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J Thorac Cardiovasc Surg 1995;110:63-74
© 1995 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Madison, Wis.
Supported by National Heart, Lung, and Blood Institute grant HL-34579-08.
Received for publication June 2, 1994. Accepted for publication Oct. 24, 1994. Address for reprints: Robert M. Mentzer, Jr., MD, Chairman, Division of Cardiothoracic Surgery, University of Wisconsin, Department of Surgery, Clinical Science Center, H4/358, 600 Highland Ave., Madison, WI 53792.
Abstract
Augmentation of endogenous adenosine levels is associated with decreased myocardial ischemic-reperfusion injury. The purpose of this study was to determine whether exogenous adenosine administered before ischemia could attenuate postischemic myocardial dysfunction. Regional myocardial stunning was induced by 15 minutes of coronary artery occlusion and 90 minutes of reperfusion in an open-chest canine preparation. Regional ventricular function was assessed by measurement of systolic wall thickening. Control untreated hearts were compared with two groups of hearts treated immediately before ischemia with intracoronary adenosine (5µg/kg per minute and 50µg/kg per minute). A fourth group of hearts was treated for the first 30 minutes of reperfusion with adenosine (50µg/kg per minute). Preischemic adenosine administration increased coronary flow sixfold to sevenfold without altering regional function, mean arterial pressure, or left ventricular end-diastolic pressure. Both adenosine pretreatments attenuated stunning compared with results in control animals (14.7%±5.1% and 21.6%±7.3% of preischemic systolic wall thickness versus -14.0%±10%). Adenosine treatment during reperfusion transiently increased function in parallel with increased coronary blood flow, but after termination of the infusion regional function was not different from that in control stunned hearts (-5.0%±13.1% of preischemic systemic wall thickness). These results indicate that adenosine pretreatment is associated with attenuation of stunning, an effect that can be produced at doses that do not alter systemic hemodynamics. (J THORAC CARDIOVASC SURG 1995;110:63-74)
Postischemic myocardial dysfunction that follows a brief ischemic episode insufficient to cause irreversible injury is referred to as stunned myocardium.
1 This dysfunction can persist for hours to days depending on the severity and duration of the antecedent ischemic event and occurs despite restoration of normal coronary blood flow (CBF). There is evidence that myocardial stunning is seen clinically after cardiac surgery and coronary thrombolysis. 2 Although the mechanism or mechanisms remain unknown, 3 much interest has been generated to develop therapeutic interventions to prevent or minimize myocardial stunning.
One of the agents currently under investigation is the rapidly metabolized purine nucleoside adenosine. Adenosine has been reported to enhance myocardial energy status, 4 prolong the time to onset of ischemic contracture, 5 and reduce infarct size. 6 Elevation of endogenous adenosine levels with adenosine metabolism inhibitors has been reported to reduce postischemic dysfunction. 7-10 Adenosine has also been proposed to mediate the infarct-size-reducing effect of ischemic preconditioning. 11
Adenosine exerts its numerous cardiovascular effects by interacting with specific membrane proteins, referred to as adenosine A1 and A2 receptors, located primarily on cardiac myocytes and endothelial cells, respectively. 12 The results of studies with adenosine A1 receptor agonists and antagonists support the hypothesis that the cardioprotective effect of adenosine is mediated via the interaction of adenosine with the A1 receptor. 5,6,13 The adenosine A1 receptor mechanism is contingent on accumulation of adenosine in the interstitial fluid (ISF) that bathes the cardiac myocytes. There are few if any in vivo studies, however, that have directly tested this hypothesis, most likely because of the rapid metabolism of adenosine and potential systemic hemodynamic side effects. The purpose of this study was therefore to determine (1) whether exogenous adenosine exerts a cardioprotective effect in an in vivo regional stunning model and (2) whether timing of adenosine administration is critical in altering postischemic dysfunction.
MATERIAL AND METHODS
General experimental preparation
All experiments were conducted in accordance with the guidelines set by the National Institutes of Health in the Guide for the Care and Use of Laboratory Animals (DHEW Publication No. 85-23) and were approved by the Laboratory Animal Care Committee at the University of Wisconsin-Madison.
