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Remote preconditioning reduces ischemic injury in the explanted heart by a K_ATP channel-dependent mechanism

¹Department of Cardiology, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark; ²University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and ³Hospital for Sick Children, Toronto, Ontario, Canada

Submitted 4 March 2004 ; accepted in final form 15 October 2004

	ABSTRACT

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Local and remote ischemic preconditioning (IPC) reduce ischemia-reperfusion (I/R) injury and preserve cardiac function. In this study, we tested the hypothesis that remote preconditioning is memorized by the explanted heart and yields protection from subsequent I/R injury and that the underlying mechanism involves sarcolemmal and mitochondrial ATP-sensitive K⁺ (K_ATP) channels. Male Wistar rats (300–350 g) were randomized to a control (n = 10), a remote IPC (n = 10), and a local IPC group (n = 10). Remote IPC was induced by four cycles of 5 min of limb ischemia, followed by 5 min of reperfusion. Local IPC was induced by four cycles of 2 min of regional myocardial ischemia, followed by 3 min of reperfusion. The heart was excised within 5 min after the final cycle of preconditioning, mounted in a perfused Langendorff preparation for 40 min of stabilization, and subjected to 45 min of sustained ischemia by occluding the left coronary artery and 120 min of reperfusion. I/R injury was assessed as infarct size by triphenyltetrazolium staining. The influence of sarcolemmal and mitochondrial K_ATP channels on remote preconditioning was assessed by the addition of glibenclamide (10 µM, a nonselective K_ATP blocker), 5-hydroxydecanoic acid (5-HD; 100 µM, a mitochondrial K_ATP blocker), and HMR-1098 (30 µM, a sarcolemmal K_ATP blocker) to the Langendorff preparation before I/R. The role of mitochondrial K_ATP channels as an effector mechanism for memorizing remote preconditioning was further studied by the effect of the specific mitochondrial K_ATP activator diaxozide (10 mg/kg) on myocardial infarct size. Remote preconditioning reduced I/R injury in the explanted heart (0.17 ± 0.03 vs. 0.39 ± 0.05, P < 0.05) and improved left ventricular function during reperfusion compared with control (P < 0.05). Similar effects were obtained with diazoxide. Remote preconditioning was abolished by the addition of 5-HD and glibenclamide but not by HMR-1098. In conclusion, the protective effect of remote preconditioning is memorized in the explanted heart by a mechanism that involves mitochondrial K_ATP channels.

ischemia; transplantation; infarction; ion channels; reperfusion

	MATERIALS AND METHODS

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Animals and Study Design

Male Wistar rats (M&B Taconic, 300–350 g) were randomly allocated to 1 of 10 groups: 1) control (n = 10); 2) control plus glibenclamide (10 µM, n = 10); 3) control plus 5-hydroxydecanoic acid (5-HD; 100 µM, n = 10); 4) control plus HMR-1098 (100 µM, n = 10); 5) local IPC (n = 10); 6) RPC (n = 10); 7) RPC plus glibenclamide (10 µM, a nonselective K_ATP blocker; n = 10); 8) RPC plus 5-HD (100 µM, a mitochondrial K_ATP blocker; n = 10); 9) RPC plus HMR-1098 (30 µM, a sarcolemmal K_ATP blocker; n = 10); and 10) diazoxide (10 mg/kg, a mitochondrial K_ATP activator that was included in the study to confirm the role of mitochondrial K_ATP channels in the memory of remote IPC, n = 10). Animals were handled according to national guidelines in Denmark and the guidelines of the American Heart Association for animal research.

Preparation

Animals were anesthetized with Dormicum (Midazolam, 0.25 mg/kg body wt) and Hypnorm (Fluanisone, 0.5 mg/kg body wt) and maintained on spontaneous breathing with an oxygen supply (95% O₂-5% CO₂).

Diazoxide (10 mg/kg) was administrated in vivo through the femoral vein 40 min before excision of the heart.

Local IPC and RPC

RPC. A tourniquet was placed around one hindlimb to occlude blood flow for four cycles of 5-min ischemia followed by 5-min reperfusion. Circulatory arrest in the limb was confirmed by a change in the color of the skin and by a decrease in limb temperature. Limb temperature was measured at the end of 5 min of limb ischemia by a subcutaneously placed temperature probe connected to a digital thermometer. There was no difference in the temperature decrease between groups subjected to limb ischemia (RPC, 5.5 ± 0.4°C; RPC + 5-HD, 5.7 ± 0.4°C; RPC + glibenclamide, 5.6 ± 0.4°C; RPC + HMR-1098, 5.6 ± 0.4°C, P = 0.89), indicating that all groups were subjected to equal severity of limb ischemia. Furthermore, in a subset of animals, Doppler ultrasound was used to confirm total arterial occlusion to the limb. Hearts were explanted within 5 min of the final preconditioning stimulus.

Local IPC. A snare was placed around the left main coronary artery for four cycles of 2-min ischemia and 3-min reperfusion.

