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Low-pressure reperfusion alters mitochondrial permeability transition

¹Institut National de la Santé et de la Recherche Médicale E0226, Université Claude Bernard Lyon I, and ²Hospices Civils de Lyon, Lyon, France

Submitted 25 October 2004 ; accepted in final form 12 January 2005

	ABSTRACT

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We hypothesized that low-pressure reperfusion may limit myocardial necrosis and attenuate postischemic contractile dysfunction by inhibiting mitochondrial permeability transition pore (mPTP) opening. Male Wistar rat hearts (n = 36) were perfused according to the Langendorff technique, exposed to 40 min of ischemia, and assigned to one of the following groups: 1) reperfusion with normal pressure (NP = 100 cmH₂O) or 2) reperfusion with low pressure (LP = 70 cmH₂O). Creatine kinase release and tetraphenyltetrazolium chloride staining were used to evaluate infarct size. Modifications of cardiac function were assessed by changes in coronary flow, heart rate (HR), left ventricular developed pressure (LVDP), the first derivate of the pressure curve (dP/dt), and the rate-pressure product (RPP = LVDP x HR). Mitochondria were isolated from the reperfused myocardium, and the Ca²⁺-induced mPTP opening was measured using a potentiometric approach. Lipid peroxidation was assessed by measuring malondialdehyde production. Infarct size was significantly reduced in the LP group, averaging 17 ± 3 vs. 33 ± 3% of the left ventricular weight in NP hearts. At the end of reperfusion, functional recovery was significantly improved in LP hearts, with RPP averaging 10,392 ± 876 vs. 3,969 ± 534 mmHg/min in NP hearts (P < 0.001). The Ca²⁺ load required to induce mPTP opening averaged 232 ± 10 and 128 ± 16 µM in LP and NP hearts, respectively (P < 0.001). Myocardial malondialdehyde was significantly lower in LP than in NP hearts (P < 0.05). These results suggest that the protection afforded by low-pressure reperfusion involves an inhibition of the opening of the mPTP, possibly via reduction of reactive oxygen species production.

ischemia; necrosis; cardioprotection

Mitochondrial permeability transition appears to be a pivotal event in cell death after ischemia-reperfusion (37). Mitochondrial permeability transition is due to the opening of a large nonspecific pore in the inner membrane, which results in uncoupling of the respiratory chain, efflux of Ca²⁺ and small proteins such as cytochrome c, and matrix swelling (4, 26). Mitochondrial permeability transition pore (mPTP) opening is triggered by matrix Ca²⁺ accumulation, adenine nucleotide depletion, increased inorganic phosphate concentration, and oxidative stress, all features of ischemia-reperfusion (16). Griffiths and Halestrap (15) demonstrated that the mPTP is closed during ischemia but opens in the early minutes of reperfusion. Hausenloy et al. (20) proposed that ischemic and pharmacological preconditioning may exert their protective effect by inhibiting mPTP opening at reperfusion. Several groups including ours recently proposed that pharmacological inhibition of mPTP opening at reperfusion is protective and might explain the beneficial effect of ischemic preconditioning (2, 19, 22). The aim of the present study was to determine whether a controlled, low-pressure reperfusion might limit lethal reperfusion injury by inhibiting mPTP opening.

	METHODS

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Surgical Preparation

The investigation conformed to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1996) and was approved by Institutional Animal Care and Use Committee (IACUC) of the Claude Bernard University.

Male Wistar rats, weighing 350–450 g, were anesthetized with pentobarbital sodium (50 mg/kg), and heparin (200 IU/kg) was injected into the femoral vein. Hearts were removed and immediately arrested in ice-cold St. Thomas solution. The aorta was rapidly cannulated and perfused for 10 min in the Langendorff mode using Krebs-Henseleit bicarbonate buffer (in mmol/l: 11.0 glucose, 118.5 NaCl, 4.75 KCl, 1.19 MgSO₄, 1.18 KH₂PO₄, 25.0 NaHCO₃, and 1.4 CaCl₂) at pH 7.4. The buffer was bubbled with 95% O₂-5% CO₂ at 37°C, and perfusion was performed under a hydrostatic pressure of 100 cmH₂O. The left ventricle (LV) was paced at a constant rate of 300 beats/min.

