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Ann Thorac Surg 2004;78:970-975
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Pinacidil improves contractile function and intracellular calcium handling in isolated cardiac myocytes exposed to simulated cardioplegic arrest

Ru Lin, MD, PhDa,*, Ze-Wei Zhang, MDa, Qi-Xing Xiong, MDa, Chun-Mei Cao, PhDb, Qiang Shu, MDa, Iain C. Bruce, PhDc, Qiang Xia, PhDb

a Department of Cardiothoracic Surgery, Children's Hospital, Zhejiang University, Hangzhou, China
b Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
c Department of Physiology, The University of Hong Kong, Hong Kong, China

Accepted for publication March 30, 2004.

* Address reprint requests to Dr Lin, Department of Cardiothoracic Surgery, Children's Hospital, Zhejiang University, 57 Zhu Gan Xiang, Hangzhou 310003, China
linru.008{at}163.com


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: We examined the effects of pinacidil on contractile function and intracellular calcium in isolated rat cardiomyocytes exposed to cardioplegic solution.

METHODS: Rat myocytes were incubated at 24°C for 2 hours in cardioplegic solution with or without pinacidil (50 µmol/L), then they were perfused with Krebs-Henseleit solution with a gas phase of 95% O2/5% CO2 at the same temperature. Contraction and intracellular calcium transients were then measured by video tracking and spectrofluorometry.

RESULTS: During 20 minutes of perfusion after 2 hours in cardioplegic solution with pinacidil, (1) the recovery of contractile function was significantly increased in terms of both amplitude of contraction (98.30% ± 9.90% versus 81.00% ± 11.25%; p < 0.05) and peak velocity of cell shortening (100.90% ± 13.79% versus 76.89% ± 18.14%; p < 0.01) when compared with myocytes in cardioplegic solution without pinacidil; (2) the amplitudes of the intracellular calcium transients evoked by electrical stimulation and caffeine (10 mmol/L) increased by 23.31% to approximately 40.72% and 61.73%, respectively, compared with those in cardioplegic solution without pinacidil; and (3) the decay time of the caffeine-induced intracellular calcium transient decreased by 36.64% ± 15.10% relative to that measured in cardioplegic solution without pinacidil. The effects induced by supplementing the cardioplegic solution with pinacidil were diminished in the presence of glibenclamide (10 µmol/L).

