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Ann Thorac Surg 2001;71:1281-1288
© 2001 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
Accepted for publication November 6, 2000.
Address reprint requests to Dr McCully, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Ave Louis Pasteur, Room 144, Boston, MA 02115
e-mail: james_mccully{at}hms.harvard.edu
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Abstract |
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Methods. Rabbit hearts (n = 76) were used for Langendorff perfusion. Sham hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of global ischemia and 120 minutes of reperfusion. K/Mg hearts received cardioplegia before ischemia. The role of ATP-sensitive potassium channels in K/Mg cardioprotection during ischemia and reperfusion was investigated, separately using the selective mitochondrial ATP sensitive potassium and channel blocker, 5-hydroxydecanoate, and the selective sarcolemmal ATP-sensitive potassium channel blocker HMR1883. Separate studies were performed using the selective mitochondrial ATP-sensitive potassium channel opener, diazoxide, and the nonselective ATP-sensitive potassium channel opener pinacidil.
Results. Infarct size was 1.9% ± 0.4% in sham, 3.7% ± 0.5% in K/Mg, and 27.8% ± 2.4% in global ischemia hearts (p < 0.05 versus K/Mg). Left ventricular peak-developed pressure (percent of equilibrium) at the end of 120 minutes of reperfusion was 91% ± 6% in sham, 92% ± 2% in K/Mg, and 47% ± 6% in global ischemia (p < 0.05 versus K/Mg). Blockade of sarcolemmal ATP-sensitive potassium channels in K/Mg hearts had no effect on infarct size or left ventricular peak-developed pressure. However, blockade of mitochondrial ATP-sensitive potassium channels before ischemia significantly increased infarct size to 23% ± 2% in K/Mg hearts (p < 0.05 versus K/Mg; no statistical significance [NS] as compared to global ischemia) and significantly decreased left ventricular peak-developed pressure to 69% ± 4% (p < 0.05 versus K/Mg). Diazoxide when added to K/Mg cardioplegia significantly decreased infarct size to 1.5% ± 0.4% (p < 0.05 versus K/Mg).
Conclusions. The cardioprotection afforded by K/Mg cardioplegia is modulated by mitochondrial ATP-sensitive potassium channels. Diazoxide when added to K/Mg cardioplegia significantly reduces infarct size, suggesting that the opening of mitochondrial ATP-sensitive potassium channels with K/Mg cardioplegic protection would allow for enhanced myocardial protection in cardiac operations.
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Introduction |
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The end effector of these mechanisms remains to be elucidated; however, recent investigations by us and other researchers have suggested that ATP-sensitive potassium (KATP) channels play an important role in endogenous cardioprotection such as ischemic preconditioning and adenosine-enhanced ischemic preconditioning [6, 7]. The role of KATP channels in the cardioprotection afforded by K/Mg cardioplegia and during ischemia and reperfusion was unknown.
Under normal conditions the KATP channels are closed, this inhibition occurs by free intracellular ATP ([ATP]i) and Mg2+–ATP and is responsive to changes in [ATP]i produced by glycolysis but not by increases through application of exogenous ATP [8]. The opening of KATP channels during ischemia occurs as intracellular ATP levels decrease (not extracellular ATP) and has been postulated to reduce the action potential plateau phase [8]. However, Grover and colleagues [9] have shown that when action potential duration is blocked, the cardioprotective action (decreased infarct size) of the KATP channel opener cromakalim is maintained, suggesting that the KATP channels play an alternative role such as attenuating intracellular Ca2+ accumulation thus providing protection from cellular injury and the effects of stunning.
Two KATP channel subtypes exist in the myocardium with one type located in the sarcolemma (sarcKATP) [10] and the other in the inner membrane of the mitochondria (mtKATP) [10]. Garlid and associates [11] have demonstrated that mtKATP channels play an important role in cardioprotection, and recent reports suggest that mtKATP channels may be the site of action mediating the cardioprotective effects of ischemic preconditioning [10, 12].