Experimental Design

Global normothermic ischemia was induced by clamping the aorta. The temperature was maintained by immersion of the heart in the perfusion medium at 37°C. Two different protocols were performed. The aim of protocol I was to evaluate functional recovery and tissue injury after 40 min of global ischemia and 60 or 120 min of reperfusion. Protocol II was used to assess Ca²⁺-induced mitochondrial permeability transition and measurement of malondialdehyde (MDA) production, an index of lipid peroxidation by oxygen-derived free radicals.

Protocol I. One group of hearts underwent no intervention throughout the experiment (control, n = 12). All other hearts underwent 40 min of global ischemia followed by 60 min (protocol IA) or 120 min (protocol IB) of reperfusion. In protocols IA and IB, all animals were randomly assigned to one of the two following groups (n = 6/group): 1) the normal-pressure (NP) group, in which the myocardium was reperfused at normal pressure (i.e., 100 cmH₂O) after the ischemic insult, and 2) the low-pressure (LP) group, in which the myocardium was reperfused at 70 cmH₂O.

In protocol IB, reperfusion in the LP group was set at 70 cmH₂O for the first 60 min; then normal perfusion pressure (i.e., 100 cmH₂O) was established for the remaining 60 min. These two levels of perfusion pressure were obtained by adjusting the perfusion column to the adequate height. Perfusion pressure of 100 cmH₂O is considered normal for a rat heart under physiological conditions.

Protocol II. All hearts underwent 40 min of global ischemia followed by 10 min of reperfusion. Animals were randomly assigned to one of the two previously defined groups, and cyclosporin A (CsA, 0.2 µmol/l) or its vehicle was administered before the onset of ischemia and throughout reperfusion (n = 6/group). At the end of the 10-min reperfusion, hearts were excised for Ca²⁺-induced mPTP assessment and MDA measurements.

Analysis

Functional recovery. LV systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) were measured by introducing a latex balloon into the LV and expanding it to exert a physiological end-diastolic pressure of 5 mmHg. The rate-pressure product [RPP = (LVSP – LVEDP) x HR, where HR is heart rate], the maximum rate of rise of LV pressure (dP/dt_max), and the maximum isovolumetric rate of relaxation (–dP/dt_min) were calculated. Coronary flow (CF) was measured by timed collections of the pulmonary effluent.

Myocardial necrosis. Myocardial necrosis was evaluated by measurement of creatine kinase (CK) release in the coronary effluent during the reperfusion period (Beckman Coulter kit, Galway, Ireland) and triphenyltetrazolium chloride (TTC) staining, as previously described (35). The heart was cut into four to five transverse slices, parallel to the atrioventricular groove. After removal of right ventricular tissue, heart slices were weighed and incubated for 20 min in a 1% solution of TTC at 37°C to differentiate infarcted (pale) from viable (brick-red) myocardial area. The slices were then photographed, and enlarged projections of these slices were traced for determination of the boundaries of the area of necrosis. Extent of the area of necrosis was quantified by computerized planimetry. Total area of necrosis was then calculated and expressed as percentage of total LV.

Ca²⁺-induced mitochondrial permeability transition.
Preparation of isolated mitochondria. Preparation of mitochondria was adapted from a previously described procedure (13). All operations were carried out in the cold. Myocardial sections (1 g) were placed in isolation buffer A (in mM: 70 sucrose, 210 mannitol, and 1 EDTA in 50 Tris·HCl, pH 7.4). The tissue was finely minced with scissors and then homogenized in the same buffer (1 ml buffer/g tissue) using a Kontes tissue grinder and then a Potter-Elvejem homogenizer. The homogenate was centrifuged at 1,300 g for 3 min. The supernatant was poured through cheesecloth and centrifuged at 10,000 g for 10 min. The mitochondrial pellet was resuspended in isolation buffer B (in mM: 70 sucrose, 210 mannitol, and 0.1 EDTA in 50 mM Tris·HCl, pH 7.4). After aliquots were removed for protein measurements, the mitochondria (aliquots of 6 mg of protein) were washed in isolation buffer B, centrifuged at 6,800 g for 10 min, and stored as pellets on ice before mPTP opening experiments. Protein content was routinely assayed according to Gornall's procedure, with bovine serum albumin as a standard (14).

