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Ann Thorac Surg 2006;81:154-159
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Hyperkalemic Cardioplegia-Induced Myocyte Swelling and Contractile Dysfunction: Prevention by Diazoxide

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

Accepted for publication June 20, 2005.

^_* Address correspondence to Dr Lawton, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8234, St. Louis, MO 63110-1013 (Email: lawtonj{at}msnotes.wustl.edu).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Hyperkalemic cardioplegia (9°C) results in significant myocyte swelling and reduced contractility, representing a possible mechanism of myocardial stunning. Adenosine triphosphate–sensitive potassium channel (K_ATP) openers have been shown to ameliorate stunning. This study evaluated the hypothesis that a K_ATP opener would prevent hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility.

METHODS: Isolated rabbit myocytes were perfused with 37°C Tyrode's solution for 20 minutes, followed by test solution (9°C or 37°C) including control Tyrode's, Tyrode's + 100 µmol/L diazoxide (K_ATP opener), St. Thomas's solution; or 9°C St. Thomas's + 100 µmol/L diazoxide or St. Thomas's + 100 µmol/L diazoxide + 20 µmol/L HMR1098 or 50 µmol/L 5-hydroxydeconoate (K_ATP blockers) for 20 minutes (n = 8 per group). Myocytes were then reexposed to 37°C Tyrode's solution for 20 minutes. Volume and contractility were measured by videomicroscopy and video-based edge detection, respectively.

RESULTS: St. Thomas's solution (9°C) caused significant myocyte swelling and associated reduced contractility (p < 0.05). The addition of diazoxide abolished myocyte swelling (p < 0.0001), and eliminated the associated reduced contractility (p < 0.05). Findings were unchanged by the addition of HMR 1098 and 5-hydroxydeconoate.

CONCLUSIONS: Diazoxide prevented myocyte swelling and reduced contractility secondary to hyperkalemic cardioplegia, and this was unchanged by the addition of either K_ATP channel blocker. Prevention of myocyte swelling was associated with improved contractility, consistent with the hypothesis that myocyte swelling may be a mechanism of myocardial stunning. Diazoxide may play a role in myocyte volume homeostasis by means of a mechanism separate from opening the K_ATP channel.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Hyperkalemic cardioplegia has been associated with significant myocyte swelling in multiple animal models and in isolated human myocytes [1–4]. These solutions are also associated with a reduction in myocyte contractile function at hypothermic temperatures [5]. These changes have been hypothesized to play a role in postoperative left ventricular dysfunction [1, 2, 5–7]. We have proposed that the structural (volume) changes are related to the functional (contractility) changes.

The relationship between swelling and contractile dysfunction (stunning) has been supported by a number of observations. The temporal resolution of postoperative stunning may correspond to the resolution of myocyte swelling and edema, and the elimination of myocyte swelling in an isolated heart model has been demonstrated to result in improved function [8].

Adenosine triphosphate–sensitive potassium (K_ATP) channel openers have been demonstrated to prevent osmotic cell swelling and to ameliorate ischemic cell swelling at the cellular and mitochondrial levels [9, 10]. Other investigators have demonstrated a reduction of myocardial edema [11] and better preservation of myocyte contractile function by the addition of a K_ATP channel opener to hyperkalemic cardioplegia in isolated heart models [5]. We have demonstrated that hyperosmotic stress is associated with myocyte shrinkage and improved myocyte contractility and that hyposmotic stress is associated with myocyte swelling and reduced contractility [12]. We have also demonstrated that a K_ATP channel opener prevented the myocyte swelling and the associated reduced contractility associated with mild hyposmotic stress [12]. These data provide further evidence for the link between myocyte swelling (structural change) and stunning (reduced contractility).

