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Ann Thorac Surg 2006;81:148-153
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Role of the Sarcolemmal Adenosine Triphosphate–Sensitive Potassium Channel in Hyperkalemic Cardioplegia-Induced Myocyte Swelling and Reduced Contractility

Sandip M. Prasad, MD a , Ashraf S. Al-Dadah, MD a , Gregory D. Byrd, BS a , Thomas P. Flagg, PhD b , Jefferson Gomes b , Ralph J. Damiano, Jr, MD a , Colin G. Nichols, PhD b , Jennifer S. Lawton, MD a , *

a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
b Department of Cell Biology and Physiology, 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 (Email: lawtonj{at}msnotes.wustl.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Notice From the American...
 Acknowledgments
 References
 
BACKGROUND: Hyperkalemic cardioplegia (Plegisol) has been shown to result in myocyte swelling and reduced contractility. We have demonstrated the elimination of these detrimental effects by the addition of an adenosine triphosphate–sensitive K+ (KATP) channel opener. To examine whether the mitochondrial or sarcolemmal KATP channel might be involved, volume and contractility in isolated myocytes from wild-type mice and mice lacking the sarcolemmal KATP channel (Kir6.2–/–) were evaluated.

METHODS: Myocytes were perfused for 20 minutes each with control 37°C Tyrode's solution, test solution, and then control solution. Test solutions were (n = 10 per group) either 9°C Plegisol or 9°C Plegisol with 100 µmol/L of diazoxide, a putative mitochondrial-specific KATP channel opener. Cell volume and contractility were measured by digital video microscopy at baseline and during the test solution and reexposure periods.

RESULTS: Myocytes from wild-type mice, perfused with 9°C Plegisol, demonstrated significant cell swelling (11.2% ± 0.4%; p < 0.01) and diminished contractility (32.5% ± 9.6% reduction in percent shortening, 47.2% ± 10.1% reduction in peak velocity of shortening, and 52.0% ± 8.8% reduction in peak velocity of relengthening; p < 0.05) versus baseline. Cell swelling and diminished contractility were significantly reduced by the addition of diazoxide. In Kir6.2–/– myocytes, Plegisol caused a greatly reduced level of cell swelling (3.2% ± 0.1%; p < 0.01), and this was unaffected by diazoxide. Contractility was unchanged in Kir6.2–/– myocytes after Plegisol.

CONCLUSIONS: The sarcolemmal KATP channel appears necessary for exaggerated cell swelling and reduced contractility to occur after hyperkalemic cardioplegia in mouse myocytes.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Notice From the American...
 Acknowledgments
 References
 
The use of standard hyperkalemic cardioplegia solutions has been associated with significant postoperative left ventricular systolic dysfunction, reduced diastolic compliance, loss of coronary artery compliance, arrhythmogenesis, and ischemia–reexposure injury [1–4]. Studies using isolated animal and human myocytes have shown that the administration of hyperkalemic cardioplegic solutions is associated with significant myocyte swelling [5, 6]. Additionally, experiments at the cellular and whole-organ level have demonstrated that these solutions cause a reduction in contractile function [7, 8]. Our laboratory has demonstrated an association between myocyte swelling and reduced contractility, thus linking a structural change (myocyte swelling) with a decline in function (stunning). We propose that postoperative myocardial stunning may be partly related to detrimental myocyte swelling secondary to hyperkalemic cardioplegia solutions.

We have demonstrated that myocyte swelling and associated reduced contractility (due to hyperkalemic cardioplegia or to mild osmotic stress in rabbit myocytes) may be eliminated by the addition of an adenosine triphosphate–sensitive potassium (KATP) channel opener [9, 10]. This led to the hypothesis that the KATP channel may play some role in myocyte volume regulation. This hypothesis is quite intriguing because cardiac KATP channels are known to provide endogenous protection by means of their unique property of coupling cell membrane potential to myocardial metabolism; however, the exact mechanism of their cardioprotection is unknown [11]. Adenosine triphosphate is known to inhibit KATP channel opening under nonischemic conditions; however, the enhanced metabolic demand during ischemia results in ATP hydrolysis and the accumulation of nucleotide diphosphates, which result in KATP channel opening [12]. Adenosine triphosphate–sensitive potassium channels have the highest density of all channels in the heart (approximately 2,000 to 3,000 per cell) [13]. Two KATP subtypes are proposed to be present in the myocardium, one located in the sarcolemma (sKATP) and the other in the inner mitochondrial membrane (mKATP). Sarcolemmal KATP channels are hetero-octamers formed by four pore-forming polypeptides of the inwardly-rectifying K+ channel family Kir6.x and four sulfonylurea receptor subunits of the superfamily of ATP-binding cassette transporters [14]. The sulfonylurea receptor subunit confers high-affinity block by sulfonylureas and stimulation by potassium channel openers and adenosine diphosphate, whereas ATP inhibits channel activity through interaction with the Kir6.x subunit [15, 16]. The sKATP channel in the heart is characterized as sulfonylurea receptor 2A and Kir6.2 [17]. The mKATP is less well characterized, but there is evidence that neither Kir6.1 nor Kir6.2 is present in this channel; and a recent report suggests that it contains five distinct mitochondrial proteins [18, 19].