Ca²⁺-induced mPTP opening. mPTP opening was assessed after in vitro Ca²⁺ overload. Isolated mitochondria (6 mg of protein) were suspended in 100 µl of buffer B and added in 900 µl of buffer C (in mM: 150 sucrose, 50 KCl, 2 KH₂PO₄, and 5 succinic acid in 20 Tris·HCl, pH 7.4) within a Teflon chamber equipped with a Ca²⁺-specific microelectrode, in conjunction with a reference electrode (12). Modifications of the medium (i.e., extramitochondrial) Ca²⁺ concentration were continuously recorded using custom-modified Synchronie software. Mitochondria were gently stirred for 1.5 min. At the end of the preincubation period, 20 µM CaCl₂ was administered every 60 s. Each administration of 20 µM CaCl₂ induces an abrupt rise in extramitochondrial Ca²⁺ concentration (Fig. 1). Ca²⁺ is then rapidly taken up by the mitochondria, resulting in a return of extramitochondrial Ca²⁺ concentration to near baseline. After sufficient Ca²⁺ loading, extramitochondrial Ca²⁺ concentration abruptly increases, indicating a massive release of Ca²⁺ by mitochondria due to mPTP opening (Fig. 1). The amount of Ca²⁺ required to trigger this massive Ca²⁺ release is used here as an indicator of susceptibility of the mPTP to Ca²⁺ overload.

View larger version (14K): [in this window] [in a new window]   Fig. 1. Ca2+-induced mitochondrial permeability transition pore (mPTP) opening. Typical recording of mPTP opening in isolated mitochondria from 1 normal-pressure (NP = 100 cmH2O) and one low-pressure (LP = 70 cmH2O) heart. In the NP mitochondria, a Ca2+ overload of 120 µM (6 pulses of 20 µM) was required to induce mPTP opening vs. 200 µM Ca2+ (10 pulses of 20 µM Ca2+) in the LP heart. Vertical arrows indicate administration of 20 µM Ca2+ into the NP mitochondrial suspension.

Statistics

Statistical comparisons were performed using the analysis of variance and Fisher's protected least significant difference test. Values are means ± SE. P < 0.05 was considered as indicative of a statistically significant difference.

	RESULTS

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Protocol I: Myocardial Damage and Functional Recovery After Ischemia and Reperfusion

Protocol IA: 60 min of reperfusion. In the NP group, baseline RPP averaged 30,002 ± 3,100 mmHg/min. During the reperfusion period, recovery of RPP was poor, ranging from 1,117 ± 140 mmHg/min at 10 min to 3,969 ± 534 mmHg/min at 60 min (P < 0.001 vs. baseline and control; Fig. 2). At 60 min of reperfusion, LV dP/dt_max and LV dP/dt_min were significantly decreased, averaging 300 ± 26 and 248 ± 26 mmHg/s, respectively (P < 0.001 vs. control). CF was significantly reduced, averaging 9.1 ± 0.7 ml·min^–1·g^–1 vs. 13.8 ± 0.3 ml·min^–1·g^–1 in control (P < 0.05).

View larger version (31K): [in this window] [in a new window]   Fig. 2. Postischemic functional recovery. Effects of LP and NP during reperfusion of ischemic hearts on rate-pressure product (RPP). Values are means ± SE (n = 6). *P < 0.001 vs. control.

