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Ann Thorac Surg 1997;63:981-987
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Protective Effects of Adenosine on Myocyte Contractility During Cardioplegic Arrest

Division of Cardiothoracic Surgery and Department of Anesthesiology, Medical University of South Carolina, Charleston, South Carolina

Accepted for publication October 19, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Background. Adenosine delivery to the left ventricular myocardium has been demonstrated to provide protective effects in the setting of ischemia and reperfusion. However, whether adenosine has direct protective effects on isolated myocytes in the setting of cardioplegic arrest was unclear.

Methods. Isolated porcine left ventricular myocytes were assigned to one of the following treatment groups: (1) cardioplegia: 24 mEq/L K⁺, 4°C for 2 hours followed by rewarming (cell media, 37°C; n = 29); (2) cardioplegia augmented with adenosine (1 to 200 µmol/L) followed by rewarming (n = 98); and (3) normothermic control (cell media, 37°C, 2 hours; n = 175). Myocyte contractility was measured by computer-aided videomicroscopy.

Results. Cardioplegic arrest and rewarming reduced myocyte shortening velocity compared with normothermic control (25.3 ± 2.5 µm/s versus 50.9 ± 1.4 µm/s, p < 0.05). Adenosine-augmented cardioplegic arrest improved myocyte contractility with rewarming in a concentration-dependent fashion. For example, cardioplegia augmented with 10 µmol/L adenosine improved myocyte shortening velocity by 33% (33.6 ± 3.0 µm/s versus 25.3 ± 2.5 µm/s, p < 0.05), whereas 200 µmol/L adenosine improved shortening velocity by 97% (49.9 ± 3.4 µm/s vs 25.3 ± 2.5 µm/s, p < 0.05) compared with conventional cardioplegia.

Conclusions. This study demonstrated concentration-dependent protective effects of adenosine-augmented cardioplegia on myocyte contractile function with subsequent reperfusion and rewarming. These results suggest that stimulation of putative myocyte adenosine receptors may provide enhanced protective effects on myocyte contractile processes during cardioplegic arrest.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Hypothermic, hyperkalemic cardioplegic arrest is the most widely used method to achieve cardiac quiescence during cardiac surgical procedures [1]. However, cardioplegic arrest can be associated with transient left ventricular (LV) pump dysfunction with reperfusion and rewarming [2, 3]. Preconditioning is a phenomenon in which multiple short episodes of myocardial ischemia confer protection during a subsequent prolonged period of ischemia [4]. Preconditioning has been demonstrated to preserve LV pump function after cardioplegic arrest and rewarming [5, 6]. For example, Illes and colleagues [6] demonstrated that ischemic preconditioning in isolated rabbit hearts preserved LV peak-developed pressure after cardioplegic arrest and rewarming. Although the clinical application of ischemic preconditioning in the setting of cardiac operations may be problematic, invoking the protective effects of preconditioning through pharmacologic means may provide an adjunct to cardioplegic arrest. For example, activation of adenosine receptor-mediated pathways has been implicated as a potential contributory mechanism for the protective effects of preconditioning [7–10]. Specifically, an earlier report [7] demonstrated that the myocardial protective effects of ischemic preconditioning were abolished after administration of a specific adenosine receptor antagonist. Furthermore, several earlier reports [11–16] have demonstrated that augmentation of cardioplegic solutions with adenosine preserves LV pump function after reperfusion and rewarming. However, contributory mechanisms by which adenosine provides protective effects in the setting of cardioplegic arrest remain unclear. Thus, the goal of the present study was to determine whether adenosine receptor activation during simulated cardioplegic arrest would result in protective effects on isolated myocyte contractile function after reperfusion and rewarming.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
The overall goal of the present study was to determine whether adenosine receptor activation during cardioplegic arrest would confer protective effects on isolated myocyte contractile function upon subsequent reperfusion and rewarming. To establish a physiologic range of adenosine concentrations that would influence myocyte contractile function, initial studies examined the effects of various concentrations of adenosine on myocyte contractile function under normothermic conditions. To examine the effects of adenosine augmentation of cardioplegic solutions, the present study used an isolated myocyte model of hypothermic, hyperkalemic cardioplegic arrest [17–19].

