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Ann Thorac Surg 1999;67:1732-1737
© 1999 The Society of Thoracic Surgeons

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Original Articles

Adenosine A₃ pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction

^a Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center-Cardiothoracic Research Laboratory, Emory University School of Medicine, Atlanta, Georgia, USA

Accepted for publication January 4, 1999.

Address reprint requests to Dr Vinten-Johansen, Cardiothoracic Research Laboratory, Crawford Long Hospital, 550 Peachtree NE, Atlanta, GA 30365-2225
e-mail: jvinten{at}emory.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. The cardioprotective effects of the adenosine A₃ receptor in a cardioplegia model have not been described. We tested the hypothesis that infusion of the A₃ receptor agonist, Cl-IB-MECA (100 nM), as a pretreatment (PTx) and/or as a cardioplegic (CP) additive reduces postischemic myocardial injury.

Methods. Isolated perfused rat hearts underwent 30 minutes of normothermic ischemia, 60 minutes of intermittent hypothermic cardioplegia (10°C), followed by 2 hours of reperfusion. Hearts were divided into four groups: (1) no pretreatment (PTx) and unsupplemented cardioplegia (CP) (control), (2) Cl-IB-MECA PTx and unsupplemented CP (A₃-PTx), (3) no PTx and Cl-IB-MECA CP (A₃-CP), or (4) Cl-IB-MECA PTx and Cl-IB-MECA CP (A₃-[PTx+CP]).

Results. Coronary flow was not increased after A₃ pretreatment when compared to baseline values. After 2 hours of reperfusion, left ventricular developed pressure in control and A₃-CP groups was depressed to 43% ± 3% and 47% ± 2% of baseline; while A₃-PTx and A₃-[PTx+CP] significantly increased left ventricular developed pressure (65% ± 3% and 61% ± 5%) from baseline relative to control and A₃-CP. Effluent creatine kinase activity was significantly decreased by A₃-PTx (1520 ± 32 IU/L), A₃-[PTx+CP] (1481 ± 41 IU/L) from control (1734 ± 54 IU/L) and A₃-CP (1750 ± 43 IU/L). Myocardial edema (% tissue water) was significantly less in A₃-PTx (78 ± 0.6%) and A₃-[PTx+CP] (76% ± 2%) compared with control (85% ± 0.4%) and A₃-CP (83% ± 2%).

Conclusions. Adenosine A₃ receptor stimulation as a pretreatment attenuates postischemic cardiodynamic dysfunction and creatine kinase release but has no cardioprotection as an adjunct to cold cardioplegia.

	Introduction

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Within the past decade, it has been shown that adenosine has the potential to exert beneficial effects during all three windows of cardioprotection: pretreatment (or chemical preconditioning) [1], obligate surgical ischemia [2–4], and reperfusion [5, 6]. The pretreatment and cardioplegic windows of opportunity are convenient settings for the administration of cardioprotective drugs during surgical myocardial revascularization. A brief pretreatment of adenosine has been shown to reduce infarct size in isolated perfused heart models [7], in in vivo animal models [8], and in humans [9]. Additionally, it has been shown that adenosine, when used alone [1, 4] or in combination with hyperkalemic, hypothermic crystalloid [3, 4] or blood [2], cardioplegia, improves postischemic contractile function. The benefits of adenosine to postischemic myocardium are demonstrable, but its untoward effects produced by activation of adenosine A₁ (bradycardia, negative inotropy) and A_2a (vasodilation and hypotension) receptors have impeded its routine clinical use in cardiac operations.

The recently described adenosine A₃ receptor subtype potentially avoids the complications of hypotension and bradycardia. In a rat testis cDNA library, the adenosine A₃ receptor was initially described in 1991 by Meyerhof and associates [10] and then by Zhou and colleagues [11] in 1992. In animal models of nonsurgical myocardial ischemia and reperfusion, the activation of the adenosine A₃ receptor was cardioprotective [12–14]. In addition, the stimulation of the adenosine A₃ receptor has been shown to mimic or induce myocardial preconditioning [15–17]. However, the cardioprotective effects of adenosine A₃ receptor activation as a pretreatment before cardioplegic arrest or as an adjunct to hypothermic hyperkalemic crystalloid cardioplegic solution has not been investigated.