Previously, we demonstrated that the K_ATP channel opener, pinacidil, prevents myocyte swelling secondary to hyperkalemic cardioplegia [13]. This led to the hypothesis that K_ATP channel openers may play a role in myocyte volume homeostasis secondary to stress (hyperkalemic cardioplegia, osmotic stress, or ischemia). This study evaluated the hypotheses that myocyte swelling results in contractile dysfunction, and that a K_ATP channel opener would ameliorate not only the myocyte swelling but also the reduced contractility secondary to hyperkalemic cardioplegia in the absence of ischemia. By clarifying their role in myocyte volume homeostasis, K_ATP channel openers may be specifically exploited to limit the detrimental myocyte volume and contractility changes secondary to hyperkalemic cardioplegia.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experiments were approved by the Animal Studies Committee at Washington University. Animals received humane care in compliance with the 1996 "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health.

Isolation of Rabbit Ventricular Myocytes
New Zealand white rabbits (either sex, 3 to 4 kg) were anesthetized intramuscularly (xylazine, 14.0 mg/kg; acepromazine, 1.3 mg/kg, and ketamine, 83.0 mg/kg) and heparinized (3,000 U intravenously). A maximum of two myocytes were used per each rabbit for analysis. Sternotomy and rapid cardiectomy were performed. The heart was attached to a Langendorff column for retrograde perfusion (37°C) of Tyrode's physiologic solution (in mmol/L): NaCl, 130; KCl, 5; KH₂PO₄, 0.4; MgCl₂, 3; HEPES (N-[2-hydroxyethyl]piperazine-N'-[4-butanesulfonic acid]), 5; taurine, 15; glucose, 10; and creatine, 5.7; at a height of 80 cm (pH adjusted to 7.25 by 20% NaOH titration). The heart was perfused with a solution containing 1.8 mmol/L CaCl₂ in Tyrode's physiologic solution for 5 minutes. Extracellular calcium was washed out by perfusion with a solution containing 0.1 mmol/L Na₂EGTA in Tyrode's physiologic solution for 5 minutes. Solutions were equilibrated with 95% O₂–5% CO₂. The heart was then perfused with 1,500 mg/L bovine serum albumin (Sigma Chemical Company, St. Louis, MO), 400 mg/L collagenase type II (Worthington Biomedical, Freehold, NJ), and 50 mg/L protease (Sigma) in Tyrode's physiologic solution for 18 minutes to provide enzymatic digestion. Ventricles were removed and minced over nylon mesh to remove debris, placed into a solution containing (in mmol/L) potassium glutamate, 120; KCl, 10; KH₂PO₄, 10; MgSO₄, 1.8; K₂EGTA, 0.5; taurine, 10; HEPES, 10; and glucose, 20; and stored at room temperature for 30 minutes to allow settling.

Imaging and Volume Measurement
Myocytes were visualized on a slide on a glass-bottomed chamber using an inverted microscope stage (Leitz, Wetzlar, Germany) equipped with Hoffman modulation optics (Modulation Optics, Greenvale, NY). After a 5-minute stabilization period, the chamber was perfused at a rate of 3 mL/ min with an altered control solution of Tyrode's consisting of (in mmol/L) NaCl, 130; KCl, 5; CaCl₂, 2.5; MgSO₄, 1.2; NaHCO₃, 24; Na₂HPO₄ 1.75; and glucose, 10 (buffered to a pH of 7.4 using 95% O₂–5% CO₂). Chamber temperature was controlled by a waterbath system (Thermo Haake, Karlsruhe, Germany). Cells were inspected for viability. Cell images were displayed on a video monitor using a charge-coupled device camera (KPM1U; Hitachi Denshi, Tokyo, Japan). The cell images were captured using a video-frame grabber (Scion Corporation, Frederick, MD). Cell borders were manually traced, and length, width, and area were measured using Scion Image software (Scion Corporation).

Assuming that the changes in cell width and thickness were proportional, relative cell volume was determined by the following formula:

where t and c refer to test and control, respectively. On the basis of repeated measurements of single images and measurements of multiple images of a cell, this methodology for estimating cell volume has been shown to be reproducible to less than 1% [1].