	Myocyte Isolation

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Ten age- and weight-matched pigs (Yorkshire strain; age, 6 months; weight, 25 to 30 kg) were anesthetized with isoflurane (0.5%/1.5 L/min). A median sternotomy was then performed and the heart was quickly extirpated and placed in oxygenated cold Krebs solution. The region of the LV free wall (5 by 5 cm) incorporating the left circumflex coronary artery was dissected free and used for myocyte isolation. Myocytes were isolated from the LV free wall using methods described previously [17–22]. Briefly, the left circumflex coronary artery was infused with an oxygenated collagenase solution (0.5 mg/mL, type II, 273 U/mg; Worthington Biochemical Corp, Freehold, NJ) for 20 minutes. The tissue was then minced into 2-mm sections and placed in an oxygenated solution containing bovine serum albumin (2%; Sigma Chemical Co, St. Louis, MO), deoxyribonuclease (51 Kunitz units/mL, type IV, Sigma), CaCl₂ (400 µmol/L), and collagenase. The tissue and solution were gently agitated and at 5-minute intervals, the supernatant was removed, filtered, and the cells allowed to settle. The myocyte pellet was then resuspended in standard culture medium (Media 199, 2 mmol/L Ca²⁺; Gibco Laboratories, Grand Island, NY). Aliquots of the isolated myocyte suspension (2 mL, 5 x 10⁴ cells/mL) were plated onto coverslips coated with a laminin/fibronectin matrix (Matrigel, Collaborative Research Inc, Bedford, MA) and incubated at 37°C for 1 hour in the presence of 95% O₂ and 5% CO₂. Previous studies have reported that viable myocytes included those that retained a rod shape, were calcium tolerant, responded to electrical stimulation, and excluded trypan blue [20–22]. Using this myocyte isolation method, a high yield of viable myocytes (>70%) was routinely obtained for study.

	Isolated Myocyte Function

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Isolated myocytes were placed in a thermostatically controlled chamber (37°C), fitted with a coverslip on the bottom for imaging on an inverted microscope (Axiovert IM35; Zeiss Inc, Oberkochen, Germany). Myocyte contractions were elicited by field stimulation at 1 Hz (S11; Grass Instruments, Quincy, MA) using current pulses of 5-ms duration and voltages 10% above contraction threshold. The polarity of the stimulating electrodes was alternated at every pulse to prevent build up of electrochemical by-products. Stimulated myocytes were allowed a 5-minute stabilization period after which contraction data for each myocyte was recorded from a minimum of 20 consecutive contractions. Myocyte contractions were imaged using a charge-coupled device with a noninterlaced scan rate of 240 Hz (GPCD60; Panasonic, Secaucus, NJ). Myocyte motion signals were captured with the cell parallel to the video raster lines, and this video signal input through an edge detector system (Crescent Electronics, Sandy, UT) [21]. The changes in light intensity at the myocyte edges were used to track myocyte motion. The distance between the left and right myocyte edges was converted into a voltage signal, digitized, and input to a computer (80486; Zeos International, Minneapolis, MN) for subsequent analysis [20, 21]. Parameters computed from the digitized contraction profiles include percent shortening, peak shortening velocity (micrometers per second), peak relengthening velocity (micrometers per second), and contraction duration (milliseconds).

	Myocyte Contractile Function: Effects of Adenosine

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
An initial series of experiments was performed to determine the effects of various concentrations of adenosine on myocyte contractile function under normothermic conditions. After measurement of steady-state contractile function, isolated myocytes were incubated for 5 minutes with adenosine (Fujiwasa USA Inc, Deerfield, IL) in one of four concentrations (1, 10, 100, or 200 µmol/L). To determine the effect of adenosine on myocyte ß-adrenergic responsiveness, we repeated myocyte contractile measurements in the presence of adenosine and isoproterenol (25 nmol/L; Sigma). The concentrations of adenosine used in the present study were chosen based on the results of an earlier study demonstrating that adenosine, in concentrations of 5 to 200 µmol/L, blunted the ß-adrenergic responsiveness of isolated bovine and guinea pig myocytes [23]. The concentration of isoproterenol used in the present study has been demonstrated to elicit maximal ß-adrenergic response in isolated myocytes [22].

	Myocyte Contractile Function: Effects of Adenosine-Augmented Cardioplegic Arrest and Rewarming

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
The next series of experiments examined the effects of cardioplegic solutions augmented with increasing concentrations of adenosine on myocyte contractile function after reperfusion and rewarming. The cardioplegic arrest protocol was performed as previously described [17–19] by incubating myocytes in a conventional crystalloid cardioplegic solution (lactated Ringer's solution, 24 mEq/L K⁺, 30 mEq/L HCO₃^-, partial pressure of oxygen >300 mm Hg) for 2 hours at 4°C. The cardioplegic solution was then rapidly changed with normothermic (37°C) cell culture medium. After a 5-minute period of rewarming, myocyte contractile function was examined. A separate group of myocytes were subjected to cardioplegic arrest as described previously using crystalloid cardioplegic solutions augmented with adenosine in one of four concentrations (1, 10, 100, or 200 µmol/L). After a 5-minute period of normothermic reperfusion and rewarming, myocyte contractile function was examined. Earlier reports [11–15] have demonstrated that augmentation of cardioplegic solutions with concentrations of adenosine similar to those used in the present study had protective effects on LV pump performance after reperfusion and rewarming. To determine the effect of adenosine-augmented cardioplegic arrest and rewarming on myocyte ß-adrenergic responsiveness, we repeated myocyte contractile measurements in the presence of isoproterenol (25 nmol/L). For comparison, myocytes maintained under oxygenated, normothermic conditions without cardioplegia served as controls.