The purpose of this study was to determine whether the cardioprotection afforded by K/Mg cardioplegia was modulated by KATP channels and if so, to determine the specificity of KATP channel modulation on K/Mg cardioprotection, and to determine whether this modulation occurred during ischemia or during reperfusion. Our results indicate that infarct size reduction is primarily modulated by mtKATP channels during ischemia in K/Mg cardioplegia, whereas sarcKATP channels do not appear to be involved in K/Mg cardioprotection. In addition, we show that the addition of a selective mtKATP channel opener diazoxide [12, 13] to K/Mg cardioplegia before ischemia significantly decreases infarct size, suggesting that the cardioprotection afforded by K/Mg cardioplegia can be enhanced by selective opening of mtKATP channels.
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Material and methods |
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Langendorff perfusion
All rabbits were anesthetized with ketamine (33 mg/kg) and xylazine (16 mg/kg) and heparin (200 U/kg) intravenously through the marginal ear vein. The heart was excised and placed in a 4°C bath of Krebs-Ringer solution equilibrated with 95% O2 and 5% CO2 (pH 7.4 at 37°C), where spontaneous beating ceased within a few seconds. Krebs-Ringer solution contained (in mmol/L) NaCl 100, KCl 4.7, KH2PO4 1.1, MgSO4 1.2, NaHCO3 25, CaCl2 1.7, glucose 11.5, pyruvic acid 4.9, and fumaric acid 5.4. Langendorff retrograde perfusion was performed as previously described [1, 5, 6]. In brief, a Latex balloon containing a catheter-tip transducer (Millar Instruments, Inc, Houston, TX) was inserted into the left ventricle. The volume of the water-filled balloon was determined at a constant physiological end-diastolic pressure in a range of 5 to 10 mm Hg using a calibrated microsyringe during equilibrium, and this balloon volume was maintained for the duration of the experiment. The aorta was cannulated with a metal cannula and the heart was subjected to Langendorff retrograde perfusion at a constant pressure of 75 cm H2O at 37°C. Hearts were placed through the right atrium at 180 ± 3 beats/min throughout the experiment using a Medtronic model 5330 stimulator (Medtronic, Minneapolis, MN). Hemodynamic variables were acquired using the PO-NE-MAH digital data acquisition system (Gould, Valley View, OH), with an Acquire Plus processor board, and left ventricular pressure analysis software, and were expressed as a percentage of equilibrium values.
Experimental protocol
Hearts were perfused for 30 minutes to establish equilibrium hemodynamics. Equilibrium was ceased when heart rate, coronary flow, left ventricular end-diastolic pressure (LVEDP) and peak developed pressure (LVPDP), which is defined as the difference from the left ventricular systolic pressure to the end-diastolic pressure were maintained at the same level for three continuous measurement periods timed 5 minutes apart. Sham hearts (n = 8) were perfused without global ischemia at 37°C for 180 minutes. Global ischemia hearts (GI; n = 10) were subjected to 30 minutes of GI and 120 minutes of reperfusion. Global ischemia was achieved by cross-clamping the perfusion line. The K/Mg hearts (n = 8) were perfused with normothermic (37°C) K/Mg cardioplegia (K+, 20 mmol/L, Mg2+, 20 mmol/L in Krebs-Ringer solution) for 5 minutes before ischemia.
Effect of KATP channel blockers on infarct size and functional recovery
To determine the effects of KATP channel blockers on K/Mg cardioprotection from the persistent drug effect of KATP channel blockers, sham hearts were perfused separately with the selective mtKATP channel blocker, 5-hydroxydecanoate [10, 14] (5HD; 200 µmol/L in Krebs-Ringer solution; Sigma Chemical Co, St. Louis, MO) and the selective sarcKATP channel blocker HMR 1883 [10] (HMR; 50 µmol/L in Krebs-Ringer solution; the kind gift of H. C. Englert, Hoechst-Marion-Roussel, Frankfurt, Germany) for 7 minutes before ischemia and for 2 minutes at the onset of reperfusion (sham + 5HD-IR, n = 3; sham + HMR-IR, n = 3).