Healthy, adult mongrel dogs of either sex weighing 20 to 25 kg were premedicated with morphine sulfate (3 mg/kg intramuscularly) and then anesthetized with sodium pentobarbital (30 mg/kg intravenously) with periodic supplementation (0.5 to 1.0 mg/kg intravenously). The animals were intubated and the lungs ventilated (model 613 dog respirator; Harvard Apparatus, S. Natick, Mass.) with a mixture of 100% oxygen and air. Tidal volume, respiratory rate, and inspired oxygen content were adjusted to maintain oxygen tension between 100 and 200 mm Hg, carbon dioxide tension at 35 to 45 mm Hg, and a physiologic pH. Lactated Ringer's solution was administered via a left forelimb vein to maintain hydration. Core body temperature was monitored with an esophageal temperature probe and was maintained at 38º C with a heating pad. The left femoral artery was cannulated to monitor blood pressure and to obtain samples for arterial blood gas analysis.
A left thoracotomy was done in the fifth intercostal space and the fifth rib was excised The pericardium was opened and the heart suspended in a pericardial cradle. A segment of the left anterior descending (LAD) coronary artery was dissected for a length of 2 to 3 cm just distal to the first diagonal branch. On the proximal portion of the LAD, a modified 24-gauge catheter was inserted for intracoronary infusion of phosphate-buffered saline (PBS) solution or adenosine. A snare was placed just distal to the catheter to allow placement of a bulldog clamp for occlusion of the LAD. An ultrasonic flow probe (model 2R579; Transonic Systems, Inc., Ithaca, N.Y.) for monitoring LAD CBF was placed distal to the snare. A Millar micromanometer (model MPC-500; Millar Instruments, Inc., Houston, Tex.) for monitoring left ventricular pressure was inserted through the apex of the heart into the left ventricle. This signal was electronically differentiated to obtain dP/dt, the first derivative of left ventricular pressure. Regional ventricular function, expressed as percent systolic wall thickening, was assessed with pairs of piezoelectric crystals connected to a sonomicrometer (Triton Technology, San Diego, Calif.). The endocardial crystals were embedded in the territories perfused by the LAD and left circumflex coronary arteries such that the crystals were positioned on the endocardial surface. The epicardial crystals were perpendicularly aligned with respect to the endocardial crystals, as determined by the signal output on an oscilloscope (Gould 60 MHz oscilloscope 3060; Gould, Inc., Cleveland, Ohio). Adequacy of LAD crystal placement was checked with a 40-second LAD occlusion during the equilibration period. The left circumflex artery crystal served as a control for the stability of the preparation during the experiment.
Cardiac microdialysis
Cardiac microdialysis probes were then inserted into the ventricular muscle of the beds perfused by the LAD and left circumflex arteries. The technique of cardiac microdialysis has been described in detail. 14 In brief, the microdialysis probes, which have a 2 cm dialysis window and an in vitro recovery rate of 70%, were perfused at 2 µl/min with Krebs-Henseleit buffer contained in gas-tight glass syringes. The Krebs-Henseleit buffer equilibrates with the myocardial ISF by diffusion as it passes through the dialysis fiber. The effluent or dialysate obtained by this process provides an index of myocardial ISF nucleoside concentration. The samples were collected and stored at -80º C until later analysis by high-performance liquid chromatography. Adenosine, inosine, and hypoxanthine were separated with a reverse-phase column (Supelcosil C-18; Supelco, Bellefonte, Pa.) by previously described methods. 8,14 Peaks were identified and quantitated by comparison of retention times and peak areas with external standards by use of a Maxima software package (Waters Associates, Marlborough, Mass.).
Canine experimental protocols
Protocols began after a 90-minute equilibration timed from the insertion of the dialysis probes. A previous study demonstrated that 90 minutes was required for interstitial nucleoside levels to return to baseline after insertion of the dialysis probes. 14 Figure 1 depicts the specific protocols used in the canine studies. All groups underwent 40 minutes of preischemia, 15 minutes of LAD occlusion, and 90 minutes of reperfusion, except the adenosine postischemic treatment group, which underwent reperfusion for 60 minutes. Group 1 control hearts (n = 12) received PBS in the LAD catheter in the preischemic and reperfusion periods. To determine the acute effects of adenosine-induced hyperemia in stunned myocardium, dogs received a 10-minute infusion of adenosine (50 µg/kg per minute by intracoronary administration) at 30 and 60 minutes of reperfusion. Groups 2 (n = 9) and 3 (n = 15) received intracoronary adenosine infusions for 20 minutes immediately before ischemia at doses of 5 µg/kg per minute and 50 µg/kg per minute, respectively. The length of the adenosine infusion was based on the time required to collect two 10-minute dialysate fluid collections. Similar to the protocol in group 1, the effects of brief adenosine infusions were tested during reperfusion. Group 4 animals (n = 7) were treated with adenosine (50 µg/kg per minute by intracoronary administration) for the initial 30 minutes of reperfusion. The infusion was initiated during the last minute of ischemia.