Previously, we and other investigators have used pharmacologic manipulation of the mKATP channel with diazoxide and 5-hydroxydecanoate, a putative mKATP-specific channel opener and blocker, respectively, to support that the mKATP channel is primarily responsible for observed results. However, investigators have questioned the mechanism and location of action of so-called specific KATP channel openers and inhibitors [20, 21]. Advances in the molecular and genetic understanding of the structure and function of KATP channels now allow for improved models of assessing the specific role of these channels. Specifically, inactivation or deletion of the Kir6.2 subunit of the KATP channel would selectively eliminate the sarcolemmal channel, but would be expected to have no effect on the mitochondrial channel. Kir6.2 knockout mice (Kir 6.2–/–) therefore provide a useful tool to assess the specific activity of the sarcolemmal KATP channels without pharmacologic manipulation and avoid the uncertainty surrounding the specificity of potassium channel opener action.

To clarify the role of the sKATP in volume change secondary to hyperkalemic cardioplegia, the present study evaluated the effects of diazoxide on cell volume and contractility in isolated myocytes from wild-type (WT) and Kir6.2–/– (KO, lacking all sKATP channels) mice. Localization of the relevant KATP channel will offer further insight into the mechanism of action of the KATP channel.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Notice From the American...
 Acknowledgments
 References
 
All procedures complied with the standards for the care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85–23, revised 1996).

Cardiomyocyte Isolation
The solutions used in myocyte isolation included Solution A, Solution B, and Solution C (concentrations are in mmol/L, except as noted). Solution A consisted of NaCl, 116; KCl, 5.36; Na2HPO4, 0.97; KH2PO4, 1.47; HEPES (N-[2-hydroxyethyl]piperazine-N'-[4-butanesulfonic acid]), 21.10; glucose, 11.65; phenol red, 26.50 µmol/L (Sigma Chemical Co; St. Louis, MO); MgCl2, 3.72; NaHCO3, 4.40; essential vitamins (100x, 10 mL, GIBCO, Grand Island, NY); and amino acids (50x, 20 mL, GIBCO, Grand Island, NY). Solution B consisted of solution A plus CaCl2, 100 µmol/L; collagenase (Type 2, Worthington Biochemical Corporation; Freehold, NJ), 1.2 mg/mL; and protease (Type XIV, Sigma), 0.1 mg/mL. Solution C consisted of solution A plus bovine serum albumin (Sigma), 5 mg/mL; taurine, 1.25 mg/mL; and CaCl2, 100 µmol/L.

Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide [DZX]; Sigma) is reportedly 2,000-fold more selective for cardiac mKATP channels than for sKATP channels, opening the mitochondrial channel at low concentrations (K 1/2 = 0.4 µmol) and the sarcolemmal channel at high concentrations (K 1/2 = 855 µmol) [22]. (K 1/2 is the concentration at which 50% of the maximal effect on mKATP is observed.) A dose of 100 µmol/L was effective in ameliorating cell swelling secondary to hyperkalemic cardioplegia in preliminary studies and has been used by other investigators [9, 23]. A stock solution of DZX was made by dissolving the reagent in 0.1% dimethyl sulfoxide. Dimethyl sulfoxide has no effect on cell volume [5].

Ventricular myocytes were isolated from adult (male or female) mice (either sex, 6 weeks to 5 months, 25 to 30 g body weight) using standard procedures. The heart was excised from an anesthetized (xylazine 14.0 mg/kg, acepromazine 1.3 mg/kg, ketamine 83.0 mg/kg intramuscularly) mouse (WT or KO), and the aorta was cannulated using a 28-gauge needle. The heart was attached to a Langendorff apparatus, and solution A was perfused through the aorta for 5 minutes. The heart was then perfused at 37°C for 12 minutes with solution B. The left ventricle was removed and transferred into solution C, where it was gently dispersed by glass pipette at room temperature. The cells were allowed to centrifuge by gravity, and serial washings were performed every 10 minutes for a 30-minute period. Cells were used in experiments within 5 hours after isolation. Average yield of viable myocytes was 65% to 75% per mouse. A total of 24 mice were used.