Role of mtKATP channels in K/Mg cardioprotection during ischemia and reperfusion
To investigate the role of mtKATP channels in K/Mg cardioplegic protection during ischemia and reperfusion, K/Mg hearts were perfused separately with 5HD (200 µmol/L in Krebs-Ringer solution) for 2 minutes before K/Mg cardioplegia infusion and during the 5 minutes of cardioplegia infusion before GI (K/Mg + 5HD-I; n = 8) or for 2 minutes at the onset of reperfusion (K/Mg + 5HD-R; n = 5) or during both periods (K/Mg + 5HD-IR; n = 6).
Role of sarcKATP channels in K/Mg cardioprotection during ischemia and reperfusion
To investigate the role of sarcKATP channels in K/Mg cardioplegic protection during ischemia and reperfusion, K/Mg hearts were perfused separately with HMR (50 µmol/L in Krebs-Ringer solution) for 2 minutes before K/Mg cardioplegia infusion and during the 5 minutes of K/Mg cardioplegia infusion before GI (K/Mg + HMR-I; n = 5) or both before ischemia and for 2 minutes at the onset of reperfusion (K/Mg + HMR-IR; n = 5).
Effect of KATP channel openers in global ischemia and K/Mg cardioprotection
To determine the effects of KATP channel openers on K/Mg cardioplegic protection, K/Mg hearts were perfused separately with the selective mtKATP channel opener diazoxide [12, 13] (50 µmol/L in Krebs-Ringer solution; Sigma Chemical), or with the nonselective KATP channel opener pinacidil [12, 15] (50 µmol/L in Krebs-Ringer solution; Sigma Chemical) for 5 minutes before GI in concert with K/Mg cardioplegia (K/Mg + diazoxide; n = 6, K/Mg + pinacidil; n = 4). Separate group of GI hearts were perfused with diazoxide (50 µmol/L in Krebs-Ringer solution) for 5 minutes before GI (GI + diazoxide; n = 5) in place of K/Mg cardioplegia. Diazoxide and pinacidil were dissolved in dimethyl sulfoxide (DMSO, Fisher Scientific Co, Fair Lawn, NJ) before being added into Krebs solutions. The final concentration of DMSO was less than 0.1%.
Measurement of infarct size
Infarct size was determined as previously described using 1% triphenyl tetrazolium chloride (Sigma Chemical) in phosphate buffer (pH 7.4). The area of left ventricle and the area of infarcted tissue were measured by an independent blinded observer using computer planimetry as previously described [1, 6].
Wet weight/dry weight ratios
Left ventricular tissue samples from all experimental groups were weighed (wet weight), and dried at 80°C for 24 hours for reweighing (dry weight) and then used for the determination of wet/dry weight ratios, using previously described methods [1, 6].
Statistical analysis
Statistical analysis was performed using SAS (version 6.12) software package (SAS Institute, Cary, NC). The mean ± the standard error of the mean for all data was calculated for all variables. Statistical significance was assessed using repeated measures analysis of variance with group as a between subjects factor and time as a within subjects factor. If this overall test was significant, then one-way analysis of variance was performed at individual time points, and when significant, post hoc comparisons were made between groups at a time point. Dunnett’s test was used for comparisons between K/Mg and other groups. Bonferroni correction was used for comparisons between groups other than K/Mg. One-way analysis of variance was used for infarct size. Post hoc comparisons of infarct size between K/Mg and K/Mg + diazoxide, and K/Mg and K/Mg + pinacidil were performed by least significant comparisons analysis. Statistical significance was claimed at p value less than 0.05.
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Results |
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Effect of global ischemia and K/Mg cardioplegia on functional recovery and infarct size
The LVPDP in GI hearts was significantly decreased (p < 0.05 versus sham and K/Mg) throughout 120 minutes of reperfusion (Table 1). After 20 minutes of reperfusion (80 minutes of perfusion) no significant difference in LVPDP was observed between sham and K/Mg hearts (Table 1). Similar values were observed for +dP/dt (results not shown). Coronary flow in K/Mg hearts was significantly increased at 120 to 180 minutes of perfusion (p < 0.05 versus GI, no statistical significance as compared to sham). No significant difference in coronary flow was observed between sham and K/Mg hearts throughout reperfusion (results not shown).