Cell Contractility Measurement
Myocyte contractility was measured using a video-based edge detection system (IonOptix, Milton, MA). Cells were paced using a field stimulator (MyoPacer; IonOptix) at a voltage 10% above threshold at a frequency of 1 Hz with a 5-ms duration to avoid the occurrence of fusion beats. Polarity of the stimulator was altered at every other stimulation to avoid possible build-up of electrolyte byproducts at one electrode. After a 5-minute stimulation period, data were obtained from 25 to 30 consecutive beats and averaged. Variables included percent cell shortening, maximal velocity of shortening, and maximal velocity of relengthening. Cells that showed less than 7% cell shortening at baseline period were excluded.

Experimental Protocol
Cells were perfused for 20 minutes in 37°C control Tyrode's solution to obtain baseline volume and contractility measurements. Cells (n = 8 myocytes in each group, up to two myocytes per rabbit) were then perfused for 20 minutes with 9°C or 37°C test solution followed by a 20-minute reexposure period to 37°C control Tyrode's solution. The perfusion temperature of 9°C was chosen because this is clinically relevant and mimics myocardial temperature during cardioplegic arrest. No ischemic period was used for the experimental protocol. This protocol was used to identify the myocyte changes caused by exposure to hyperkalemic cardioplegia alone.

Test solutions included (1) control Tyrode's solution (Tyr), (2) Tyr with 100 µmol/L diazoxide (DZX; Sigma), a putative specific mitochondrial K_ATP channel opener, (3) St. Thomas's solution (StT, Plegisol; Abbott Laboratories, North Chicago, IL), (4) StT with 100 µmol/L DZX, (5) StT with 100 µmol/L DZX and 20 µmol/L HMR1098 (putative specific sarcolemmal K_ATP channel inhibitor; gift from Aventis Pharma Deutschland Gmbh, Frankfurt, Germany), and (6) StT with 100 µmol/L DZX and 50 µmol/L 5-hydroxydeconoate (5-HD, putative specific mitochondrial K_ATP channel inhibitor; Sigma). HMR1098 was added to attempt to eliminate any sarcolemmal K_ATP channel activity, and 5-HD was added to attempt to eliminate any mitochondrial K_ATP channel activity. St. Thomas's solution consisted of (in mmol/L) NaCl, 110; NaHCO₃, 10; KCl, 16; MgCl₂, 32; and CaCl₂, 2.4; and was equilibrated with 95% O₂–5% CO₂ and titrated to correct to pH 7.3. A stock solution of DZX was made by dissolving it in dimethyl sulfoxide (0.1%). Dimethyl sulfoxide has no effect on cell volume [1].

Volume measurements were recorded at baseline, at 2 minutes after the start of a new solution, every 5 minutes during test solution, and during reexposure to Tyr solution. Contractility measurements were recorded at baseline and at 10 and 20 minutes after reexposure to Tyr solution and averaged. All variables were expressed as a percentage of baseline.

Statistical Analysis
Results are expressed as mean ± standard error of the mean with n equal to the number of cells in each group. A repeated-measures analysis of variance was used for sequential time-based measurements for each test solution against its own baseline value. Using Fisher's least significant difference test, post hoc multiple comparisons between different solutions were made separately during the test solution and reexposure periods. Statistical significance was defined as p less than 0.05. Statistical analysis was performed using Stat View 5.0 (Abacus Concepts, Inc, Berkeley, CA).

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The mean width, length, and area of cardiomyocytes at baseline were 24.6 ± 0.6 µm, 125.7 ± 2.3 µm, and 3,032 ± 101 µm², respectively. Assuming that the cross section of the myocytes was a square, the mean volume of a single myocyte at baseline was 79.1± 4.7 pL. However, if cells are actually cylindrical, this initial assumption overestimates cell volume by a factor of 1.27 (4/) [14]. To avoid this uncertainty, cell volume changes were presented relative to baseline values (which were calculated assuming the baseline volume was a square).