Knockout Kir6.2–/– mice were generated by disruption of the Kir6.2 gene [24]. The absence of expression of the Kir6.2 transcript has been previously confirmed by reverse-transcription polymerase chain reaction and whole-cell membrane currents in the KO mice used [24].

Imaging
An aliquot of isolated myocytes was placed on a slide on a glass-bottomed chamber on 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 37°C control Tyrode's solution (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). Cell images were displayed on a video monitor using a charge-coupled device camera (KPM1U; Hitachi Denshi, Tokyo, Japan). Cells were assessed for viability using the following criteria: normal rod shape, smooth edges, sharp borders and clear striations, absence of vacuoles or blebbing, and lack of spontaneous beating [5]. Digital images of cells were captured at a rate of 120 frames per second using a video-frame grabber (Scion Corporation, Frederick, MD) and were manually traced using Scion Image software (Scion Corporation). Length, width, and area were measured and recorded.

To calculate cell volume, it was assumed that changes in cell width and thickness were proportional. Relative cell volume change was determined by the following formula [5]:


{148.0501163X.si1}

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 with an error of less than 1% [5].

Contraction Analysis
Cells were stimulated using a field stimulator (IonOptix, Milton, MA) with alternating bipolar 15-V pulses, 5 milliseconds in duration at a rate of 1 Hz. Contraction data for each myocyte were recorded for a minimum of 30 consecutive contractions and averaged. Variables were computed using digitized contraction profiles generated by IonWizard edge-detection software (IonOptix). These included percentage shortening, peak velocity of shortening, and peak velocity of relengthening. Myocyte shortening was calculated as the percent difference between maximum and minimum cell length for each contraction. Peak velocity computations were generated by calculating the maximal derivative of the downward and the upward portions of the digitized contraction curve to determine shortening and relengthening, respectively. The peak velocities were normalized to myocyte length by dividing the peak velocity of shortening and relengthening by the resting myocyte length measured just before contraction.

Experimental Protocol
Myocytes from WT and KO mice were perfused with control 37°C Tyrode's solution for 20 minutes to obtain baseline measurements. Any baseline changes in cell volume secondary to the isolation or imaging protocol would be evident during this period. Cells (n = 10 myocytes in each test group, up to two myocytes per each mouse used) were then perfused for 20 minutes with 9°C test solution followed by a 20-minute reexposure period to 37°C control Tyrode's solution. Test solutions were administered at 9°C to mimic the intraoperative myocardial temperature during cardioplegic arrest. Myocytes were not subjected to ischemia or modified ischemia in this protocol to delineate changes caused by the stress of exposure to cardioplegia alone. Two test solutions were used for the WT and KO cells (n = 10 per group): 9°C cardioplegia and 9°C cardioplegia with 100 µmol/L of diazoxide, a purported mKATP-specific channel opener. Plegisol cardioplegic solution (Abbott Laboratories, North Chicago, IL; osmolarity, 299 mOsm) was used as the cardioplegic solution in this study and contains (in mmol/L) NaCl, 110; KCl, 16; MgCl2, 16; and CaCl2, 1.2, equilibrated with 95% O2–5% CO2 and titrated to pH 7.4 with 10% NaHCO3 solution. The solution osmolarity was not significantly changed by the addition of DZX (298 ± 5 mOsm).

Volume measurements were made at 2 minutes after the start of a new solution and every 5 minutes thereafter during the baseline, test solution, and reexposure periods. Contractility measurements were taken at the end of the baseline period and at 10 and 20 minutes after the start of the reexposure period.

Statistical Analysis
All data are presented as mean value ± 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 test groups were made separately during the test solution and reexposure periods. Probability values less than 0.05 were considered significant. Statistical analysis was performed using SyStat 10.2 (SyStat Corporation, Point Richmond, CA).


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Notice From the American...
 Acknowledgments
 References
 
Myocyte Volume
The mean area of myocytes (n = 40) at baseline was 1,170 ± 108 µm2, with no statistical difference between test groups. Assuming that the cross-sectional configuration of the myocytes was a square, the mean volume of a single myocyte at baseline would overestimate cell volume by a factor of 4/{pi}, or 1.27, if cells were actually cylindrical [25]. To avoid this uncertainty, cell volume changes are presented relative to baseline values (which were calculated assuming the baseline volume was a square) taken during perfusion with 37°C control Tyrode's solution.