Induction of Myocardial Infarction

Hearts were cannulated in situ, mounted in a Langendorff preparation at a constant pressure of 80 mmHg, and perfused with a fully oxygenated Krebs-Henseleit buffer. Regional ischemia was induced by tightening a 4-0 ligature snare around the left main coronary artery. The perfusion protocol was 40 min of stabilization and 45 min of ischemia followed by 120 min of reperfusion. Glibenclamide (10 µM), 5-HD (100 µM), and HMR-1098 (30 µM, a gift from Aventis Pharma Deutchland; Frankfurt, Germany) was administered 20 min before I/R in the Langendorff preparation.

Assessment of Ventricular Function and Coronary Flow

In all animals, left ventricular (LV) pressure was monitored continuously by a fluid-filled balloon placed in the LV. Data were acquired and collected using Acqnowledge software (Biopac). Preload was adjusted to 7 mmHg. Coronary flow was measured continuously by an in-line flow probe (Transonic).

Assessment of Myocardial Infarction

While still in the Langendorff preparation, the area at risk (AAR) was defined by ligating the left anterior descending coronary artery at the site of the occlusion and infusing 2.5 ml of 1% Evans blue solution. Hearts were perfused with 3 ml of 1% 2,3,5-triphenyltetrazolium chloride (Sigma) at 37°C for 10 min at pH 7.4. The LV was cut into 2-mm slices, weighed, and photographed. The AAR, area of the LV, and infarct size (IS) were assessed by computer planimetry (Olympus Analysis software). The ratios of IS/AAR and AAR/LV were calculated. All analyses were performed blinded.

Statistics and Calculations

All values are expressed as means ± SE. LV developed pressure (LVDP) was calculated as LV systolic pressure minus LV end-diastolic pressure, and the rate-pressure product (RPP) was calculated as LVDP multiplied by heart rate. Hemodynamic comparisons during reperfusion between groups were performed by two-way ANOVA for repeated measures, whereas hemodynamic comparisons before ischemia, hindlimb temperature reduction after hindlimb ischemia, and IS/AAR were performed by one-way ANOVA. If the ANOVAs were significant, a post hoc pairwise comparison was performed using an unpaired t-test with the Bonferroni correction. P < 0.05 was considered statistical significant.

	RESULTS

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Myocardial I/R Injury

Compared with the control group, we found no significant differences in IS/AAR in the control + glibenclamide (P = 0.71), control + 5-HD (P = 0.76), and control + HMR-1098 groups (P = 0.85) (Fig. 1). IS/AAR was decreased 50% (P < 0.05) in the RPC groups and 70% (P < 0.01) in the IPC groups compared with the control group. However, the reduction of IS/AAR afforded by RPC was abolished with the addition of 5-HD and glibenclamide but not with the addition of HMR-1098. There was no significant difference in the reduction of IS/AAR between the protocols of RPC and IPC used in the present study (P = 0.81). Diazoxide also reduced IS/AAR by 50% (P < 0.05) compared with control, confirming the role mitochondrial K_ATP channels as an effector mechanism for memorizing RPC. We found no significant differences in the AAR expressed as a percentage of the total LV weight between IPC (0.46 ± 0.3), RPC (0.46 ± 0.4), RPC + glibenclamide (0.43 ± 0.3), RPC + 5-HD (0.45 ± 0.2), RPC + HMR-1098 (0.45 ± 0.3), diazoxide (0.47 ± 0.5), control (0.42 ± 0.2), control + glibenclamide (0.44 ± 0.3), control + HMR-1098 (0.42 ± 0.3), and control + 5-HD (0.42 ± 0.4) (P = 0.78).

View larger version (15K): [in this window] [in a new window]   Fig. 1. Ischemia-reperfusion injury [infarct size (IS)/area at risk (AAR)] after 45 min of ischemia and 120 min of reperfusion in explanted hearts. Remote preconditioning (RPC), local preconditioning (IPC), and diazoxide (Diaz) reduced IS compared with control (Con). Glibenclamide (Glib) and 5-hydroxydecanoic acid (5-HD) but not HMR-1098 abolished the effect of RPC. Glibenclamide, 5-HD, and HMR-1098 did not per se aggravate myocardial injury. Values are means ± SE; n = 10 in all groups. *P < 0.05 vs. control; P < 0.01 vs. control.

Postischemic recovery of LVDP (Fig. 2) and RPP (Fig. 3) were superior in the RPC (LVDP: P < 0.05, RPP: P < 0.05), IPC (LVDP: P < 0.05, RPP: P < 0.05), and diazoxide groups (LVDP: P < 0.05, RPP: P < 0.05) compared with the control group. The beneficial effect of RPC on postischemic hemodynamic recovery was abolished with the addition of 5-HD and glibenclamide but not with the addition of HMR-1098. There were no differences between control + glibenclamide, control + 5-HD, and control groups in postischemic recovery of LVDP (P = 0.43) and RPP (P = 0.59) (data not shown). Coronary flow did not differ between groups (P = 0.57).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Left ventricular developed pressure (LVDP) before, during, and after ischemia. LVDP was significantly improved in RPC (dotted line, solid triangles), local IPC (solid line, solid diamonds), and diazoxide (solid line, open circles) groups compared with control (solid line, solid squares). Glibenclamide (dotted line, open circles) and 5-HD (dotted line, open squares) but not HMR-1098 (dotted line, open triangles) abolished the effect of RPC. Values are means ± SE; n = 10 in all groups.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Rate-pressure product [RPP, in mmHg·beats·min–1 (mmHg·bpm)] before, during, and after ischemia. RPP was significantly improved in RPC (dotted line, solid triangles), local IPC (solid line, solid diamonds), and diazoxide (solid line, open circles) groups compared with control (solid line, solid squares). Glibenclamide (dotted line, open circles) and 5-HD (dotted line, open squares) but not HMR-1098 (dotted line, open triangles) abolished the effect of RPC. Values are mean ± SE; n = 10 in all groups.