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An average of three consecutive heartbeats was used to calculate hemodynamic and functional data. For the calculation of systolic wall thickening, end diastole was defined as the onset of peak positive dP/dt and end systole as 20 msec before peak negative dP/dt. Percent systolic wall thickness (% SWT) was calculated by the following formula: % SWT = (ESWT - EDWT)/EDWT x 100%, where ESWT and EDWT are defined as end-systolic wall thickness and end-diastolic wall thickness, respectively.
Porcine experimental protocols
Similar regional stunning experiments were done in a small set of pigs (n = 4 per group) to determine whether the effects of adenosine in the ischemic heart were dependent on the presence of preexisting collaterals. It is thought that the porcine heart is similar to human myocardium with respect to its low native coronary collateral flow. 15 Durok-Landrace pigs (29 to 34 kg) were premedicated with ketamine (1 gm intramuscularly) and then anesthetized with sodium pentobarbital (25 mg/kg intravenously) with maintenance by a pentobarbital drip (10 to 15 mg/kg per hour). A tracheostomy was done for airway control followed by anterior chest wall removal. The subsequent instrumentation was identical to that used in the canine model including placement of piezoelectric crystals and cardiac microdialysis probes. All pigs underwent 20 minutes of preischemia, 10 minutes of regional LAD occlusion, and 90 minutes of reperfusion. Reduction of the occlusion time from 15 to 10 minutes was necessary to avoid a high fibrillation rate and avoid any irreversible ischemic injury. Control pigs were treated with PBS infused into the LAD catheter during preischemia and reperfusion. The pigs were administered lidocaine (2.5 mg/kg intravenously) 30 seconds before reperfusion. Animals pretreated with adenosine were administered intracoronary adenosine (100 µg/kg per minute) for 10 minutes immediately before ischemia.
Materials
Adenosine was purchased from Sigma Chemical (St. Louis, Mo.). A stock solution of 2.5 mg/ml of adenosine was made in PBS and was infused at 0.45 to 0.52 ml/min. All chromatography reagents were high-performance liquid chromatography grade.
Statistical analysis
All data are expressed as means plus or minus the standard error of the mean. Functional, hemodynamic, and metabolic differences within groups were determined with either one-way repeated-measures analysis of variance or analysis of covariance. If a significant F ratio was obtained, further comparisons were determined with Newman-Keuls post-hoc test. Differences between groups were ascertained with orthogonal planned comparisons among the groups, and F ratios with p < 0.05 were considered significant.
RESULTS
Canine preparation
Of the 75 dogs entered into the study 32 were excluded from final data analysis. Exclusion was based on the following criteria: (1) absence of dyskinesis during LAD occlusion, (2) ventricular fibrillation during ischemia or reperfusion, and (3) the presence of heartworms, which was assessed at the conclusion of each experiment (Table I). A 
2 analysis did not demonstrate any differences in the rate of fibrillation among the groups. The remaining 43 animals were included in all hemodynamic and functional data assessments. The ischemic bed sizes were expressed as a percent of the left ventricle. There were no significant differences in the size of the ischemic beds among the groups (35.0% ± 1.7%, 30.2% ± 2.6%, 33.8% ± 2.0%, and 30.7% ± 1.4% for groups 1 through 4, respectively). The effects of the various treatments on hemodynamic parameters are presented in Table II. Baseline mean arterial pressure, heart rate, and left ventricular end-diastolic pressure were similar among the groups, with the exception of +dP/dt, which was lower in the pretreatment low-dose group. Preischemic infusion of adenosine increased heart rate at the 5 µg/kg per minute dose and increased both heart rate and +dP/dt at 50 µg/kg per minute. During ischemia there were no intergroup differences in mean arterial pressure, heart rate, or left ventricular end-diastolic pressure. The only significant difference in systemic hemodynamic parameters among the groups during reperfusion was better preservation of baseline mean arterial pressure and +dP/dt in the animals pretreated with high-dose adenosine.
