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J Thorac Cardiovasc Surg 1994;107:1356-1363
© 1994 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

The role of adenosine in extended myocardial preservation with the University of Wisconsin solution

Madison, Wis.

Supported by a grant to Dr. Lasley from the American Heart Association, Wisconsin Affiliate, and to Dr. Mentzer (RO1 HL-34579) from the National Institutes of Health.

Received for publication May 25, 1993. Accepted for publication Sept. 8, 1993. Address for reprints: Robert D. Lasley, PhD, Department of Surgery, University of Wisconsin School of Medicine, H4-383 Clinical Sciences Center, 600 Highland Ave., Madison, WI 53792.

Abstract

The purpose of this study was to determine the role that adenosine plays in enhanced myocardial preservation during cold storage with the University of Wisconsin solution. Hearts from adult rabbits were flushed with University of Wisconsin solution with or without adenosine and stored at 4° C for 24 hours. Interstitial fluid purine levels during the period of cold storage were estimated with cardiac microdialysis probes. In a second series of experiments hearts were flushed with University of Wisconsin solution with or without adenosine or St. Thomas' Hospital cardioplegic solution and stored for 18 hours (4° C). Functional recovery was assessed by reperfusing the hearts on a Langendorff apparatus (100 cm H₂O) for 45 minutes with Krebs-Henseleit buffer. During cold storage dialysate adenosine concentrations in hearts flushed with University of Wisconsin solution were 20- to 40-fold greater than adenosine levels in hearts flushed without adenosine. After 45 minutes of reperfusion hearts preserved with University of Wisconsin solution exhibited a rate-pressure product of 11,098 ± 576 mm Hg/min, significantly greater than that for hearts flushed with University of Wisconsin solution minus adenosine (8106 ± 780 mm Hg/min) and St. Thomas' Hospital solution (7317 ± 768 mm Hg/min). These results suggest that adenosine plays a major role in enhanced myocardial preservation with the University of Wisconsin solution, possibly by maintaining elevated interstitial fluid adenosine levels during the period of cold storage. (J THORACCARDIOVASCSURG1994;107:1356-63)

Prolonged cold-storage organ preservation for transplantation is characterized by high-energy phosphate depletion, intracellular acidosis, cell swelling, and interstitial edema. The University of Wisconsin (UW) preservation solution was developed to minimize these deleterious aspects of cold storage ¹ and has successfully extended preservation times of the liver, kidney, and pancreas. ^2-4 The UW solution, in addition to having an intracellular-based electrolyte composition, contains many constituents designed to reduce ischemic and reperfusion injury. Raffinose, lactobionic acid, and hydroxyethyl starch were added to reduce cellular and interstitial edema. Glutathione and allopurinol were included to reduce injury mediated by oxygen free radicals.

Another component of the UW solution is the purine nucleoside adenosine, which was added to stimulate adenosine triphosphate repletion via the purine salvage pathway. Adenosine has been shown to have a beneficial effect on the normothermic ischemic myocardium, reducing both irreversible and reversible injury. ^5-10 Although the exact mechanism by which adenosine exerts this cardioprotective effect is not known it appears to be mediated via the interaction of adenosine with specific membrane-bound adenosine A₁ receptors located on the cardiac myocytes. ¹¹ This hypothesis is supported by the observations that the cardioprotective effect of adenosine is mimicked by adenosine A₁ receptor agonists and blocked by adenosine A₁ receptor antagonists. ^8,9 In addition, augmentation of endogenous myocardial adenosine levels in the interstitial fluid (ISF) is associated with improved postischemic regional function. ¹²

There are few studies on the cardioprotective effects or metabolism of adenosine during hypothermic conditions, especially at temperatures used during cold-storage organ preservation (4° C). The purpose of this study was to assess ISF purine levels during prolonged cold storage with UW solution and to determine whether adenosine exerts a cardioprotective effect during these extreme hypothermic conditions.

MATERIALS AND METHODS

All animals in this study received humane care according to the guidelines set forth by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985). Adult New Zealand White rabbits (2 to 4 kg) were anesthetized with sodium pentobarbital (40 mg/kg) and heparinized (1000 units/kg). The hearts were rapidly excised and immediately placed in ice-cold saline to produce cardiac arrest.