CONCLUSIONS: Addition of the adenosine triphosphate–sensitive potassium-channel opener, pinacidil, to a high potassium cardioplegic solution improves recovery of contractile properties and cytosolic calcium in isolated rat cardiac myocytes.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Cardioplegic arrest during cardiac surgery has traditionally been accomplished through administration of a hyperkalemic cardioplegic solution [1]. However, left ventricular dysfunction has been shown to occur after hyperkalemic cardioplegic arrest [2], and this may involve alterations in ionic homeostasis [3]. Adenosine triphosphate (ATP)–sensitive potassium (KATP) channels open in response to reduction in intracellular ATP or ischemia [4–8]. Activation of KATP channels before hypothermic, hyperkalemic cardioplegic arrest or hyperpolarized cardioplegic arrest improves functional recovery of the myocardium [9–12]. Our previous study demonstrated that cardioplegia with pinacidil improves preservation of myocardial ultrastructure [13]. Cardioplegic arrest with simultaneous activation of KATP channels preserves myocyte contractile processes and attenuates the accumulation of intracellular calcium ([Ca2+]i) [14]. However, the role of intracellular cation homeostasis in KATP channel–induced cardioprotection is poorly understood. The isolated myocyte model of simulated cardioplegic arrest is useful in determining mechanisms responsible for contractile dysfunction with reperfusion as well as potential strategies to prevent these effects. The objectives of the present study therefore were to examine the effects of cardioplegic arrest with or without pinacidil on myocyte contractile function and on [Ca2+]i during perfusion after exposure to cardioplegia.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Preparation of isolated ventricular myocytes
All procedures used in this study were approved by the Zhejiang University Ethics Committee for the Use of Experimental Animals. Single ventricular myocytes were isolated from the hearts of male Sprague-Dawley rats (weighing 242.52 ± 9.82 g) by enzymatic dissociation [15]. Immediately after decapitation, the heart was rapidly removed and rinsed in ice-cold, calcium-free Tyrode's solution containing (in mmol/L): NaCl, 100; KCl, 10; KH2PO4, 1.2; MgSO4, 5; taurine, 20; glucose, 20; and MOPS, 10, pH 7.2 with KOH. The heart was perfused by means of a Langendorff apparatus with a 100% oxygenated, nonrecirculating, calcium-free Tyrode's solution. Then the perfusion solution was switched to a 100% oxygenated, recirculated, low calcium (50 µmol/L) Tyrode's solution containing 0.03% collagenase and 1% bovine serum albumin for 10 minutes. The left ventricles were cut, minced, and gently triturated with a pipette in the low-calcium Tyrode's solution containing bovine serum albumin at 37°C for 10 minutes. The cells were filtered through 200-µm nylon mesh and resuspended in the Tyrode's solution, and the calcium concentration was gradually increased to 1.25 mmol/L during more than 40 minutes. A 2-mL aliquot of the isolated myocyte suspension was plated onto coverslips stabilized at 24°C in oxygenated media for approximately 1 to 2 hours. The yield of viable myocytes was more than 80%. Only rod-shaped cells with clear cross-striations were used for experiments. After stabilization, myocytes were assigned randomly to one of four treatment protocols to mimic cardioplegic arrest: (1) control (n = 8), incubation at 24°C for 2 hours in Ringer's lactate solution (in mmol/L): NaCl, 102; KCl, 4; CaCl2, 1.5; sodium lactate, 28; pH 7.4; (2) cardioplegic solution only (n =9), incubation at 24°C for 2 hours in Ringer's lactate solution containing 20 mmol/L potassium; (3) cardioplegic solution + pinacidil (n = 10), incubation at 24°C for 2 hours in Ringer's lactate solution containing 20 mmol/L potassium and 50 µmol/L pinacidil; and (4) cardioplegic solution + pinacidil + glibenclamide (n = 8), incubation at 24°C for 2 hours in Ringer's lactate solution containing 20 mmol/L potassium, 50 µmol/L pinacidil, and 10 µmol/L glibenclamide. After each of these incubation protocols, myocytes were added to the bottom of a glass chamber; after approximately 1 to 2 minutes, the cells automatically attached to the glass, and were then superfused at 2 mL/min by Krebs-Henseleit (K-H) buffer (in mmol/L: NaCl, 118.5; NaHCO3, 25; KCl, 4.75; MgSO4, 1.2; KH2PO4, 1.2; CaCl2, 2.5; glucose, 11.0; pH 7.4) containing 1% bovine serum albumin and with a gas phase of 95% O2/5% CO2 at the same temperature. Contractile functions, [Ca2+]i transients, and sarcoplasmic reticulum (SR) calcium release were then determined.

The concentration of pinacidil selected (50 µmol/L) was determined on the basis of previous studies documenting improved cardioprotection after global ischemia in isolated heart preparations [13]. The concentration of glibenclamide selected (10 µmol/L) has been demonstrated to block the protective effects of pinacidil on global ischemia [13].

Measurement of myocyte contraction
Myocyte contraction was elicited by electrical field stimulation at a frequency of 0.5 Hz, and at an intensity twice the contraction threshold. After myocytes had been perfused with K-H buffer for 3 minutes to wash out the cardioplegic solution, the contraction variables were measured as baseline (0 minutes). Myocytes were then continuously perfused for 20 minutes. A video-tracking system was used to measure the amplitude of contraction, the end-diastolic length, the peak velocity of cell shortening, and the peak velocity of cell relengthening of single myocytes [15].