Perfusion with 9°C Plegisol resulted in significant swelling in both WT and KO myocytes, but swelling was significantly greater in WT than KO myocytes (11.2% ± 0.4% versus 3.2% ± 0.1%; p < 0.01; Fig 1, n = 10 cells per group). In WT myocytes, the addition of DZX to Plegisol resulted in a significant amelioration of cell swelling (11.2% ± 0.4% versus 2.8% ± 0.1%; p < 0.01), but there was no effect in the KO group (3.2% ± 0.1% versus 2.3% ± 0.2%; p = 0.17; Fig 1, n = 10 cells per group).



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  		Fig 1. Mean percent change from baseline myocyte volume in wild-type and Kir6.2–/– mice (n = 10 per group). Myocytes were exposed to control Tyrode's physiologic solution (time 0 to 20 minutes), test solution (time 20 to 40 minutes), and reexposure (40 to 60 minutes). Values are represented as mean ± standard error of the mean. *p < 0.05 versus baseline. (DZX = diazoxide; KO = knockout; Pleg = Plegisol; WT = wild-type.)

 
After Plegisol and reexposure to 37°C control Tyrode's solution, cell volume was significantly decreased versus baseline in KO myocytes (–2.5% ± 0.2%; p < 0.01 versus baseline) but not in the WT group (1.4% ± 0.2%; p = 0.28). After Plegisol plus DZX and reexposure to control Tyrode's solution, WT and KO myocytes demonstrated a significant decrease in cell volume versus baseline (5.3% ± 0.1% and 4.4% ± 0.3%, respectively; p < 0.01 versus baseline for both).

In all groups, a statistically significant reduction in cell volume was observed between the test solution period and the reexposure period (p < 0.01, Fig 1).

Myocyte Contractility
Myocyte contractile function at 10 and 20 minutes after reexposure to Tyrode's for the WT and KO groups is summarized in Figure 2. The percentage shortening, peak velocity of shortening, and peak velocity of relengthening were significantly diminished in WT myocytes exposed to 9°C Plegisol at 10 and 20 minutes. The addition of diazoxide to this group ameliorated the changes in contractility at both 10 and 20 minutes, and all three variables were not significantly different from baseline.



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  		Fig 2. Contractility measurements at 10 minutes (left) and 20 minutes (right) after reexposure to Tyrode's physiologic solution. Values are represented as mean ± standard error of the mean. *p < 0.01 versus baseline. (DZX = diazoxide.)

 
In KO myocytes, the administration of Plegisol with and without DZX did not result in any statistical change in contractile function in any of the three variables measured after 10 and 20 minutes of reexposure to Tyrode's solution (Fig 2).


   Comment
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 Introduction
 Material and Methods
 Results
 Comment
Notice From the American...
 Acknowledgments
 References
 
Exposure to hypothermic hyperkalemic cardioplegia results in myocyte swelling in both human and animal myocytes, and there is long-standing evidence that the administration of hypothermic, hyperkalemic cardioplegia results in a reduction in isolated myocyte contractile function [5–7, 26]. Previous work from our laboratory has implicated cell swelling as a potential cause of postoperative myocardial stunning, and the present study strongly supports this etiologic link [27]. The consistent relationship between myocyte swelling and reduced contractility led us to hypothesize that cell swelling, secondary to hyperkalemic cardioplegia, may be responsible for myocardial dysfunction observed after cardiac surgery.

We have previously demonstrated that a KATP channel opener ameliorates myocyte swelling secondary to hyperkalemic cardioplegia [9]. The present study was performed to attempt to delineate the specific location of the KATP channel responsible for this effect. In this study, WT mice demonstrated significant myocyte swelling and reduced contractility, which was ameliorated by the KATP channel opener DZX. Interestingly, we found that WT mice lacking the sarcolemmal KATP channel (Kir6.2–/–) did not swell or exhibit reduced contractility after exposure to hyperkalemic cardioplegia. These results further strengthen the hypothesis of a direct mechanistic link between cell swelling and loss of contractility.