View larger version (16K): [in this window] [in a new window]   Fig. 3. Estimates of myocardial infarct size. A: creatine kinase (CK) release from hearts reperfused at NP and LP vs. control (sham) hearts. Values are means ± SE (n = 6). *P < 0.01 vs. LP. B: infarct size assessed by tetraphenyltetrazolium chloride staining. Each symbol represents 1 heart. Horizontal bars depict mean of the group. LV, left ventricle. Values are means ± SE (n = 6). *P < 0.01 vs. NP.

At 120 min of reperfusion, RPP averaged 25,790 ± 1,440, 2,330 ± 1,800, and 5,240 ± 3,350 mmHg/min in control (sham), NP, and LP hearts, respectively (P < 0.05, LP vs. NP).

Infarct size averaged 34 ± 5 and 17 ± 1% of the LV weight in the NP and LP groups, respectively (P < 0.05). At 120 min of reflow, mean CK release averaged 150 ± 20 and 80 ± 6 IU/l in NP and LP groups, respectively, whereas lactate dehydrogenase release averaged 65 ± 8 and 41 ± 2 IU/l in NP and LP groups, respectively (P < 0.05 for both). In other words, the difference between NP and LP groups at 60 min was maintained when the reperfusion duration was extended to 120 min.

Protocol II: Ca²⁺-Induced Mitochondrial Pore Transition and MDA Production

In the control group, the amount of Ca²⁺ required to open the mPTP averaged 280 ± 10 µM (Fig. 4). This Ca²⁺ load was significantly reduced in the NP group, averaging 128 ± 16 µM (P < 0.001 vs. control). The Ca²⁺ load required to open the mPTP was significantly higher in the LP than in the NP hearts, averaging 232 ± 10 µM. CsA (0.2 µmol/l) significantly inhibited mPTP opening in NP hearts: the Ca²⁺ overload required to open the mPTP averaged 233 ± 7 µM in CsA-treated NP hearts (P < 0.05 vs. NP, P = NS vs. LP). CsA did not modify mPTP opening in LP hearts (216 ± 5 µM; Fig. 4).

View larger version (37K): [in this window] [in a new window]   Fig. 4. Ca2+-induced mPTP opening. Ca2+ load required to induce mPTP opening in hearts reperfused for 10 min at LP or NP after 40 min of global ischemia in the presence or absence of cyclosporin A (CsA, 0.2 µmol/l). Values are means ± SE (n = 6). *P < 0.05 vs. sham. **P < 0.05 vs. NP.

View larger version (32K): [in this window] [in a new window]   Fig. 5. Malondialdehyde (MDA) levels of hearts reperfused for 10 min at LP and NP. Values are means ± SE (n = 6). *P < 0.05; ***P < 0.001 vs. control. P < 0.05 vs. NP.

	DISCUSSION

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Although there is no doubt that reperfusion salvages a significant amount of jeopardized tissue, it has also been recognized as a "double-edged sword," because it can trigger arrhythmias, myocardial stunning, and no reflow (7). Among various interventions aimed at reducing the deleterious effects of reperfusion, several authors used modifications of the conditions of reperfusion (33). Limiting Ca²⁺ overload, scavenging oxygen-derived free radicals, reducing arterial PO₂, or applying a transient acidosis in the early minutes of reperfusion can improve functional recovery after an ischemic insult (8, 10, 24, 27). In the present study, we reported that low-pressure reperfusion reduced infarct size and improved functional recovery after a prolonged global normothermic ischemia in the rat heart. Here, we confirmed a recent study from our group in which we observed the beneficial effect of low-pressure reperfusion after warm ischemia, but not after a cardioplegic arrest or cold ischemic preservation in the rat model (28). The present results are in agreement with studies demonstrating that controlled reperfusion (reduced coronary perfusion pressure or flow) may improve functional recovery after brief or sustained ischemic episodes (5, 21, 25, 30, 34), although low PO₂ or a reperfusion pressure <50 mmHg may be detrimental, especially after a cold cardioplegic arrest (23). Low-pressure reperfusion has also been successfully used after cold preservation of rat and pig lungs (1, 6, 18) and helped our group transplant human cardiac grafts subjected to a prolonged cold ischemia lasting up to 10–13 h (29).