Volume and Contractility—Control Solution
During perfusion of control hypothermic (9°C) Tyr solution, cell volume remained stable for 15 minutes, and then increased versus baseline (Fig1). With reexposure to 37°C control Tyr solution, the cell volume remained stable for 5 minutes, and then significantly decreased (p < 0.05 versus baseline, Fig 1). During normothermic (37°C) perfusion of Tyr solution, myocyte volume remained unchanged throughout the experimental period (Fig 2).

View larger version (21K): [in this window] [in a new window]   Fig 1. Diazoxide (Dzx) eliminates myocyte swelling secondary to hypothermic hyperkalemic cardioplegia. After a 20-minute equilibration period in 37°C Tyrode's solution (Tyr), cells were exposed to 9°C test solution (n = 8 cells in each) for 20 minutes, followed by 20 minutes of reexposure to 37°C Tyrode's solution. In this and subsequent figures, cell volumes are presented relative to the baseline value obtained during the equilibration period. *p < 0.05 versus baseline volume. Filled symbols represent statistically significantly different points between groups as listed on the figure. (St. T = St. Thomas's solution.)

View larger version (17K): [in this window] [in a new window]   Fig 2. Normothermic diazoxide (Dzx) causes cell shrinkage. After a 20-minute equilibration period in 37°C Tyrode's solution (Tyr), cells were exposed to 37°C test solution for 20 minutes, followed by 20 minutes of reexposure to 37°C Tyrode's solution. *p < 0.05 versus baseline volume. Filled symbols represent statistically significantly different points between groups as listed on the figure. (St. T = St. Thomas's solution.)

View larger version (32K): [in this window] [in a new window]   Fig 3. Diazoxide (DZX) prevents reduced contractility secondary to hypothermic hyperkalemic cardioplegia. After a 20-minute equilibration period in 37°C Tyrode's solution, cells were exposed to 9°C test solution for 20 minutes, followed by 20 minutes of reexposure to 37°C Tyrode's solution. Contractility is represented as percentage shortening, velocity of shortening, and velocity of relengthening. Contractility measurements are represented as an average of values at 10 and 20 minutes after reexposure to Tyrode's solution and represented as percent change from baseline. *p < 0.05 versus Tyrode's solution, STT + DZX, and STT + DZX + 5-HD. (5HD = 5-hydroxydeconoate; STT = St. Thomas's solution.)

Volume After Exposure to Diazoxide Alone—Hypothermia
The addition of DZX to Tyr solution at 9°C resulted in myocyte swelling (versus baseline) by 35 minutes of exposure; however, this change was not significantly different from control (Fig 1). Upon reexposure to Tyr solution, the relative cell volume remained unchanged from baseline for 10 to 15 minutes, and then decreased below baseline (Fig 1).

Volume After St. Thomas' Solution—Normothermia
Cell volume remained stable during exposure to 37°C StT solution. However, on reexposure to 37°C Tyr solution, the cell volume significantly decreased and remained decreased thereafter (p < 0.0001 versus baseline, p < 0.005 versus Tyr; Fig 2).

Volume and Contractility After St. Thomas' Solution—Hypothermia
Exposure to 9°C StT solution resulted in rapid myocyte swelling. After 5 minutes of exposure, the cells swelled to a maximum of 6.7% ± 2.2% above baseline (p < 0.0005), and remained significantly enlarged versus control during the entire exposure (Figs 1, 4). On reexposure to 37°C control Tyr solution, cells immediately recovered to their baseline size (Figs 1, 4). The significant swelling noted after exposure to StT was associated with a significant decline in myocyte contractility (velocity of shortening and velocity of relengthening; p < 0.05 versus control; Fig 3).