	DISCUSSION

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Inherent to the concept of IPC is the unique feature of memory, which is associated with alterations in gene expression and transcription (21) and involves K_ATP channels (4, 20). The concept of RPC extends memory from a temporal storage of information to a spatial storage of information because the recognition of ischemia and reperfusion in one tissue is transferred to a virginal tissue not subjected to such preceding episodes (17). Although circulating humoral factors and neuronal mechanisms are involved in the initiation and transfer of such information (3, 6), our study shows that the information is memorized within the explanted heart independently of ongoing humoral and neuronal stimulation. We used the specific K_ATP activator diazoxide and K_ATP blockers to investigate the role of K_ATP channels in memorization in RPC. Because Pell et al. (14) already demonstrated that activity of mitochondrial K_ATP channels is a prerequisite for triggering RPC (14), we focused on the effector mechanism and added K_ATP blockers once the heart had been explanted. Glibenclamide (a nonselective K_ATP blocker) and 5-HD (a selective mitochondrial K_ATP blocker) abolished the protection afforded by RPC to the same extent. However, HMR-1098 (a selective sarcolemmal K_ATP blocker) did not influence the protection afforded by RPC. HMR-1098 per se has no effect on myocardial infarct size and postischemic LV function in time-matched drug-treated controls (7, 19), although it may have some hemodynamic effects during early but not late reperfusion (18). Diazoxide administrated before excision of the heart conferred protection against I/R injury to the same extent as RPC, indicating that mitochondrial K_ATP channels account for the cardioprotective effect of RPC. Thus like in local IPC mitochondrial K_ATP channels serve both trigger and effector functions and are involved in the mechanisms for memorizing RPC (1, 5).

Our study does not allow any conclusion about the mechanism by which opening of mitochondrial K_ATP channels could be potentially cardioprotective. Opening of these channels decreases mitochondrial calcium overload, thus preserving mitochondrial integrity (12, 13). Mitochondrial volume is also regulated by mitochondrial K_ATP channels. Volume changes of the mitochondria are important because they modify energy flow through the electron system, thereby influencing efficient energy transfer between mitochondria and cellular ATPases (11). However, because opening of the channels is necessary not only during triggering but also during and after the index ischemia, mitochondrial K_ATP channels may also be a signal transduction element rather than an effector mechanism. Regardless of the prevailing mechanism, our data also show that the memory of RPC is critically dependent on mitochondrial K_ATP channels.

Although cardiac protection by RPC has been less extensively studied than local IPC, it has greater clinical applicability. The procedure described in the present study is more easily conducted than local IPC, which requires transient periods of aortic cross-clamping, and its effectiveness appears similar. Indeed, the 50% reduction in I/R we obtained with RPC obtained in studies of explanted hearts is of a magnitude that carries clinical significance and concurs with our previous in vivo studies of myocardial infarct reduction in a porcine model using a similar limb ischemia RPC protocol (10). The protection RPC affords is subsequently independent of continued neural or humoral stimulus. As such, preconditioning before profound hemodilution (e.g., cardiopulmonary bypass), in the presence of imposed regional anemia (e.g., skin flap surgery), or, for example, before heart transplantation are all potential applications of the technique.

The limitation of the present study is mainly related to the specificity of the K_ATP channel blockers. A former study (2) has shown that 5-HD prevented the ischemia-induced shortening of the action potential that is usually associated with the opening of sarcolemmal K_ATP channels. However, the concentrations of 5-HD and HMR-1098 used in the present study affect only mitochondrial and sarcolemmal K_ATP channels, respectively (15, 16).

In conclusion, we have shown that RPC applied in vivo exerts protection upon the heart after explantation from the body and therefore has potential beneficial effects in relation to heart transplantation, cardiopulmonary bypass, and under circumstances of predictable I/R injury of the heart. The mechanism of action is dependent on functioning mitochondrial K_ATP channels. The stimulus we used can easily be transferred into the clinical situation, although temporal adjustments may be required.

	GRANTS

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This study was financially supported by the Danish Heart Foundation.

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. B. Kristiansen, Dept. of Cardiology, Skejby Sygehus, Aarhus Univ. Hospital, DK-8200 Aarhus N, Denmark (E-mail: sbk{at}iekf.au.dk)

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.

	REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 288/3/H1252    most recent 00207.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Kristiansen, S. B. Articles by Bøtker, H. E. Search for Related Content PubMed PubMed Citation Articles by Kristiansen, S. B. Articles by Bøtker, H. E.