Therefore, we tested the hypothesis that stimulation of the adenosine A₃ receptor with the highly selective A₃ receptor agonist, 2-chloro-N6-(3-iodobenzyl) adenosine-5'-N-methyluronamide (Cl-IB-MECA, 100 nM), would reduce postischemic dysfunction and morphologic injury in a neutrophil-free isolated perfused rat heart model when administered as a pretreatment or as an additive to crystalloid cardioplegia.

	Material and methods

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Experimental preparation
The animals in the investigation were handled in full accordance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH Publication No. 85-23, revised 1996), and the protocol was approved by the Institutional Animal Care and Use Committee of Emory University. Sprague-Dawley rats weighing approximately 200 to 250 g were anesthetized with pentobarbital sodium (30 mg/kg) intraperitoneally and heparinized intravenously with 1,000 U sodium heparin. After adequate heparinization, the heart was excised then mounted on a Langendorff perfusion apparatus (Radnoti Glass Technology Inc, Monrovia, CA), and retrograde aortic perfusion was initiated in a nonrecirculating fashion using modified Krebs-Henseleit (K-H) buffer containing 4.7 mmol/L KCl, 1.2 mmol/L KH₂PO₄, 1.2 mmol/L MgSO₄, 118 mmol/L NaCl, 2.04 mmol/L CaCl₂, 0.05 mmol/L ethylenediamene tetraacetic acid tetrasodium salt, 25 mmol/L NaHCO₃, and 11 mmol/L dextrose. The perfusate was pH balanced to 7.4 after full aeration and filtered through a 5-µm magna nylon membrane (Fisher Scientific, Pittsburgh, PA). The perfusate temperature was maintained at 37°C using a circulating water-bath heater (Precision Scientific, Chicago, IL) and was continuously oxygenated with 95% O₂ and 5% CO₂. The heart was suspended in a water-jacketed chamber to maintain the temperature at 37°C.

During a 25-minute stabilization period, a latex fluid-filled balloon on the end of a PE-100 catheter was inserted into the left ventricle across the mitral annulus. The balloon was inflated to achieve an end-diastolic pressure between 7 and 10 mm Hg and no further alterations in balloon volume were made. Additionally, two electrodes were placed on the right ventricle, the sinoatrial node was crushed, and the heart was paced at 250 beats per minute using a Grass S9 Stimulator (Grass Medical Instruments, Kings Park, NY).

The left ventricular balloon pressure and the perfusion pressure were monitored with fluid-filled pressure transducers (TRN050 blood pressure transducer) and connected to a TRN005 base instrument amplifier (Kent Scientific Corporation, Litchfield, CT). Coronary perfusion pressure was maintained between 70 and 80 mm Hg. Coronary flow was continuously measured with an in-line ultrasonic flow probe and ultrasonic blood flow meter (Model T101; Transonic Systems Inc, Ithaca, NY). The pressure and flow signals were sampled at 250 Hz by a personal computer using an analog-to-digital converter (Data Translation, Marlboro, MA). The data were captured, stored, and analyzed using SPECTRUM cardiovascular acquisition and analysis software (Wake Forest University, Winston-Salem, NC).