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Infarct size was 1.9% ± 0.4% in sham hearts, and was significantly increased to 27.8% ± 2.4% in GI hearts (p < 0.05 versus sham). Infarct size in K/Mg hearts was significantly decreased to 3.7% ± 0.5% (p < 0.05 versus GI). No significant difference in infarct size was observed between sham and K/Mg hearts (Fig 1).
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Role of mtKATP channels in K/Mg cardioprotection during ischemia and reperfusion
The LVPDP in K/Mg + 5HD-I hearts was significantly decreased at 80 to 120 minutes of perfusion (p < .05 versus K/Mg), but was not significantly different from that observed in K/Mg hearts at 150 to 180 minutes of perfusion (Table 2). The LVPDP in K/Mg + 5HD-I hearts was significantly increased as compared to GI hearts throughout the 120 minutes of reperfusion. The LVPDP in 5HD-IR hearts was significantly decreased as compared to K/Mg hearts, but was significantly increased as compared to GI hearts at 80 to 180 minutes of perfusion. Similar findings were observed for +dP/dt (results not shown). No significant differences in LVEDP or coronary flow were observed between K/Mg, K/Mg + 5HD-I, K/Mg + 5HD-R, and K/Mg + 5HD-IR hearts throughout 120 minutes of reperfusion (results not shown).
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Role of sarcKATP channels in K/Mg cardioprotection during ischemia and reperfusion
After 20 minutes of reperfusion (80 minutes of perfusion), no significant difference in LVPDP was observed between K/Mg + HMR-I and K/Mg + HMR-IR hearts as compared to K/Mg hearts throughout 120 minutes of reperfusion (Table 3). After 10 minutes of reperfusion (70 minutes of perfusion) LVPDP in K/Mg + HMR-I and K/Mg + HMR-IR was significantly increased (p < 0.05) as compared to GI hearts throughout reperfusion. No significant differences in LVEDP, dP/dt, or coronary flow were observed between K/Mg and K/Mg + HMR-I and K/Mg + HMR-IR hearts throughout reperfusion (results not shown).
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Effect of KATP channel openers in global ischemia and K/Mg cardioprotection
No significant difference in LVPDP was observed between K/Mg and K/Mg + diazoxide hearts throughout 120 minutes of reperfusion (Table 4). In contrast LVPDP in GI + diazoxide hearts was significantly decreased as compared with K/Mg hearts (p < 0.05) throughout reperfusion. No significant difference in LVPDP was observed between GI and GI + diazoxide hearts. LVEDP in GI + diazoxide hearts was significantly increased as compared to K/Mg hearts at 180 minutes of perfusion, and +dP/dt was significantly decreased at 150 to 180 minutes of perfusion (p < 0.05 versus K/Mg; results not shown). No significant difference in coronary flow was observed between K/Mg, K/Mg + diazoxide, and GI + diazoxide hearts throughout perfusion.
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Comment |
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Previous reports have suggested that mtKATP and sarcKATP channels function separately in the modulation of infarct size and functional recovery and that the mtKATP but not sarcKATP channels modulate cell viability [6, 9, 11, 12]. Our data would support this hypothesis as our results indicate that the blockade of sarcKATP channels had no effect on the cardioprotection afforded by K/Mg cardioplegia.
The blockade of sarcKATP channels has been shown to increase cytosolic calcium ([Ca2+]i) accumulation through the interaction of a series of receptor mediated events [10]. Our results indicate that sarcKATP channel blockade before ischemia (K/Mg + HMR-I) or both before ischemia and at the immediate start of reperfusion (K/Mg + HMR-IR) had only a transient effect on K/Mg cardioprotection affecting postischemic functional recovery only during early reperfusion (70 to 80 minutes of perfusion). The sarcKATP channel blockade had no effect on K/Mg infarct size reduction. These results are in agreement with previous reports by us [6] and other researchers [9, 11, 12] in which sarcKATP channels were shown not to modulate cell viability.