	Data Analysis

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Statistical analyses were performed using a multiway analysis of variance. If the analysis of variance revealed significant differences, pair-wise tests of individual group means were compared using Bonferroni bounds [24]. All statistical procedures were performed using the BMDP statistical software package (BMDP Statistical Software, Inc, Los Angeles, CA). Results are presented as mean ± standard error of the mean. Values of p less than 0.05 were considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Myocyte Contractile Function: Effects of Adenosine
Indices of steady-state myocyte contractile function and ß-adrenergic responsiveness in the presence of adenosine were examined under normothermic conditions (Table 1). Indices of myocyte contractility were reduced in the presence of increasing concentrations of adenosine compared with baseline normothermic conditions (see Table 1). Changes in steady-state contractile function caused by adenosine are shown in Figure 1. With respect to both steady-state contractility and ß-adrenergic responsiveness, the presence of adenosine at a concentration of 10 µmol/L resulted in maximal reductions in contractile function.

View larger version (17K): [in this window] [in a new window]   Fig 1. . (A) Changes in myocyte shortening velocity from steady-state values in the presence of increasing concentrations of adenosine under normothermic control conditions. Under normothermic control conditions, adenosine caused a decline in myocyte shortening velocity that appeared to plateau at 10 µmol/L of adenosine. (B) Changes in normothermic myocyte ß-adrenergic responsiveness in the presence of increasing concentrations of adenosine were evaluated by stimulation with 25 nmol/L isoproterenol [18, 22]. Under normothermic control conditions, the absolute change in myocyte shortening velocity after ß-receptor stimulation was reduced in the presence of increasing concentrations of adenosine. The negative inotropic effects of adenosine under normal control conditions is consistent with earlier reports [27]. (*p < 0.05 versus 0 concentration of adenosine.)

	Myocyte Contractile Function: Effects of Adenosine-Augmented Cardioplegic Arrest and Rewarming

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

View larger version (16K): [in this window] [in a new window]   Fig 2. . Myocyte ß-adrenergic responsiveness after adenosine-augmented cardioplegic arrest and rewarming. Augmentation of cardioplegic arrest with adenosine resulted in a concentration-dependent increase in both percent shortening (A) and shortening velocity (B) in the presence of isoproterenol (25 nmol/L) after reperfusion and rewarming. (*p < 0.05 versus cardioplegia alone [no adenosine added].)

View larger version (13K): [in this window] [in a new window]   Fig 3. . Changes in myocyte relengthening velocity reflect alterations in active relaxation processes, an energy-dependent phase of the contraction cycle. To examine more carefully the effects of adenosine-augmented cardioplegic arrest on this determinant of the contractile process, we determined changes in the relengthening velocity from steady-state values after ß-receptor stimulation with 25 nmol/L isoproterenol. Cardioplegic arrest without adenosine (0 concentration) blunted the effects of ß-receptor stimulation on myocyte relengthening velocity when compared to normothermic values (see Table 2). Adenosine-augmented cardioplegia improved myocyte relengthening velocity with ß-receptor stimulation in a concentration-dependent manner. (*p < 0.05 versus cardioplegia alone [no adenosine added].)

	Comment

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

The protective effects of adenosine-augmented cardioplegic arrest on overall LV function after reperfusion and rewarming have been documented in both in vivo models and isolated heart preparations (Table 3) [11–16]. In these previous studies, LV systolic function, diastolic function, and myocardial high-energy phosphate content were improved with adenosine-augmented cardioplegic solutions, compared with conventional hyperkalemic cardioplegia, with subsequent reperfusion and rewarming. For example, augmentation of cardioplegic solution with adenosine (50 to 5,000 µmol/L) has been demonstrated to result in increased LV developed pressure with rewarming, compared with conventional cardioplegia [9, 10, 12, 16]. However, adenosine administration is associated with multiple systemic and myocardial effects, including decreased systemic vascular resistance, alterations in coronary smooth muscle tone, and alterations in cardiac electrophysiologic properties [13]. Thus, determining whether the beneficial effects of adenosine augmented cardioplegic arrest were the result of direct effects on myocyte contractile function can be problematic. This laboratory has previously shown that an isolated myocyte system can be used to detect fundamental contractile abnormalities that occur after cardioplegic arrest and rewarming [17–19]. The present study used this isolated myocyte system to examine more carefully the effects of adenosine-augmented cardioplegia on myocyte contractile function after rewarming. In the present study, adenosine-augmented cardioplegia resulted in improved steady-state myocyte contractile function after reperfusion and rewarming, compared with conventional hyperkalemic cardioplegia. Taken together, the results from previous reports and the present study suggest that a contributory mechanism for the improved LV function observed after adenosine-augmented cardioplegic arrest and rewarming is through a direct improvement in myocyte contractile processes.