Intracellular calcium recording
Intracellular calcium transients were recorded by a spectrofluorometric method using the calcium-sensitive dye fura-2 as a calcium indicator. The isolated myocytes were incubated with 1 µmol/L fura-2/AM at 24°C for 30 minutes. Then the loaded cells were washed three times with fresh K-H buffer solution containing 1% bovine serum albumin. After 2 hours of simulated cardioplegic arrest, a small aliquot of fura-2-loaded cells was placed on the bottom of a glass chamber and perfused with K-H solution (95% O2/5% CO2 at 24°C). After washout for 3 minutes, the [Ca2+]i transients were recorded to provide a baseline value (0 minutes), after which recordings were made every 5 minutes for 20 minutes. Fluorescence was measured on an Olympus inverted microscope equipped with a fluorometer system (T.I.L.L. Photonics GmbH, Gräfelfing, Germany). The calcium-dependent fura-2 signal was obtained by illuminating the sample at 340 and 380 nm and recording the light emitted at 510 nm. The background fluorescence was automatically subtracted. As in previous studies from our laboratories, we calculated the fluorescence ratio, which is believed to accurately represent the [Ca2+]i. The [Ca2+]i transient was induced by suprathreshold stimuli at 0.5 Hz delivered by a stimulator through two platinum field-stimulation electrodes in the bathing fluid [15].

In another series of experiments to determine calcium release from the SR, the field-stimulation was discontinued, and caffeine (10 mmol/L) was applied to the cell 15 seconds later. The peak amplitude of the caffeine-induced [Ca2+]i transient was measured to evaluate SR calcium release. Because application of caffeine prevents reuptake of calcium into the SR, the decay time of the caffeine-induced [Ca2+]i transient provides information about calcium extrusion by the sodium-calcium exchanger [16]. This decay time was defined as extending from the peak of the [Ca2+]i transient to the point at which its amplitude had declined by 95%. The calculations were made using pClamp software (Axon Instrument, Inc, Union City, CA).

Chemicals
Pinacidil, glibenclamide, collagenase (type I), and fura-2/AM were purchased from Sigma Chemical Company (St. Louis, MO). Pinacidil and glibenclamide were dissolved in dimethyl sulfoxide before addition to solutions. The final concentration of dimethyl sulfoxide was less than 0.1%.

Statistical analysis
Data were expressed as the percentage change (mean ± standard deviation) in contraction and [Ca2+]i transient. In Table 1, we used two-way analysis of variance with post hoc Bonferroni test in analysis of time course effect of perfusion time, and used one-way analysis of variance with post hoc Newman-Keuls test to compare two groups. The [Ca2+]i transient data were analyzed by one-way analysis of variance with post hoc Bonferroni test. The data from the caffeine experiments were expressed as medians and percentiles and examined with the Mann-Whitney U test. Values of p less than 0.05 were considered significant.


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  		Table 1. Recovery of Myocyte Contractile Function After Simulated Cardioplegic Arrest

 

   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Recovery of contractile function
During perfusion after 2 hours of simulated cardioplegic arrest, the steady-state contractile functions of myocytes from each solution were measured (Table 1). The control group showed the least recovery of contractile variables. A significant recovery in amplitude of contraction and peak velocity of cell shortening was observed in myocytes exposed to pinacidil compared with those in cardioplegic solution alone. The contractile variables of myocytes exposed to pinacidil and glibenclamide were similar to those in cardioplegic solution alone.

Recovery of intracellular calcium transient
The control group showed the least recovery of the [Ca2+]i transient evoked by electrical stimulation during perfusion (Fig 1). The [Ca2+]i transient after simulated cardioplegic arrest was also decreased significantly in myocytes exposed to cardioplegic solution alone. In contrast, incubation with pinacidil significantly attenuated the drop in peak [Ca2+]i amplitude, which was approximately 23.31% to 40.72% greater than that in myocytes from cardioplegic solution alone. In the presence of glibenclamide, the amplitude of the [Ca2+]i transient was reduced almost to control levels.



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  		Fig 1. Recovery of intracellular calcium ([Ca2+]i) transient in isolated rat cardiomyocytes during perfusion with Krebs-Henseleit solution (95% O2/5% CO2 at 24°C) after cardioplegic arrest for 2 hours. Data are expressed as mean ± standard deviation. *p < 0.05; **p < 0.01 versus control (n = 8); ##p < 0.01 versus cardioplegic solution only (CP; n = 8); {Delta}{Delta}p < 0.01 versus cardioplegic solution + pinacidil (CP+P; n = 12). (CP+P+G = cardioplegic solution + pinacidil + glibenclamide [n = 12].)