View larger version (21K): [in this window] [in a new window]   Fig 4. Diazoxide (Dzx) eliminates myocyte swelling secondary to hypothermic hyperkalemic cardioplegia despite adenosine triphosphate–sensitive potassium channel blockers. After a 20-minute equilibration period in 37°C Tyrode's solution (Tyr), cells were exposed to 9°C test solution (n = 8 cells in each) for 20 minutes, followed by 20 minutes of reexposure to 37°C Tyrode's solution. *p < 0.05 versus baseline volume. Filled symbols represent statistically significantly different points between groups as listed on the figure. (5HD = 5-hydroxydeconoate; St. T = St. Thomas's solution.)

The addition of DZX (with or without 5-HD) to StT significantly improved myocyte contractility (p < 0.05 versus StT; Fig 3). Contractility in the StT + DZX groups (with or without 5-HD) was not different from control Tyr (Fig 3).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
These data demonstrate both significant myocyte swelling and associated reduced contractility after exposure to StT solution (9°C). These two associated findings have been demonstrated independently by other investigators. Significant myocyte swelling or edema has been demonstrated in animal models after exposure to standard hyperkalemic (16 mmol/L) cardioplegia solution under hypothermic conditions [1, 2, 4, 15] and in isolated human myocytes [3, 16]. In addition, reduced contractility has been demonstrated in myocytes after ischemia with exposure to hyperkalemic cardioplegia [5]. We propose that the two findings are related, as elimination of the swelling by the addition of a K_ATP channel opener also eliminates the reduced contractility.

Interestingly, myocytes also demonstrate a significant reduction in contractility after osmotic stress or ischemia, stresses that also result in myocyte swelling [1, 12, 17]. We have demonstrated that the myocyte swelling and reduced contractility secondary to mild hyposmotic stress is also eliminated by the addition of a K_ATP channel opener [12]. Elimination of swelling after exposure to hyperkalemic cardioplegia by the substitution of chloride with an impermeant anion also prevented the reduction in contractility secondary to hyperkalemic cardioplegia [8]. The significant reduction in contractility seen with osmotic stress or after exposure to hyperkalemic cardioplegia links myocyte swelling with a functional outcome, which may underlie one of the mechanisms of postoperative myocardial stunning. These data uniquely confirm the link between a structural change (myocyte swelling) and a resultant functional change (reduced contractility).

The observed myocyte volume changes are not caused by changes in solution osmolarity alone, as the addition of a K_ATP channel opener to hyperkalemic cardioplegia does not significantly alter the osmolarity of the solution (324 mOsm/L), which is similar to that of blood (330 mOsm/L). In addition, StT at 37°C (with identical osmolarity) does not cause myocyte swelling.

We initially hypothesized that DZX eliminated myocyte swelling (secondary to hyperkalemic cardioplegia) by means of the mechanism of opening the K_ATP channel. Two subtypes of K_ATP channels are thought to coexist in the myocardium (mitochondrial and sarcolemmal). The mitochondrial-specific K_ATP channel opener (DZX) was specifically used to evaluate the effect of opening the mitochondrial K_ATP channel on cellular volume changes caused by hyperkalemic cardioplegia. The dose of 100 µmol/L was chosen as it has been demonstrated to open mitochondrial K_ATP channels by other investigators [18]. In an attempt to eliminate any sarcolemmal K_ATP channel activity, a specific sarcolemmal K_ATP channel blocker (HMR1098) was used. In an attempt to eliminate any mitochondrial K_ATP channel activity, a specific mitochondrial K_ATP channel blocker (5-HD) was used. The addition of DZX + HMR1098 to StT solution completely inhibited myocyte swelling and reduced contractility (secondary to hyperkalemic cardioplegia). This would suggest that the mitochondrial K_ATP channel may be primarily active in this process. However, DZX has been demonstrated to open sarcolemmal K_ATP channels in the presence of adenosine diphosphate, and HMR1098 may not be entirely specific to the sarcolemmal channel. Moreover, significant controversy exists regarding the presence of a mitochondrial K_ATP channel [19, 20]. The addition of 5-HD to StT + DZX also completely inhibited myocyte swelling and reduced contractility (secondary to hyperkalemic cardioplegia). This would suggest a role for the sarcolemmal K_ATP channel in this process. These data cast further doubt on the specificity of channel openers and inhibitors, as the presence of "specific" blockers may not eliminate all channel activity. Alternatively, these data suggest that DZX may have some other unknown mechanism of action responsible for the findings that is independent of K_ATP channels. Other investigators have suggested that DZX may block succinate dehydrogenase or have some other effect on mitochondrial metabolism [21].