The initial expectation of the present study was that DZX may be acting on the mitochondrial KATP channel to block cell swelling, and that the sarcolemmal KATP channel would have less of a role. It is thus surprising that when the sKATP is absent, cell swelling is almost completely abolished. These results parallel the initially unexpected findings that preconditioning is abolished in sKATP KO animals and raises related questions regarding the mechanistic involvement [28]. As discussed above, DZX is at least more potent in its action on the mKATP channel than the sKATP channel, and so the abolition of Plegisol-induced swelling in myocytes from both rabbit and WT mouse could be taken to implicate mKATP in the process [9, 22]. However, this study demonstrates that the sKATP appears to be essential for significant cell swelling to occur, as its genetic deletion results in no findings of significant cell swelling and reduced contractility. We can hypothesize that the initial swelling involves ion fluxes through the sKATP channel, which can provide an extremely high-conductance sarcolemmal ion pathway [29]. Diazoxide amelioration may involve the secondary activation of mKATP channels (which may increase resistance to swelling); however, this has not been confirmed. Alternative hypotheses could include the presence of a yet undetermined ion channel with a Kir6.2 subunit or the possibility of another ion current by means of the KATP channel. Future experiments to more precisely pharmacologically or genetically separate mKATP and its role in myocyte volume homeostasis will clearly be required.

Significant myocyte shrinkage was observed during the reexposure to Tyrode's physiologic solution in all test groups except the WT Plegisol group (Fig 1). This finding is consistent with other work using rabbit ventricular myocytes, and may be a result of the dysfunctional reactivation or "overshoot" of temperature-dependent ion channels [5]. With the change in temperature from 9°C to 37°C, ion channels that provide homeostatic protection against cell swelling in normothermic conditions become reactivated and may overcompensate to correct cell volume, yielding the cell shrinkage observed in this study. Further investigation is warranted given the potential clinically relevant effects of cell shrinkage. A potential culprit may be the Na+-K+ pump, as ouabain (an inhibitor of the Na+-K+ pump) has been shown to eliminate the cell shrinkage observed after the administration of hypothermic, hyperkalemic cardioplegia [5].

A molecular tool (Kir6.2–/– mice), rather than pharmacologic manipulation, was used to determine the role of the sKATP channel in hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility. These results implicate the sKATP channel in myocyte swelling and reduced contractility secondary to hyperkalemic cardioplegia. Diazoxide may play some role by means of the mKATP channel or through some other mechanism. Clarification of the role of the KATP channel in myocyte volume regulation could potentially lead to improved cardioplegia solutions and to its pharmacologic exploitation during any form of myocardial ischemia.

Study Limitations
Isolated myocytes were used because they allow for repeated measurements of cell volume and function in the absence of ischemia. This model is not intended to mimic the clinical situation of ischemia and reperfusion. 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 complexity of the extracellular space and vascular, hormonal, and neural elements.

Clinically used cardioplegia solutions include both blood-based and crystalloid solutions. Crystalloid solutions were used for this study to be consistent with previous work using rabbit myocytes [9]. Crystalloid solutions may independently result in myocyte swelling. Any baseline myocyte swelling in this study would be evident in the control Tyrode's 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.


   Notice From the American Board of Thoracic Surgery
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 Material and Methods
 Results
 Comment
 Notice From the American...
Acknowledgments
 References
 
The 2006 Part I (written) examination will be held on Monday, December 4, 2006. It is planned that the examination will be given at multiple sites throughout the United States using an electronic format. The closing date for registration is August 1, 2006. Those wishing to be considered for examination must apply online at http://www.abts.org.

To be admissible to the Part II (oral) examination, a candidate must have successfully completed the Part I (written) examination. A candidate applying for admission to the certifying examination must fulfill all the requirements of the Board in force at the time the application is received.

Please address all communications to the American Board of Thoracic Surgery, 6333 N St. Clair St, Suite 2320, Chicago, IL 60611; telephone: (312) 202-5900; fax: (312) 202-5960; e-mail: mailto:info{at}abts.org.


   Acknowledgments
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Notice From the American...
 Acknowledgments
References
 
This work was supported in part from a Medical Student Research Fellowship from the Howard Hughes Medical Institute (SMP). We gratefully acknowledge the gift of Kir6.2 knockout mice from Susumu Seino, MD, DM Sci, of the Graduate School of Medicine, Chiba, Japan.


   References
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Notice From the American...
 Acknowledgments
 References
 

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A. S. Al-Dadah, R. K. Voeller, R. B. Schuessler, R. J. Damiano Jr, and J. S. Lawton
Maintenance of Myocyte Volume Homeostasis During Stress by Diazoxide is Cardioprotective
Ann. Thorac. Surg., September 1, 2007; 84(3): 857 - 862.
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