 
Sarcoplasmic reticulum calcium release
To determine whether the lower steady-state twitch amplitude (Table 1) observed in the myocytes exposed to cardioplegic solution alone was attributable to reduced fractional SR calcium release, a series of experiments was performed by exposing fura-2-loaded cells to caffeine (Fig 2). The amplitude of the [Ca2+]i transient evoked by caffeine in myocytes exposed to cardioplegic solution and pinacidil was significantly elevated compared with that seen with cardioplegic solution alone and with cardioplegic solution plus pinacidil and glibenclamide (Fig 3).



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  		Fig 2. Representative traces of calcium transients elicited by field stimulation and rapid application of caffeine. (CP = cardioplegic solution only; CP+P = cardioplegic solution + pinacidil; CP+P+G = cardioplegic solution + pinacidil + glibenclamide.)

 


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  		Fig 3. Box plot of the amplitude of the intracellular calcium ([Ca2+]i) transient evoked by the rapid application of caffeine (10 mmol/L). **p < 0.01 versus control (n = 8); ##p < 0.01 versus cardioplegic solution only (CP; n = 8); {Delta}p < 0.05 versus cardioplegic solution + pinacidil (CP+P; n = 9). (CP = cardioplegic solution only; CP+P = cardioplegic solution + pinacidil; CP+P+G = cardioplegic solution + pinacidil + glibenclamide [n = 8].)

 
To determine the role of the sodium-calcium exchanger in the effect of pinacidil on the [Ca2+]i transient induced by caffeine, we measured the duration of the decay of the transient. The ratio of the decay time after exposure to caffeine to that after electrical field stimulation was reduced in myocytes incubated with pinacidil, and was significantly smaller than the decay times from myocytes exposed to cardioplegic solution alone and with pinacidil and glibenclamide (Fig 4).



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  		Fig 4. Box plot of the ratio between the intracellular calcium ([Ca2+]i) transient's decay time in response to caffeine and that induced by electrical stimulation. *p < 0.05; **p < 0.01 versus control (n = 9); #p < 0.05; ##p < 0.01 versus cardioplegic solution only (CP; n = 8); {Delta}{Delta}p < 0.01 versus cardioplegic solution + pinacidil (CP+P; n = 8). (CP = cardioplegic solution only; CP+P = cardioplegic solution + pinacidil; CP+P+G = cardioplegic solution + pinacidil + glibenclamide [n = 8].)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The most significant findings of the present study were that (1) pinacidil supplementation resulted in a significant increase in recovery of contractile function and [Ca2+]i transients under conditions comparable to those occurring during hyperkalemic cardioplegic arrest; and (2) pinacidil supplementation preserved SR calcium release triggered by caffeine and enhanced extrusion of calcium by the sarcolemmal sodium-calcium exchanger to better maintain [Ca2+]i homeostasis.

Although hyperkalemic cardioplegia is effective in cardiac protection, many studies have provided evidence of impaired myocardial function after exposure to this solution. A significant reduction in myocyte contractile function and increased [Ca2+]i occurs after hyperkalemic cardioplegic arrest [14]. The prolonged extracellular hyperkalemia associated with traditional cardioplegia causes membrane depolarization and subsequently increases in [Ca2+]i by several mechanisms, including potentiation of calcium influx through the opening of voltage-dependent calcium channels, which subsequently induces additional release of calcium from the SR [17–19]. An additional contributory mechanism for increased [Ca2+]i during hyperkalemic cardioplegic arrest and reperfusion may involve sodium-calcium exchange activity [20–22]. The mechanisms involved in the decreased [Ca2+]i transient after high potassium cardioplegia are not clear. Increased [Ca2+]i appears to depress the activity of ryanodine receptors, which then contributes to the decreased SR calcium release [23]. Furthermore, hyperkalemic cardioplegic arrest increases the intracellular hydrogen ion concentration [24]. Hydrogen ion decreases SR calcium release and inhibits [Ca2+]i binding to myofibrillar troponin C, thereby reducing actomyosin ATPase activation and force generation [25–29]. The present findings show that myocytes exposed to pinacidil during conditions mimicking cardioplegic arrest demonstrate better recovery of contractile function, peak systolic [Ca2+]i, and SR calcium preservation, suggesting that pinacidil supplementation in cardioplegia may help myocytes to maintain intracellular calcium homeostasis. Differences between myocytes exposed to cardioplegic solution alone and those with pinacidil were apparent in the decay time of the [Ca2+]i transient evoked by caffeine, suggesting that pinacidil enhances the effectiveness of [Ca2+]i extrusion by sodium-calcium exchange and thus accelerates myocyte relaxation [30–32].

