC might be an alternative mechanism to open mKATP-channels (32). However, the exact mechanism leading to mKATP-channel opening remains unclear.

It has been proposed that opening of the mKATP-channels leads to a depolarization of the mitochondrial membrane that would be favorable by reducing the driving force for ATP generation (33). This was speculated to preserve mitochondrial function during ischemia and reperfusion by attenuating Ca2+ loading that would disrupt mitochondrial function by inducing Ca2+ permeability transition (34). Riess et al. (35) assessed NADH in isolated but energized hearts and found that anesthetic exposure increased NADH (reduction) in isolated hearts, which is different from the findings of Kohro et al. (36) who reported that an anesthetic exposure increased flavoprotein oxidation in de-energized isolated cardiac cells.

Others suggested that mKATP-channels opening significantly increased mitochondrial matrix volume without changing membrane potential. Uptake of K+ through the mKATP-channels would maintain mitochondrial matrix volume (25).

Recently, it was shown that short ischemic periods interspersed with reperfusion were also cardioprotective when administered after the sustained infarct inducing ischemia, i.e., during reperfusion (3,17). Two major mechanisms of cardioprotection induced by postconditioning were discussed. First, there are "passive" effects that modify reperfusion injury by reduction of neutrophil accumulation (37), reduced membrane peroxygenation by impaired oxygen radical generation and a reduced mitochondrial Ca2+ load. Prevention of sarcoplasmatic calcium oscillations during early reoxygenation by volatile anesthetics prevents hypercontracture of isolated cardiomyocytes, thereby reducing the lethal cell injury (38).

As a more "active" part of postconditioning, the activation of different kinases, such as PI3-AKT kinase or ERK1/2 kinase, was postulated to inhibit opening of the mitochondrial permeability transition pore by phosphorylation of downstream targets such as endothelial nitric oxide synthase (17). A recent study of Chiari et al. (11) demonstrated that brief administration of 0.5 MAC of isoflurane during reperfusion provided cardioprotection. They suggested that the ischemia-induced phosphorylation of PI3-AKT kinase might be enhanced in the presence of isoflurane. However, the involvement of PI3-AKT kinase and a possible interaction with mKATP-channels requires further investigations.

Similar to anesthetic-induced preconditioning, administration of a PKC inhibitor at the time of reperfusion partially reduced infarct size in pigs (39). Therefore, it was speculated that PKC might also be involved in mediating the protection against reperfusion injury. However, this hypothesis also has to be confirmed.

It is unknown whether the protection conferred by preconditioning is caused by effects occurring during ischemia or during initial reperfusion. An et al. (8) demonstrated that sevoflurane preconditioning reduced Ca2+ loading during ischemia, thereby attenuating myocardial cell damage and improving myocardial function during reperfusion. The protection of volatile anesthetics appears to depend on the time of administration. Varadarajan et al. (40) demonstrated, in isolated guinea pig hearts, that even if sevoflurane was given directly before ischemia the protection against ischemia-reperfusion injury was much better than when sevoflurane was only given during reperfusion. They speculated that the small decrease in metabolic rate before ischemia metabolically triggers a protective mechanism that might decrease myocardial hypercontracture at the beginning of reperfusion.

Oxygen radicals play a dual role in protection against ischemia and reperfusion injury. Although in preconditioning ROS activate PKC-dependent cardioprotective signaling pathways (41), they cause irreversible cell damage during early reperfusion by direct membrane destruction and lipid peroxidation (42,43). Administration of a mKATP-channel opener before ischemia abolished the ROS burst at the beginning of reperfusion (44). Therefore, one might speculate that the cell injury by ROS during reperfusion was reduced by abolished ROS release caused by preconditioning and by the administration of sevoflurane during reperfusion.

Haelewyn et al. (45) demonstrated that administration of desflurane before, during, and after ischemia resulted in a maximal protective effect. Unfortunately, the preconditioning protocol was different from that used in the group that received desflurane during the total procedure. Therefore, direct comparison between groups is difficult. The authors demonstrated that the amount of infarct size reduction was similar when desflurane was given before or after myocardial ischemia.

Most often, 5HD is used as specific blocker of mKATP-channels in studies performed on ischemic or pharmacologic preconditioning. The specificity of 5HD has been questioned by Hanley et al. (46,47) who demonstrated that 5HD is activated inside the mitochondria and further metabolized via ß-oxidation. Although other possible mechanisms of action of 5HD are discussed (e.g., inhibition of mKATP-channels by putative cytosolic 5HD or 5HD-CoA, by intermediates of 5HD metabolism, or by inhibition of the respiratory chain), the lack of inhibition of sevoflurane preconditioning remained unclear (47).

In the present study, we used continuous administration of 5HD to avoid possible hemodynamic or pharmacological side effects of bolus injections. This protocol resulted in different administration times and total doses of 5-HD. We found no effect of 5HD on infarct size when given for the longest time in the 5HD group. Administration time of 5HD was shortest in the S-Pre + 5HD group and we cannot completely exclude that this differences in the protocol might have influenced the results of the study, i.e., that it might explain the tendency of a "smaller" blockade in the S-Pre + 5HD group. However, the drug was given for the same time before coronary artery occlusion in the S-Post + 5HD group and the effect of sevoflurane during reperfusion was totally blocked.

The mechanism whereby opening of mKATP-channels leads to cardioprotection remains unclear. Several possible mechanisms have been proposed. Opening of mKATP-channels might lead to a depolarization of the mitochondrial membrane, causing dissipation of the mitochondrial potential and reducing the force for Ca2+ uptake and preservation of mitochondrial function during ischemia and reperfusion (48). Others suggest that opening of mKATP-channels increased mitochondrial matrix volume while membrane potential remains nearly stable (25).

Several studies have shown that apoptosis might contribute to cardiac death, and that apoptosis induced by H2O2 can be inhibited by mKATP-channels opening or be blocked by administration of 5HD (49). In the present study, we used TTC staining after 2 hours of reperfusion to determine infarct size. Thus, we cannot speculate about the mechanism of cell death and the effect of sevoflurane on these mechanisms.

In conclusion, the present study demonstrates that mKATP-channels are not only involved in sevoflurane preconditioning but also in postischemic cardioprotection by sevoflurane, i.e., anesthetic postconditioning. Whether anesthetic preconditioning or anesthetic postconditioning will become suitable strategies in the clinical setting remains unclear. A recent study by De Hert et al. (50) demonstrated that only administration of sevoflurane throughout the surgical procedure reduced troponin I levels and length of stay on the intensive care unit in patients undergoing coronary artery surgery, whereas only prebypass (preconditioning) or administration only during reperfusion (postconditioning) were ineffective.

The work of Maximillane Kratz, cand. MD, is gratefully acknowledged.


   Footnotes
 
Accepted for publication June 15, 2005.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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