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Dialysate adenosine levels were similar among the groups at baseline (Fig 2). Pretreatment with 5 µg/kg per minute adenosine had no effect on dialysate adenosine values compared with control values. In contrast, dialysate adenosine concentration doubled during adenosine infusion at 50 µg/kg per minute (0.55 ± 0.12 µmol/L to 1.25 ± 0.30 µmol/L, p < 0.05). The majority of the nucleosides in this group were in the form of the adenosine metabolites inosine, which increased eightfold, and hypoxanthine, which increased fourfold. During regional ischemia there was a comparable fivefold to sixfold increase in dialysate adenosine levels in all groups. ISF adenosine was rapidly washed out during reperfusion, such that by 20 minutes of reperfusion, adenosine levels returned to preischemic values in control and both pretreated groups. The brief adenosine infusions (50 µg/kg per minute) at 30 minutes of reperfusion in control animals and animals pretreated with adenosine increased dialysate adenosine concentration (0.39 ± 0.07 µmol/L to 1.38 ± 0.52 µmol/L and 0.41 ± 0.09 µmol/L to 0.99 ± 0.20 µmol/L, respectively, p < 0.05). Dialysate adenosine levels rapidly returned to preinfusion values with cessation of the adenosine infusion. A similar response was seen during a second adenosine infusion at 60 minutes of reperfusion.
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The effects of the various treatments on myocardial stunning are illustrated in Fig 3. The LAD percent systolic wall thickening was similar at baseline (16.6% ± 1.6%, 19.2% ± 1.6%, 16.7% ± 1.3%, and 17.5% ± 1.9% for groups 1 through 4, respectively). During preischemic adenosine infusion there was no change in regional function from baseline (19.2% ± 1.6% versus 19.8% ± 1.7% and 16.7% ± 1.3% versus 17.6% ± 1.6% for the low-and high-dose adenosine groups, respectively). All groups demonstrated comparable levels of systolic thinning during LAD occlusion. After 10 minutes of reperfusion both adenosine pretreatment groups exhibited elevated systolic wall thickening (21.6% ± 7.3% and 19.0% ± 10.9% of preischemic values, respectively), whereas control hearts exhibited systolic thinning. After 90 minutes of reperfusion regional function in the low-dose group was 14.7% ± 5.1%, whereas in the pretreated high-dose group it was 26.2% ± 10.0%. Adenosine infusion during the initial 30 minutes of reperfusion was associated with a slight, but not significant, increase in regional function. However, on termination of the adenosine infusion, function rapidly decreased from 3.6% ± 17.4% to -11.1% ± 13.2% of baseline. At 60 minutes of reperfusion, LAD regional function was -5.0% ± 13.1% in this group, comparable to that in control animals (-14.0% ± 10.0% at 60 minutes of reperfusion) (Fig. 3).
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The alterations in dialysate adenosine levels are illustrated in Fig 5. Dialysate adenosine levels were similar between the groups at baseline (0.64 ± 0.15 µmol/L and 0.79 ± 0.03 µmol/L for control and adenosine-pretreated groups, respectively). Intracoronary adenosine infusion (100 µg/kg per minute) significantly increased dialysate adenosine levels ninefold in the pretreatment group (6.98 ± 2.45 µmol/L, p < 0.001), but, similar to results in the dog, the majority of the nucleosides were in the form of adenosine metabolites inosine and hypoxanthine. There were no further differences in dialysate adenosine levels during ischemia or reperfusion.
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Intracoronary infusion of adenosine immediately before ischemia was associated with elevated ISF adenosine levels, minimal systemic hemodynamic effects, and a sustained attenuation of myocardial stunning in canine and porcine hearts. In contrast, administration of adenosine for 30 minutes at the onset of reperfusion only marginally increased regional ventricular function, an effect that rapidly dissipated on termination of the adenosine infusion in parallel with a return of CBF to basal levels. These findings are consistent with the hypothesis that adenosine is a cardioprotective agent in vivo and suggest that the optimum time for adenosine administration is before the onset of ischemia.
There is substantial evidence that adenosine exerts beneficial effects in both reversibly and irreversibly injured myocardium. 5,6,13 The majority of in vivo studies have been done with adenosine metabolism inhibitors and slowly metabolized adenosine receptor analogs. Elevation of endogenous adenosine level with nucleoside transport 9,10 or adenosine deaminase inhibitors 7-9 has been shown to decrease in vivo postischemic ventricular dysfunction. In these studies adenosine levels were either not measured 7,10 or total tissue levels were assessed. 9 Tissue adenosine measurements comprise intracellular, interstitial, and vascular compartments and thus provide little information on adenosine levels in the compartments in contact with adenosine A1 and A2 receptors (that is, interstitial and vascular compartments, respectively). Dorheim et al., 8 using the same microdialysis technique as used in this study, reported that treatment before ischemia with the adenosine deaminase inhibitor 9-erythro-2-(hydroxy-3-nonyl) adenine (EHNA) increased ISF adenosine levels and postischemic recovery of regional ventricular function. Because myocyte adenosine A1 receptors are in contact with ISF, these results supported the hypothesis that adenosine attenuates myocardial stunning by an A1 receptor hypothesis.