Armstrong and colleagues [9] reported functional adenosine A₁ receptors in isolated rabbit cardiocytes. In that study, activation of these myocyte A₁ receptors provided protective effects during a metabolic insult. However, several adenosine receptor subtypes have been described, as well as cloned [33, 34]. Thus, although results from the present study demonstrated that adenosine augmentation of the cardioplegic solution provided a concentration-dependent protective effect with respect to myocyte contractile processes, whether these effects are mediated by selective activation of an adenosine receptor subtype remains unknown. Relatively specific adenosine receptor subtype agonists and antagonists have been developed that have pharmacologic activity in myocardial preparations [7–10, 35]. For example, Lasley and Mentzer [35] reported that an adenosine A₁ receptor agonist provided similar protective effects to that of adenosine in ischemic-isolated heart preparations. More recently, Armstrong and Ganote [10] reported that activation of an adenosine A₃ receptor in rabbit cardiocytes provided cardioprotective effects. In light of the findings of the present study, future studies that use specific adenosine receptor agonists and antagonists in this model of simulated cardioplegic arrest are warranted.

The present study used an isolated myocyte system to examine the effects of adenosine-augmented cardioplegic arrest on myocyte contractile function after rewarming. Myocyte contractile performance was examined after external loading conditions had been removed. Previous studies [36, 37] have demonstrated that isolated myocyte contractile function directly reflects intrinsic potential of the LV myocardium to respond against an external load. Thus, the improved isolated myocyte contractile function that was observed in the present study after adenosine-augmented cardioplegic arrest would likely be reflected in improved capacity to respond to an external load. Further evidence to support this conclusion is that adenosine-augmented cardioplegic arrest improved the capacity of the myocyte to respond to an inotropic stimulus: ß-receptor stimulation. Nevertheless, although this isolated myocyte system provides a means to directly examine contractile behavior after specific interventions, there are several problematic issues that prevent direct extrapolation of the results from these in vitro studies to the intact LV myocardium. First, this in vitro system examined the effects of adenosine on the myocyte independent of the effects of the extracellular matrix, nonmyocyte cell populations, and neurohormonal influences. Thus, myocytes undergoing simulated cardioplegic arrest were continuously exposed to an elevated potassium concentration for the entire arrest period, which differs from intermittent, multidose cardioplegia techniques. Second, the myocytes were directly exposed to exogenous adenosine in the absence of any buffering or osmotic influences of the extracellular matrix that may be operative in vivo. This isolated myocyte system also differs from in vivo preparations in which capillary perfusion distances are affected by coronary artery disease, hypertrophy, and nonuniform maintenance and control of temperature. However, the goal of the present study was to investigate the specific effects of adenosine augmentation of cardioplegic solution on intrinsic myocyte contractile processes. In light of the findings of the present study, additional investigations are warranted to further elucidate the cellular mechanisms for the protective effects of adenosine in the setting of cardioplegic arrest.

Hypothermic, hyperkalemic cardioplegic arrest remains the cornerstone for achieving and maintaining cardiac quiescence in most cardiac surgical procedures. However, cardioplegic arrest can be associated with transient LV dysfunction upon reperfusion and rewarming. The present study demonstrated that adenosine augmentation of hyperkalemic cardioplegic solutions conferred concentration-dependent protective effects on myocyte contractile function after rewarming, compared with conventional cardioplegia. Thus, adenosine may be a useful pharmacologic adjunct to conventional hyperkalemic cardioplegic solutions.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
This study was supported by National Institutes of Health grant HL-45024, a Grant-in-Aid from the South Carolina Heart Association, and a Grant-in-Aid from the American Heart Association. Mr Cox is a Medical Student Research Fellow of the American Heart Association. Doctor Spinale is an Established Investigator of the American Heart Association.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 
Address reprint requests to Dr Spinale, Cardiothoracic Surgery, Rm 418 CSB, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.

	References

Top Footnotes Abstract Introduction Material and Methods Myocyte Isolation Isolated Myocyte Function Myocyte Contractile Function:... Myocyte Contractile Function:... Data Analysis Results Myocyte Contractile Function:... Comment Acknowledgments References

 

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