Metabolic studies
In series 1 experiments the hearts (n = 5 per group) were immediately flushed with 40 ml cold (4° C) UW solution or UW solution minus adenosine (UW–ADO) at a perfusion pressure of 100 cm H₂O. When adenosine was omitted from UW solution, adenine (5 mmol/L) was added to maintain constant osmolarity. A dialysis fiber with a 1 cm exposed window was then inserted into the left ventricular free wall to estimate cardiac ISF purine levels during the period of cold storage. The heart was placed into a small dish filled with the same flush solution and transferred to a cold room (4° C). The dialysis fiber was perfused with Krebs-Henseleit buffer at a rate of 2 µl/min, and sample collection times were 10 minutes. The samples were diluted with distilled H₂O containing sodium azide and frozen at –70° C until analysis. Samples were collected over a 24-hour period at the following times after probe insertion: 20, 40, 60, and 90 minutes and 2, 3, 4, 5, 6, 7, 10, 18, and 24 hours. In addition, in hearts flushed with standard UW solution a sample of pulmonary effluent was collected to measure nucleoside levels.

Functional studies
In series 2 experiments the effects of different cold-storage solutions on function after preservation were assessed. Rabbit hearts were excised, arrested in cold saline, and flushed with 40 ml (4° C; 100 cm H₂O perfusion pressure) of either standard UW solution, UW–ADO, or St. Thomas' Hospital cardioplegic solution (n = 6 to 7 per group). The compositions of UW solution and St. Thomas' Hospital solution are shown in Table I. When adenosine was omitted from the UW solution, adenine (5 mmol/L) was added to maintain constant osmolarity. After 18 hours of cold storage in a small bag filled with the flush solution and stored in ice, the hearts were reperfused at a constant perfusion pressure of 100 cm H₂O on a Langendorff apparatus with Krebs-Henseleit buffer. The reperfusion function of preserved hearts was compared with the function of freshly excised rabbit hearts (nonpreserved controls). The Krebs-Henseleit buffer consisted of (in millimoles per liter) NaCl 118, KCl 4.7, MgSO₄ 1.2, KH₂PO₄ 1.2, CaCl₂ 1.25, NaHCO₃ 25.0, and glucose 11.0. The perfusate was filtered (0.45 µm); bubbled with 95% oxygen and 5% carbon dioxide resulting in a pH 7.35 to 7.45, carbon dioxide tension 35 to 40 mm Hg, and oxygen tension 560 to 620 mm Hg; and maintained at 37° C in a constant temperature reservoir. Myocardial temperature was maintained at 37° C by submersing the heart in a water-jacketed chamber filled with Krebs-Henseleit buffer.

Cardiac microdialysis
Cardiac microdialysis is essentially a modification of microdialysis techniques established in the early 1980s and currently used extensively in the brain to measure metabolites in the ISF. ¹³ The cardiac microdialysis technique as used in ourlaboratory has been described in detail. ^14,15 In brief, it involves the implantation of a small hollow dialysis fiber within the myocardial tissue and the continuous perfusion of the dialysis fiber with Krebs-Henseleit buffer. Diffusion occurs between the ISF surrounding the fiber and the fluid within the dialysis fiber. Adenosine and other molecules present in the ISF therefore enter the dialysis fiber and can be collected in the effluent. The concentration of a compound in the effluent (termed the dialysate concentration) is representative of the intramyocardial ISF concentration of that substance. The in vitro percent recovery of the dialysis fibers was determined by placing fibers (1.0 cm window, n = 6) into a small chamber filled with Krebs-Henseleit buffer supplemented with adenosine 10 µmol/L and maintained at 4° C. The fibers were perfused with cold Krebs-Henseleit buffer at a flow rate of 2.0 µl/min, then stored and analyzed by a method similar to that used for biologic samples.

Biochemical analysis
Adenosine, inosine, and hypoxanthine in pulmonary effluent and dialysate samples were analyzed by high-performance liquid chromatography (HPLC; Waters Chromatography Division of Millipore, Marlborough, Mass.). Samples were injected onto a C-18 reverse phase analytical column (Supelcosil C-18, Bellafonte, Pa.) and eluted via a step gradient method over a period of 20 minutes. The initial buffer consisted of 100 mmol/L KH₂PO₄ plus 1% methanol (pH 5.3) and the second buffer consisted of 50% methanol and 50% water. Peaks of interest were determined by absorbance at 254 nm and identified by comparison of retention times to known external standards. Peak quantification was determined by peak area using the Maxima data acquisition system (Waters Chromatography).

All reagents for the preservation and perfusion solutions were analytical grade. All solutions were made the day of the experiment. Reagents for HPLC were HPLC grade.