Normothermic StT solution was evaluated in this study to determine the role of temperature change on myocyte swelling. Although hypothermia alone does not result in significant myocyte swelling, some physiologic change in cell volume homeostasis occurs at hypothermic temperatures that permits myocyte swelling secondary to hyperkalemic cardioplegia, as this swelling was not seen in the normothermic group. This is likely related to the fact that active ion pumps are functional at normothermic temperatures, thereby maintaining volume homeostasis. It is important to note that whereas warm cardioplegia has been shown to provide superior myocardial protection in some clinical situations, the inclusion of this group may not be clinically relevant as StT solution is used clinically at hypothermic temperatures [22].

Contractility was not evaluated after normothermic test solutions. The only significant volume change noted during normothermia was the cell shrinkage associated with K_ATP channel openers (with or without StT). This volume change would likely be associated with improved contractility, as previous experiments involving osmotic stress demonstrated that cell shrinkage secondary to hyperosmotic stress was associated with improved myocyte contractility [12].

Significant cell shrinkage was observed during the reexposure to Tyr solution in all normothermic test solution groups (Fig 2). Similar cell shrinkage was noted in the hypothermic test solution groups on reexposure to warm Tyr solution (Figs 1, 4). The Na⁺-K⁺ pump may contribute to this cell shrinkage, as ouabain, an inhibitor of the Na⁺-K⁺ pump, has been demonstrated to abolish this phenomenon after perfusion with hypothermic hyperkalemic cardioplegia [1]. This observation may represent the overcompensation of a homeostatic protective mechanism that becomes reactivated when temperature-dependent ion channels resume activity, as this shrinkage was also noted to be significant in the control Tyr solution group. Further investigation is needed to elucidate the mechanisms responsible for this phenomenon, as this significant shrinkage may also affect contractility, and, thus, be potentially clinically relevant.

This study demonstrates significant myocyte swelling and reduced contractility after exposure to hypothermic hyperkalemic cardioplegia solution. The swelling and reduced contractility were eliminated by the addition of DZX. The K_ATP channel inhibitors, however, did not reverse these effects. These findings may be related to a yet undetermined mechanism and unrelated to the K_ATP channel. These cellular changes may be important in the understanding of myocardial stunning after cardiac surgery.

Study Limitations
Isolated myocytes are advantageous because they allow for repeated measurements of cell volume. This model is not intended to mimic the clinical situation of ischemia and reperfusion. This model was used to document volume and contractility changes caused by exposure to hyperkalemic cardioplegia alone in the absence of ischemia. This model allows for the independent evaluation of one stress at a time (hyperkalemic cardioplegia, ischemia, or osmotic stress) and a more careful evaluation of the effects of K_ATP channel openers. Caution must therefore be taken in applying the findings in this study to the whole organ or organism level because they do not reflect the complex milieu of the extracellular space and vascular, hormonal, and neural elements.

The solutions evaluated in this study were crystalloid solutions, which may result in myocyte swelling. Clinically used cardioplegia solutions include both blood-based and crystalloid solutions. Any baseline myocyte swelling in this study would be evident in the control Tyr physiologic solution group. Our comparison to control crystalloid solution and the representation of all data as a percentage of baseline should correct for any direct effect of the solutions themselves.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The authors acknowledge Aventis Pharma (Frankfurt, Germany) for the generous gift of HMR1098.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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