There are few, if any, in vivo studies, however, on the effects of exogenous adenosine on reversible postischemic function. This is most likely because adenosine is rapidly metabolized by vascular endothelial and red blood cells 16 and consequently high doses of adenosine must be delivered to achieve adequate myocardial levels. Intracoronary adenosine at a dose (5 µg/kg per minute) that produced maximal coronary vasodilation did not increase ISF adenosine levels as determined by microdialysis. A 10-fold greater infusion rate increased ISF adenosine levels only twofold (from 0.6 ± 0.1 µmol/L to 1.2 ± 0.3 µmol/L), whereas the metabolites inosine and hypoxanthine increased eightfold and fourfold, respectively. Increasing the adenosine infusion rate to 100 µg/kg per minute in the pig increased ISF adenosine levels ninefold. Although plasma adenosine levels were not measured in this study, we have measured coronary venous plasma levels during a 50 µg/kg per minute intracoronary adenosine infusion in the pig. This dose increased ISF adenosine levels similar to the increase in the dog (from 0.5 ± 0.05 µmol/L to 2.0 ± 0.1 µmol/L), but the plasma adenosine level increased 50-fold (from 0.3 ± 0.09 µmol/L to 15.2 ± 1.8 µmol/L, unpublished observations). These results provide in vivo evidence of the metabolic barrier to exogenous adenosine as has been reported in vitro. 16
The infusion of 5 µg/kg per minute adenosine in the dog produced no detectable change in dialysate adenosine concentration but was associated with enhanced postischemic function. Although plasma adenosine levels were undoubtedly increased, it is possible that adenosine was completely metabolized before reaching the interstitial space. This would suggest that adenosine need not accumulate in the ISF to exert its protective effect. Although this may in fact be the case there are several alternative explanations. If the adenosine was completely metabolized by endothelial cells, we would have expected to see increased inosine and hypoxanthine levels, which was not the case. The inability to detect any increase in dialysate adenosine levels with this treatment may also be a result of the adenosine-induced hyperemia. Although the dialysis technique has several advantages, it provides only an estimate of interstitial metabolites and is influenced by changes in blood flow. 17,18 Increased CBF results in increased washout and an increase in the volume of the interstitial space. It is also possible that the resulting increase in myocardial oxygen supply may have actually decreased adenosine production. 17 Most likely, the higher dose of adenosine produced a sufficient plasma concentration to overcome the effects of rapid metabolism and increased interstitial washout.
Although there has been much concern expressed over the potential hemodynamic effects of the administration of adenosine, the three dosages used in this study were associated with few systemic hemodynamic effects. The lower adenosine dosage (5 µg/kg per minute) in the dog and the higher dosage (100 µg/kg per minute) in the pig had no systemic effects. The 50 µg/kg per minute adenosine infusion in the dog was associated with a small drop in arterial pressure and significant increases in heart rate and left ventricular +dP/dt, most likely because of baroreceptor reflex mechanisms or the activation of sympathetic afferents as has been suggested to occur in conscious human beings. 19,20 Although these effects are suggestive of increased myocardial oxygen demand at the onset of ischemia, this group exhibited the greatest attenuation of myocardial stunning in the canine study. It is evident from these results that the cardioprotective effect of adenosine was independent of and not compromised by its hemodynamic effects.
Although the mechanism of adenosine-mediated cardioprotection was not directly addressed in this study, the results do provide some insight into potential mechanisms. The observation that adenosine-enhanced postischemic function was associated with elevated preischemic ISF adenosine levels is consistent with the adenosine A1 receptor hypothesis because the concentration of adenosine in the interstitial space determines the amount of adenosine in the vicinity of the A1 receptor. The role of A1 receptors in the beneficial effect of adenosine is based on studies with adenosine receptor agonists and antagonists. 5,6,11,13 However, this is the first study that documents an association between exogenous adenosine-mediated increases in ISF adenosine levels and an attenuation of myocardial stunning.