Statistical analysis
All results are expressed as mean plus or minus the standard error of the mean. Differences between dialysate purine levels in UW and UW - ADO hearts were analyzed by one-tailed Student's t test. Postpreservation functional data were analyzed by a one-way analysis of variance with statistical significance between the groups determined by Duncan's test. A p value of less than 0.05 was considered statistically significant.

RESULTS

Metabolic studies
In hearts preserved with standard UW solution pulmonary effluent concentrations of adenosine, inosine, and hypoxanthine at the end of the flush were 4.51 ± 0.14 mmol/L, 0.13 ± 0.04 mmol/L, and 0.05 ± 0.02 mmol/L, respectively. Dialysate purine levels in hearts flushed and cold-stored in standard UW solution are shown in Fig. 1. The in vitro percent recovery of the dialysis fibers used in this study was 25% ± 3%. During the first collection period dialysate adenosine, inosine, and hypoxanthine levels were 154.0 ± 38.5 µmol/L, 50.5 ± 8.5 µmol/L, and 4.2 ± 0.7 µmol/L, respectively. Adenosine levels progressively decreased to 40.8 ± 4.0 µmol/L after 10 hours and remained stable thereafter. Inosine levels peaked at 4 hours of cold storage (64.7 ± 9.2 µmol/L) and decreased to 42.4 ± 4.5 µmol/L at 24 hours. Dialysate hypoxanthine concentrations steadily increased to 11.0 ± 1.4 µmol/L during cold storage.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Dialysate purine levels during 24 hours of cold storage in hearts (n = 5) flushed with UW solution. Dialysis fibers 1 cm in length were perfused with Krebs-Henseleit buffer at flow rate of 2.0 µl/min. Samples were collected over 10-minute period. All values are significantly greater than corresponding values in Fig. 2.

View larger version (19K): [in this window] [in a new window]   Fig. 2. Dialysate purine levels during 24 hours of cold storage in hearts (n = 5) flushed with UW–ADO. Adenine (5 mmol/L) was added to UW solution to maintain constant osmolarity.

View larger version (16K): [in this window] [in a new window]   Fig. 3. Effects of 18 hours of cold storage with UW, UW–ADO, and St. Thomas' Hospital (STS) solutions on rate-pressure product (RPP) of isolated perfused hearts. Rate-pressure product of fresh control hearts is shown for comparison. Asterisk indicates p < 0.05 versus UW group.

View larger version (15K): [in this window] [in a new window]   Fig. 4. Effect of dobutamine (125 µg bolus) on rate-pressure product (RPP) after 18 hours of cold storage with UW, UW–ADO, and St. Thomas' Hospital (STS) solutions. Rate-pressure product of fresh control hearts is shown for comparison. Asterisk indicates p < 0.05 versus UW hearts. RP, Reperfusion.

The results of this study indicate that adenosine exerts a cardioprotective effect during cold-storage preservation of the heart with UW solution. Hearts preserved with UW solution exhibited greater reperfusion function after 18 hours of cold storage than hearts preserved with UW–ADO and St. Thomas' Hospital cardioplegic solution. Estimates of ISF purine levels with the cardiac microdialysis technique indicated that enhanced reperfusion function with UW solution preservation was associated with augmented ISF adenosine levels during cold storage.

Numerous studies have compared UW preservation solution with other crystalloid preservation solutions, most commonly St. Thomas' Hospital cardioplegic solution. ^16-21 The majority of these studies, conducted in rat, pig, and canine hearts, concluded that UW solution provided superior myocardial preservation, ^16-18,20,21 consistent with the results obtained in this study in the rabbit heart. The UW solution has also been shown to provide superior cardiac preservation compared with the modified Collins', Stanford, and Bretschneider's cardioplegic solutions, which have low sodium and low chloride electrolyte compositions in addition to glucose or mannitol, or both, added as impermeants. ^16,22-25 The superior preservation with UW solution is presumably a result of its intracellular-based electrolyte composition and inclusion of lactobionate, raffinose, and hydroxyethyl starch. The low-sodium, high-potassium formulation of UW solution presumably retards cell swelling by reducing the electrochemical gradients of these ions. Lactobionate, raffinose, and hydroxyethyl starch were added as impermeants to reduce interstitial edema. Recently Ko and associates ²⁶ reported that the intracellular-based electrolyte composition and inclusion of hydroxyethyl starch appeared to be important components of UW solution, but raffinose could be omitted and chloride substituted for lactobionate with little if any effects on postpreservation function.