Experimental design
Animals were randomly assigned to four groups (6 in each group): (group 1 [control]) no pretreatment (PTx) and unsupplemented cardioplegia, (CP), (group 2) Cl-IB-MECA (100 nM) PTx and unsupplemented CP (A₃-PTx), (group 3) no PTx and Cl-IB-MECA (100 nM) CP (A₃-CP), and (group 4) Cl-IB-MECA PTx and Cl-IB-MECA CP (A₃-[PTx+CP]). Cl-IB-MECA was administered for 12 minutes before ischemia via a syringe infusion pump (Harvard Apparatus, South Natick, MA) in a side-port located just proximal to the aortic cannulation site. After stabilization and drug administration, all hearts underwent 30 minutes of normothermic (37°C) global ischemia by discontinuing electrical pacing and ceasing all buffer perfusion to the heart to sensitize the myocardium to injury. Multidose hypothermic (10°C) cardioplegia (Plegisol) was administered for 3 minutes at 50 mm Hg every 20 minutes for 1 hour of cardioplegic arrest followed by 2 hours of reperfusion. The final dose of cardioplegia was delivered at 27°C. Reperfusion was initiated by restoring buffer perfusion to the heart; pacing was resumed 5 minutes after initiation of reperfusion. Cardiodynamic measurements were obtained before and after drug administration, and at 15, 30, 60, 90, and 120 minutes during reperfusion. Coronary effluent was collected before and after drug administration, and 1, 5, 15, 30, 60, 90, and 120 minutes during reperfusion to measure creatine kinase activity. At the end of 2 hours of reperfusion, all hearts were weighed and myocardial water content was determined by weighing hearts before (wet weight) and after 48 hours (dry weight) of heat desiccation. The myocardial water content was calculated by (wet weight minus dry weight) divided by the wet weight times 100%.

Creatine kinase determination
Creatine kinase (Sigma Diagnostics, St. Louis, MO) activity was calculated spectrophotometrically from the effluent collected at the aforementioned time points. The sum of the individual creatine kinase values for each time point is represented as the cumulative creatine kinase activity and is expressed as Units/L.

Statistical analysis
The data were analyzed by a one-way analysis of variance or repeated measures two-way analysis of variance for analysis of group, time, and group-time interactions. Tukey’s posthoc method was used to determine pairwise differences among groups. A p value less than 0.05 was considered statistically significant. Data are expressed as mean ± standard error of the mean.

Preparation and dosage of drugs
The selective A₃ agonist, 2-chloro-N6-(3-iodobenzyl) adenosine-5'-N-methyluronamide (Cl-IB-MECA) was reconstituted in dimethylsulfoxide (DMSO) to achieve a final perfusate concentration of 100 nM. At this concentration of Cl-IB-MECA, Thourani and colleagues [14] have shown cardioprotective effects without concomitant vasodilatory consequences. The perfusate concentration of DMSO was 0.01 nM. Before the addition of sodium bicarbonate (10 mL of an 8.4% solution), the concentration of electrolytes (per liter of Plegisol [Abbott Laboratories, North Chicago, IL]) was sodium 110 mEq, chloride 160 mEq, potassium 16 mEq, calcium 2.4 mEq, and magnesium 32 mEq.

	Results

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Left ventricular developed pressure
After 2 hours of reperfusion, control hearts had a 43% ± 3% recovery in left ventricular developed pressure (LVDP) from baseline values (Fig 1). In the A₃ cardioplegia group (no A₃ agonist pretreatment), LVDP at the end of 2 hours of reperfusion was comparably depressed (47% ± 2%). In contrast, LVDP was significantly greater with Cl-IB-MECA in the pretreatment groups A₃-PTx (65% ± 3%) and A₃-[PTx+CP] (61% ± 5%).

View larger version (24K): [in this window] [in a new window]   Fig 1. Left ventricular developed pressure (mm Hg) as determined from a fixed-volume, fluid-filled balloon within the left ventricle. (A3 = adenosine A3 receptor agonist Cl-IB-MECA; base = before administration of Cl-IB-MECA; CP = cardioplegia; postdrug = 12 minutes after pretreatment in with K-H buffer or Cl-IB-MECA; r15m, r30m, r60m, r90m, r120m = minutes of reperfusion; PTx = pretreatment.) All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP.

View larger version (25K): [in this window] [in a new window]   Fig 2. Peak positive dP/dt (dP/dtmax). Abbreviations are as in Figure 1. All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP.

View larger version (24K): [in this window] [in a new window]   Fig 3. Left ventricular end-diastolic pressure (mm Hg). Abbreviations are as in Figure 1. All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP.

View larger version (25K): [in this window] [in a new window]   Fig 4. Coronary perfusate flow (percentage of baseline) as determined by an in-line ultrasonic flow probe within the perfusate tubing of the Langendorff apparatus. Abbreviations are as in Figure 1. All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP. #p < 0.05 A3-PTx versus control and A3-CP. +p < 0.05 A3-[PTx+CP] versus A3-CP. p < 0.05 control versus A3-CP. @p < 0.05 A3-PTx and A3-[PTx+CP] versus A3-CP.