The mechanism by which supplementation of hyperkalemic cardioplegic solutions with a potassium-channel opener induces cardioprotection may include modulation of the membrane potential and energy-dependent processes. Activation of the sarcolemmal KATP channel promotes potassium efflux and subsequent hyperpolarization of the cell membrane. At hyperpolarized membrane potentials, transmembrane ion transport is minimized, which reduces the metabolic demand on the myocyte [31]. This conservation of the energy substrate by potassium-channel openers is confirmed in ischemic myocardium, in which ATP is preserved by pretreatment with cromakalim [33]. Moreover, in vivo studies show that cardioplegia with an ATP-sensitive potassium-channel opener (nicorandil) significantly increases the calcium-binding capacity of SR, and improves left ventricular contractility and myocardial energetics [34, 35]. Although existing evidence supports roles for both sarcolemmal and mitochondrial KATP channels in cardioprotection, data are accumulating to indicate that the mitochondrial KATP channel plays the more important role [36]. However, it is still accepted that opening the sarcolemmal KATP channel probably acts to reduce cytosolic calcium influx though the L-type calcium channels and to enhance calcium efflux by means of the sodium-calcium exchanger, thereby reducing the calcium-related energy cost of contraction and providing protection from cellular injury and the effects of stunning [32, 36].

The present study may have an important clinical implication. Reduced effectiveness of SR calcium release and [Ca2+]i extrusion by the sodium-calcium exchanger appears to play an important role in myocardial reperfusion injury by contributing to the reduction in contractile function. Because ionic homeostasis and contractile functions are significantly impaired in myocytes after hyperkalemic cardioplegic arrest, weaning patients from cardiopulmonary bypass presents a significant difficulty. However, the clinical applications of potassium-channel openers are limited. First, the onset of electromechanical arrest with potassium-channel openers is significantly delayed relative to hyperkalemic arrest [14]. Second, some potassium-channel openers appear to be associated with an increased incidence of ventricular fibrillation on reperfusion [10]. Further evaluation of potassium-channel openers in terms of safety and efficacy in cardioplegic arrest is needed.

The isolated myocyte model used in the present study allows direct examination of contractile function and [Ca2+]i level in a precisely controlled milieu so that the effects of compounds such as pinacidil can be assessed. Examination of the contractile properties in isolated myocytes has additional advantages, including the absence of neurohormonal influences, invariant loading conditions, and no alterations in coronary perfusion; in vivo, these factors can have uncontrolled effects on ventricular performance. The isolated myocyte model also has limitations. The optimal solute diffusion between cytosol and extracellular milieu that is present in the isolated myocyte system does not exist in vivo. Continuous exposure to the hyperkalemic environment may differ from typical clinical conditions during aortic cross-clamping.

The underlying pathophysiology of cardioplegia-associated ventricular dysfunction is complex and not fully understood, but it could be related, in part, to [Ca2+]i loading induced by high potassium concentrations present in cardioplegic solutions [37]. A better understanding of the alterations in ionic homeostasis and contractile function caused by hyperkalemia may be derived from models of cardioplegia that mimic the clinical scenario more precisely.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by grants from the Natural Science Foundation (M303839) and the Bureau of Science and Technology (2003C33022), Zhejiang Province.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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