How low-perfusion pressure can protect the reperfused heart remains unknown. Takeo et al. (34) attributed this protective effect to a limitation of the cytosolic accumulation of Na⁺ and Ca²⁺ after 35 min of global ischemia in the isolated rat heart. Hori at al. (21) demonstrated that staged reperfusion after a 15-min coronary artery occlusion in the dog heart attenuates myocardial stunning via a delayed correction of acidosis during the first minutes of reperfusion. We observed here that the protection was efficient as soon as 10 min after reflow and persisted when normal pressure was briefly resumed 1 h later. The protective effect was maintained when reperfusion was extended up to 120 min, suggesting that irreversible injury was actually limited, rather than simply delayed. This strongly suggests that low pressure prevents irreversible myocardial injury by acting during the early minutes of reperfusion.

Because mPTP opening occurs in the early minutes of reperfusion and plays an important role in lethal injury, we investigated whether low pressure may inhibit mitochondrial permeability transition (17, 19). We demonstrated that mitochondria isolated from myocardium reperfused at a low pressure display a reduced susceptibility to in vitro mPTP opening. The mitochondrial permeability transition inhibitor CsA increased the resistance of the transition pore to in vitro Ca²⁺ overload, whereas it did not affect that of mitochondria from hearts that had been reperfused with a low pressure. In our experimental conditions, LP mitochondria behaved as if they had been pretreated with CsA. One might question whether Ca²⁺-induced mPTP opening might be a consequence, rather than a cause, of the improved myocardial viability observed in LP reperfused hearts. We, however, recently demonstrated in the rabbit heart model that in vivo inhibition of mitochondrial permeability transition by CsA or preconditioning modifies Ca²⁺-induced mPTP opening in a way very similar to low-pressure reperfusion; importantly, this was observed after a fully reversible (i.e., 10 min of ischemia followed by 5 min of reperfusion) ischemia-reperfusion (2). This observation demonstrates that a modification of Ca²⁺-induced mPTP opening is not a consequence of reduced cardiomyocyte death. Although we have not demonstrated a causal relation, this strongly suggests that altered Ca²⁺-induced mPTP opening in myocardium excised from hearts with low-pressure reperfusion is not a consequence (but possibly a cause) of improved myocardial viability. Specific pharmacological inhibition of the transition pore by the nonimmunosuppressive cyclosporin derivative NIM-811 also provided comparable protection (2).

A decrease in matrix Ca²⁺ accumulation and/or a limited production of free radicals are the two main explanations for this enhanced resistance of LP mitochondria to transition pore opening. We found that myocardial MDA content at 10 min of reflow was reduced in these hearts, indirectly suggesting that low-pressure reperfusion limited the production of oxygen-derived free radicals. Yet we cannot exclude that a diminished mitochondrial Ca²⁺ overload also played a role, because we previously reported that a reduced CF subsequent to low-pressure reperfusion, as observed in the present study, limits cytosolic Ca²⁺ overload after normothermic ischemia in the pig heart (11). Peng et al. (31a) also reported that controlled flow during reperfusion limits cytosolic accumulation of Ca²⁺, increases the rate of mitochondrial oxidative phosphorylation, and preserves myocardial ATP content.

Protection afforded by low-pressure reperfusion shares similarities with the recently described "postconditioning" phenomenon (36). Zhao et al. (36) reported that repeated brief episodes of ischemia-reperfusion in the early minutes of reflow after a sustained ischemia can dramatically reduce infarct size. They attributed this protection to a limitation of reactive oxygen species production. We recently demonstrated that postconditioning modulates mPTP opening (3). Further investigations are required to determine whether postconditioning might represent a form of controlled reperfusion.

	GRANTS

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This study was supported by La Fondation de France.

	ACKNOWLEDGMENTS

 
The authors are grateful to Colette Berthet for excellent technical assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. Ovize, Inserm E0226, Laboratoire de Physiologie Lyon-Nord, 8, Ave. Rockefeller, 69373 Lyon Cedex 08, France (E-mail: ovize{at}sante.univ-lyon1.fr)

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.

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