The results of this study indicate that adenosine also plays a significant role in enhanced preservation with UW solution. Rabbit hearts cold-stored for 18 hours with UW solution exhibited significantly greater reperfusion function than hearts preserved with UW–ADO and St. Thomas' Hospital solution. Adenosine was originally added to UW solution to accelerate adenosine triphosphate resynthesis via stimulation of the purine salvage pathway, ¹ and adenosine administration has been reported to stimulate postischemic adenine nucleotide pool repletion. ^27,28 However, recently obtained results suggest that the beneficial effect of adenosine on reperfusion function after normothermic ischemia is independent of its effects as an adenine nucleotide precursor. ^9,11 In addition, it is currently recognized that total myocardial adenosine triphosphate content does not correlate well with postischemic recovery of left ventricular function. ^29,30 Consistent with these findings, the majority of myocardial preservation studies with UW solution have reported no beneficial effect on myocardial adenosine triphosphate content. ^{16,18-20,24,31}

Current evidence indicates that adenosine exerts its cardioprotective effect via interaction with membrane-bound adenosine A₁ receptors located on the cardiac myocytes. This hypothesis is supported by the observation that the cardioprotective effect of adenosine is mimicked by adenosine A₁ receptor agonists and blocked by adenosine A₁ receptor antagonists, whereas adenosine A₂ receptor antagonists have no beneficial effect. ^8-10 We did not test the efficacy of adenosine A₁ receptor agonists or antagonists in this model, but the results obtained in this study with the cardiac microdialysis technique are consistent with this hypothesis. Cardiac microdialysis samples the ISF compartment, which is in direct contact with the myocytes, thus the concentration of adenosine in the ISF determines the effective concentration of adenosine at the A₁ receptor. Although this is the first study that documents an association between increased ISF adenosine levels during cold-storage preservation and enhanced reperfusion ventricular function, there is other evidence to support this hypothesis. The nucleoside transport inhibitor R75231 has been shown to increase survivability and in vitro left ventricular function in canine hearts subjected to 24 hours of cold storage. ^32,33 Nucleoside transport inhibitors increase interstitial adenosine concentration by diminishing the cellular uptake of adenosine, thereby reducing its metabolism. In addition, Dorheim and associates ¹² reported that treatment with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine augmented endogenous ISF adenosine levels during coronary artery occlusion in the dog and improved postischemic regional ventricular function.

It must be pointed out that the dialysate purine measurements reported here, although representative of myocardial ISF, provide only an estimate of true ISF concentration. Because of tissue trauma during probe implantation dialysate adenosine levels are initially elevated, but rapidly decrease and stabilize within 60 to 90 minutes. ^12,14 Thus the dialysate levels during the first hour of cold storage in the UW–ADO hearts may actually overestimate ISF purine levels. Under the conditions used in this study (1 cm dialysis window, 2 µl/min perfusion rate, 4° C) in vitro percent recovery is 25%. Actual percent recovery in situ may be even less, especially with prolonged implantation (24 hours) of the fiber.

Despite the limitations of cardiac microdialysis, several conclusions can be drawn from the dialysis purine measurements in this study. Inclusion of adenosine in the UW solution elevated dialysate adenosine levels during cold storage 20- 40-fold compared with levels in hearts flushed and stored in UW–ADO. These results suggest that ISF adenosine concentration was significantly augmented during storage with UW solution. A comparison of purine levels in the pulmonary effluent (during the UW solution flush) and the first dialysate sample (20 minutes after probe insertion) revealed significant metabolism of adenosine as it crosses the coronary endothelium, even at 4° C. These results are consistent with previously published reports of extensive metabolism of adenosine as it traverses the coronary endothelium. ^34,35

The beneficial effect of adenosine observed in these studies was demonstrated in Krebs-perfused, nonejecting hearts. Obviously more extensive in vivo studies are needed to determine whether adenosine provides a similar cardioprotective effect in clinically relevant myocardial preservation models. Despite these limitations, the results of this study suggest that UW solution provides superior myocardial preservation compared with St. Thomas' Hospital cardioplegia solution. Functional and metabolic results obtained with omission of adenosine from UW solution support the hypothesis that adenosine plays a major role in prolonged cold-storage myocardial preservation possibly via interaction with myocardial adenosine A₁ receptors.

Acknowledgments

We thank Mr. Timothy L. Beard, Mr. Gregory M. Anderson, and Mr. Patrick A. Konyn for their expert technical assistance.

References

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