In this report sarcKATP channel blockade had only a transient effect on K/Mg postischemic functional recovery. This is in contrast to our recent report indicating that sarcKATP channels modulate postischemic functional recovery with the modified endogenous cardioprotection of adenosine-enhanced ischemic preconditioning [6]. These differences are explained by the mechanisms by which K/Mg cardioplegia and adenosine-enhanced ischemic preconditioning provide for cardioprotection [3, 16]. Previously, we have shown that the cardioprotection afforded by K/Mg cardioplegia occurs through the significant decrease in [Ca2+]i accumulation through inhibition of L-type Ca2+ channels and sarcoplasmic reticulum Ca2+ release channels [5]. The mechanism of action of adenosine-enhanced ischemic preconditioning is different from that of K/Mg and does not involve the amelioration of [Ca2+]i accumulation through Ca2+ channels. In this report, we have not measured [Ca2+]i, however, in previous reports we have shown that K/Mg cardioplegia ameliorates [Ca2+]i accumulation during global ischemia [3, 5]. We speculate that the effects of sarcKATP channel blockade are masked by the decrease in [Ca2+]i accumulation with K/Mg cardioplegia.
The blockade of mtKATP channels with 5HD has been previously shown by other investigators to decrease mitochondrial depolarization and permit Ca2+ entry into the mitochondria [10, 17]. Under homeostatic conditions the mitochondrial inner membrane (cristae) that contains the electron transport chain expels protons to the cytosol, creating a charge gradient that provides the passive energy for Ca2+ influx by the Ca2+ uniporter. Increased mitochondrial Ca2+ accumulation destabilizes the inner mitochondrial membrane, and causes the inner membrane pore to open and permit further cation movement ("futile calcium cycling") [18]. It has been speculated that this futile calcium cycling in the mitochondrion, an energy-dependent process requiring ATP to transport calcium against the electrochemical gradient out of the mitochondrion, uses needed ATP required for the maintenance of cell viability [17, 19]. Our results showing that mtKATP channel blockade either before ischemia or both before ischemia and at the immediate start of reperfusion completely abolished K/Mg infarct size reduction would support this mechanism leading to cellular injury.
The mechanism by which cardioplegia provides for enhanced cardioprotection remains to be elucidated fully, and previous reports by other researchers have shown that superior cardioprotection can be achieved through the addition of nonselective KATP channel openers to K+ or Mg2+ cardioplegia [20, 21]. The specific role of sarcKATP or mtKATP channels in cardioplegic cardioprotection, however, was unknown. In this report we have used pinacidil, a nonselective KATP channel opener [12, 15] and diazoxide, a selective mtKATP channel opener [12, 13].
Pinacidil, a nonselective KATP channel opener, has been shown to open both sarcKATP and mtKATP channels in rabbit ventricular myocytes at concentrations of 50 and 100 µmol/L [15], and provides dose-dependent myocardial protection when used at concentrations between 10 and 200 µmol/L [20]. We have used 50 µmol/L pinacidil with K/Mg cardioplegia. In our investigation, K/Mg cardioplegia with pinacidil significantly decreased postischemic functional recovery (p < 0.05 versus K/Mg, NS versus GI) and significantly increased infarct size to 17.4% ± 6.7% (p < 0.05 versus K/Mg, NS versus GI).
The opening of the sarcKATP channels with potassium channel openers, such as pinacidil, has been shown to decrease [Ca2+]i accumulation by hyperpolarization of the sarcolemmal membrane [10]. It is important to note that all hearts receiving K/Mg cardioplegia and pinacidil in our investigation had ventricular fibrillation immediately upon reperfusion that lasted for approximately 14 minutes followed by spontaneous defibrillation. Previous reports have shown that ventricular fibrillation results in increased [Ca2+]i, decreased high energy phosphate, and hypoperfusion of the subendocardium because of high end-diastolic pressure, and significantly contributes to cellular injury and decreased functional recovery [22].