View larger version (18K): [in this window] [in a new window]   Fig 5. Cumulative effluent creatine kinase activity values from perfusate samples taken during reperfusion. Abbreviations are as in Figure 1. All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP.

View larger version (17K): [in this window] [in a new window]   Fig 6. Myocardial water content as determined by percentage of heart water weight from left ventricular myocardium sampled at the end of the experiment. Abbreviations are as in Figure 1. All values are mean ± standard error of the mean. *p < 0.05 A3-PTx and A3-[PTx+CP] versus control and A3-CP.

	Comment

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The endogenous autacoid, adenosine, as well as exogenous adenosine analogues might offer therapeutic opportunities to reduce postsurgical ischemia and reperfusion injury in a subset of high-risk patients who have coronary artery bypass operations. The ability of adenosine to attenuate myocardial injury during ischemia and reperfusion makes it a good candidate as a protective agent during the multiple episodes of ischemia and reperfusion that occur during cardiac surgical procedures. Despite the well-described cardioprotective benefits of adenosine, the undesirable effects of the activation of adenosine A₁ (bradycardia, negative inotropy) and A₂ (vasodilation, hypotension) receptor subtypes have precluded the routine use of these agents during surgical myocardial revascularization.

Although the adenosine A₃ receptor shares sequence similarity with the adenosine A₁ and A₂ receptor subtypes, it has specific pharmacologic characteristics not typical of adenosine A₁ or A₂ receptors [18]. The adenosine A₃ receptor agonist, Cl-IB-MECA, displays a K₁ value of 0.33 nM and is highly selective for A₃ versus A₁ and A_2a receptors by 2500- and 1400-fold, respectively [18]. The adenosine A₃ receptor has been isolated from several animal species and humans [18]. Although Cl-IB-MECA has been reported to have a vasodilator effect mediated by histamine release from mast cells [19], Cl-IB-MECA did not cause any significant coronary vasodilation at the concentration used in the present study and a previous study by Thourani and colleagues [14]. We found that the adenosine A₃ agonist, Cl-IB-MECA, when administered as a pretreatment independent of inclusion in crystalloid cardioplegia attenuated postischemic systolic and diastolic dysfunction and reduced creatine kinase release. In contrast, Cl-IB-MECA–supplemented hypothermic cardioplegia alone did not further enhance cardioprotection in this model. Therefore, when Cl-IB-MECA cardioplegia was used in conjunction with Cl-IB-MECA pretreatment, the cardioprotective effects afforded by adenosine A₃ receptor activation were not further enhanced. The present study found that selective stimulation of the adenosine A₃ receptor before 30 minutes of normothermic global myocardial ischemia and during 60 minutes of hypothermic cardioplegic arrest attenuates postischemic dysfunction without vasodilator effects.

The cardioprotective effects of the adenosine A₃ receptor have been studied in a limited number of models of myocardial ischemia and reperfusion [12, 13]. Furthermore, studies found that the activation of the adenosine A₃ receptor mimics or induces myocardial preconditioning [15–17]. In the current study, we did not mimic chemical preconditioning, which incorporates a drug washout period. Instead, the adenosine A₃ analogue was infused before normothermic global ischemia without a washout interval, thereby allowing tissue levels of Cl-IB-MECA to be achieved at the time of global ischemia. In the current study, the presence of Cl-IB-MECA during ischemia attenuated postischemic systolic and diastolic function.