It is possible that the beneficial effects of adenosine could have been secondary to enhanced collateral blood flow during ischemia, which would have limited the degree of injury and facilitated functional recovery. It is well known that collateral blood flow is an important determinant of ischemic injury, especially in dogs. 21 Because collateral blood flow was not measured this potential mechanism cannot be excluded. However, the adenosine infusion was terminated at the onset of ischemia and there were no differences in dialysate adenosine levels during ischemia among the groups. With the rapid metabolism of adenosine it is unlikely that adenosine infused into the LAD accumulated in the systemic circulation at levels great enough to promote coronary collateral vasodilation. Furthermore, the results from the porcine model, which has been shown to have very little native collateral blood flow, 15 indicate that the cardioprotective effect of adenosine is independent of collateral blood flow.
The inability to detect an increase in dialysate adenosine levels during the 5 µg/kg per minute adenosine infusion does not preclude the interaction of adenosine with the A1 receptor, but it is possible that the lower adenosine dosage protected the heart independent of adenosine A1 receptor activation. Adenosine increased CBF sixfold to sevenfold, which indicates activation of adenosine A2 receptors. However, the results of numerous studies with adenosine receptor agonists suggest that the adenosine A2 receptor plays little role in protecting the ischemic heart. 5,6,11,13 Early studies on the protective effect of adenosine were based on the role of adenosine as an adenine nucleotide precursor, but there is now substantial evidence that adenosine-mediated cardioprotection 13,22 and postischemic recoveryof function 23 are not dependent on tissue adenosine triphosphate levels.
There are several reports that treatment with adenosine transport/metabolism inhibitors attenuates myocardial stunning. 7-10 It is not clear from these studies what the exact mechanism of cardio-protection is, but we have reported that adenosine deaminase inhibition and adenosine transport blockade both increase ISF adenosine levels. , 10,24 These results are thus consistent with an adenosine A1 receptor mechanism. It has also been proposed that by preventing adenosine metabolism, these agents decrease the substrates (hypoxanthine and xanthine) for xanthine oxidase-induced oxygen free radical production. 9 Although this may be a potential mechanism, the 50 µg/kg per minute adenosine infusion in the dogs, which increased hypoxanthine levels fourfold, appeared to exert no detrimental effects. In addition, adenosine treatment in the pig heart, which similar to human myocardium has little xanthine oxidase activity, 25 was also cardioprotective.
The observation that adenosine treatment during the early reperfusion period failed to attenuate stunning indicates that adenosine must be administered (that is, the adenosine A1 receptor activated) before the onset of or during ischemia to attenuate postischemic ventricular dysfunction. These results suggest that adenosine exerts its protective effect during the ischemic period. Adenosine infusion transiently increased regional function in the stunned heart, but not in the normal heart. This effect, which has been reported by others, 26-28 is most likely an indirect effect because adenosine has no direct inotropic effects in mammalian ventricular myocardium. 12 The apparent positive inotropic effect of adenosine in the stunned heart appears to be related to increased CBF, inasmuch as it dissipated with the same time course as adenosine-induced hyperemia when the infusion was terminated. This effect may be related to the hyperemia-induced increase in wall thickness 29 or caused by an increase in oxygen delivery.
Adenosine has received much interest recently in its role in the infarct-size-reducing effect of ischemic preconditioning. 11 Although adenosine reduces both reversible and irreversible myocardial ischemic injury, the mechanisms by which it does so remain unclear. Neither ischemic preconditioning 30,31 nor a transient infusion of adenosine followed by washout attenuates myocardial stunning. 32-34 It thus appears that myocardial adenosine levels must be elevated and adenosine A1 receptors activated at the time of onset of ischemia to enhance postischemic function. For these reasons we refer to our treatment as "adenosine pretreatment" not "adenosine preconditioning."
Adenosine has been used clinically for the treatment of supraventricular arrhythmias, 35 coronary perfusion imaging, 36 and postoperative hypertension, 37 but because of its rapid metabolism and systemic effects these intravenous adenosine regimens may not be practical for protecting the ischemic heart. The results of this study, and of human studies, 19,20 however, suggest that intracoronary adenosine is well tolerated and may be cardioprotective in certain clinical settings, such as heart surgery and angioplasty.
Acknowledgments
We gratefully acknowledge the technical assistance of Julia Hegge, Gregory Anderson, Zhandong Zhou, and Patrick Konyn. The assistance of Karen E. Luh, PhD, and Dennis Heisey, PhD, in conducting the statistical analyses is particularly appreciated.
References
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p < 0.01 versus groups 1, 2, and 4. Values are expressed as mean plus or minus standard error of mean.