Our results are in agreement with Fagbemi and colleagues [23], who have also reported that in the isolated buffer perfused rabbit heart, all hearts treated with pinacidil exhibited ventricular fibrillation upon reperfusion. Our results also agree with Dorman and associates [21] who have shown that SR47063 (50 µmmol/L), a nonspecific KATP channel opener, when used with cardioplegia in the in situ blood perfused pig heart, induced refractory arrhythmogenesis. They concluded that the application of nonspecific KATP channel openers as a pretreatment may be problematic in the setting of cardiac surgery. These results, however, are in contrast with that of Lawton and colleagues [20] who have shown that pinacidil alone provides superior protection as compared to St. Thomas’ Hospital cardioplegic solution in the isolated blood perfused rabbit heart model.
Garlid and coworkers [13] have shown that diazoxide decreases cell injury in a dose-dependent manner at concentrations between 1 and 30 µmol/L, whereas concentrations from 30 to 100 µmol/L diazoxide afford a similar level of cardioprotection. In this study we have used 50 µmol/L diazoxide to investigate the role of mtKATP channels in cardioprotection. We have not used diazoxide during reperfusion as our results indicate that infarct size is modulated by mtKATP channels during ischemia, not reperfusion [6].
Our data (Fig 3) indicate that diazoxide, when used independently in GI hearts (GI + diazoxide), significantly decreased (p < 0.05) infarct size as compared to GI hearts, but that infarct size was significantly greater (p < 0.05) than that observed in K/Mg hearts. Diazoxide when added to K/Mg cardioplegia significantly decreased (p < 0.05) infarct size to 1.5% ± 0.4% as compared to 3.7% ± 0.5% in K/Mg hearts.
Recent reports suggest that mitochondrial membrane depolarization caused by K+ entry through the opening of mtKATP channels would reduce mitochondrial Ca2+ overload [11, 24]. Subsequently, these events are believed to result in ATP production and cell salvage [10, 24]. In this study, we have not measured the action potential of the sarcolemmal membrane or the oxidation of flavoprotein [12–14] as indicators of the activities of sarcKATP or mtKATP channels as we have investigated the role of these channels in the whole heart model, not the in vitro isolated cardiomyocyte model; however, this mechanism would agree with our previous report in which we have shown that K/Mg cardioplegia ameliorates [Ca2+]i accumulation during ischemia but had no direct effect on mitochondrial Ca2+ accumulation [4]. Mitochondrial Ca2+ accumulation was found to be increased similarly during ischemia in both GI and K/Mg hearts in the mature rabbit [4]. Although we have not measured mitochondrial calcium, the mechanism by which mtKATP channels afford enhanced cardioprotection has been previously suggested by others to occur through a K+ conductance into the mitochondria leading to the depolarization of the mitochondrial membrane and resulting in increased mitochondrial matrix volume and improved respiration through preservation of electron transport function [10, 25].
Our results suggest that the opening of mtKATP channels when used with K/Mg cardioplegia would appear to provide for additive cardioprotection significantly enhancing the infarct size reduction afforded by K/Mg cardioplegia alone. In this study we have investigated the role of KATP channels in the isolated buffer-perfused Langendorff heart model and therefore, the effects of neutrophils and plasma-borne inflammatory components on cardioprotection were not assessed. However, in earlier reports, we have shown that the beneficial effects of K/Mg cardioplegia are preserved in the in situ blood perfused heart model [1, 2]. The role of KATP channels in the cardioprotection afforded by K/Mg cardioplegia in the blood perfused model remain to be elucidated. It should be noted that in our model electrical defibrillation could not be performed and therefore the effects of ventricular fibrillation on infarct size and postischemic functional recovery most likely represent a "worst case" example. In total, our results suggest that the cardioprotection afforded by K/Mg cardioplegia is modulated by KATP channels and that the effect of these channels on cardioprotection occurs primarily during ischemia. K/Mg infarct size reduction is primarily modulated by mtKATP channels during ischemia. Our results also indicate that diazoxide when added to K/Mg cardioplegia would appear to enhance infarct size reduction, suggesting that opening of mtKATP channels with K/Mg cardioplegic protection would allow for enhanced myocardial protection in cardiac operations.
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