Recently we [14] showed that pretreatment with Cl-IB-MECA for 12 minutes (without a washout period) before 30 minutes of normothermic global ischemia in rat hearts reduced postischemic myocardial systolic and diastolic dysfunction and attenuated morphologic injury. However, studies evaluating the cardioprotective effects of adenosine A₃ receptor activation in a surgical model of cardioplegic arrest have not been reported. In the present study, we pretreated rat hearts with Cl-IB-MECA for 12 minutes before 30 minutes of normothermic global ischemia (to sensitize the myocardium) followed by 60 minutes of hypothermic cardioplegic arrest. Similar to our previous results [14], we found that pretreatment with adenosine A₃ agonists before normothermic global ischemia significantly reduced postischemic myocardial systolic and diastolic dysfunction. It is possible that adenosine A₃ analogues as a pretreatment to ischemia exert pharmacologic actions in a normothermic environment, whereas less effect is exerted during profound hypothermia. Accordingly, the activation of adenosine A₃ receptors before myocardial ischemia was cardioprotective in the present cardioplegia model. The lack of protection in hearts that received adenosine A₃ agonist during cardioplegic arrest alone (A₃ cardioplegia group) might be caused by the inhibition or downregulation of agonist-receptor interactions during hypothermia or by the development of ischemic injury before cardioplegia was delivered. It is possible that adenosine A₃ agonist supplementation with an initial warm cardioplegic infusion could provide cardioprotection by decreasing the effects of hypothermia on agonist-receptor and postreceptor interactions.

The mechanisms associated with the cardioprotection afforded by Cl-IB-MECA activation of the adenosine A₃ receptor have not been clearly defined. However, the structural similarity between the adenosine A₁ receptor and the A₃ receptor could indicate similarity in function. The activation of adenosine triphosphate-sensitive potassium channels (K_ATP) is involved in the cardioprotective effects of adenosine A₁-receptor activation in ischemic-reperfused myocardium [20]. Accordingly, activation of the adenosine A₃ receptor might mediate cardioprotection by activation of K_ATP channels. In an isolated rat heart model, Thourani and colleagues [21] demonstrated that glybenclamide, a K_ATP channel blocker, partially reversed the cardioprotective effects of Cl-IB-MECA. That finding suggests that the cardioprotection afforded by the activation of the adenosine A₃ receptor, like the adenosine A₁ receptor, could be mediated by opening of K_ATP channels.

Another possible mechanism of action of the adenosine A₃ receptor is the inhibition of neutrophil function and neutrophil-mediated injury to the endothelium and myocardium. Studies by Jordan and associates [22] have shown that Cl-IB-MECA inhibits neutrophil adherence to coronary artery endothelium in a dose-dependent manner. Although the present study did not investigate putative antineutrophil effects, it would be interesting to study the cardioprotective effects of A₃ receptor agonist in an in vivo model in which antineutrophil and neutrophil-independent mechanisms might be exerted.

The limitations in our study are inherent to the crystalloid perfused Langendorff model. The effects of the activation of the adenosine A₃ receptor on individual cell types (eg, neutrophils) can not be assessed because our perfusate lacked formed elements. Inflammatory mediators, ie, complement fragments and cytokines, were also absent and so the effects of A₃ receptor activation on soluble mediators can not be assessed. Consequently, the cardioprotective effects afforded by activation of the adenosine A₃ receptor might be different in a blood-based cardioplegia delivery modality. However, it was our intent in this initial study to investigate cardioprotective mechanisms independent of blood, neutrophils, or inflammatory mediators.

In conclusion, we found that pretreatment with a specific adenosine A₃ receptor agonist improved postcardioplegia contractile recovery without the vasodilator effects common to native adenosine and nonspecific adenosine agonists. However, the addition of Cl-IB-MECA to the cardioplegia solution did not further enhance the pretreatment effects. The administration of adenosine A₃ agonists before aortic cross-clamp without a washout period might be a useful pretreatment strategy for high-risk patients who have coronary artery bypass grafting.

	Acknowledgments

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Funded in part by the Thoracic Surgery Research Foundation Fellowship to Vinod H. Thourani, MD.

We thank Ms Gail Nechtman for assistance in preparation of the manuscript and Dr V. Bakthavachalam for the generous gift of Cl-IB-MECA. Cl-IB-MECA was synthesized by Research Biochemicals Inc (Natick, MA) as part of the Chemical Synthesis Program of the National Institute of Mental Health. We are grateful for the support of the research effort by the Thoracic Surgery Research Foundation and thank the Carlyle Fraser Heart Center of Crawford W. Long Hospital-Emory University School of Medicine for their continued long-standing contributions to cardiac surgical research endeavors.

	References

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