Temperature threshold and modulation of energy metabolism in the cardioplegic arrested rabbit heart.

Hypothermia protects ischemic tissues by reducing ATP utilization and accumulation of harmful metabolites. However, it also reduces ATP production, which might cause deterioration in the energy supply/demand ratio. Modulation of energy supply/demand according to temperature has not been previously studied in detail. In this study, isolated, perfused rabbit hearts (n = 60) were used to determine the effects of various temperatures on myocardial energy metabolism and function during cardioplegic arrest. Ischemia was induced by crystalloid cardioplegic solution at 4, 18, 30, and 34 degrees C for 120 min, respectively. At each temperature, the hearts were divided into a glucose-treated group which contained 22 mM glucose in cardioplegic solution as the only substrate and a control group which contained 22 mM mannitol to keep same osmolarity. Following 15 min reperfusion, recovery of left ventricular developed pressure (DP), +/- dP/dtmax, and the product of heart rate and DP were significantly higher in 30, 18, and 4 degrees C groups than those in 34 degrees C control group. The functional recovery was also significantly higher in the 34 degrees C glucose-treated group than that in the 34 degrees C control group, but there was no difference between those groups at 30 degrees C and the temperature below 30 degrees C. Myocardial ATP concentration was significantly lower in 34 degrees C control group than those in other groups. There is a close relationship between myocardial ATP concentration and functional recovery (R2 = 0.90). The accumulations of lactate and CO2 were significantly higher at 34 degrees C in glucose-treated group than those in the control group. However, there was no significant difference between these two groups at 30 degrees C and the temperature below 30 degrees C. These results indicate that under these study conditions: (1) a marked decrease in energy supply/demand occurs above 30 degrees C, implying that a temperature threshold exists; and (2) this can be ameliorated by provision of glucose as substrate in cardioplegia solution.

The use of hibernation induction triggers for cardiac transplant preservation.

Cardiac transplant is hindered by donor shortage and preservation time. Extended extracorporeal preservation could increase the number and distribution of hearts for transplantation. Interestingly, mammalian hibernation biology closely parallels the altered cardiac cellular physiology noted with hypothermic organ storage. The present study undertook to test whether treatment with hibernation induction triggers could improve myocardial functional recovery following prolonged ischemic storage in a nonhibernating mammalian model. To study this hypothesis, isolated rabbit hearts had baseline functional and metabolic parameters recorded and then received either hypothermic storage only or standard cardioplegia, or cardioplegia containing 1 mg/kg D-Ala2-Leu5-enkaphalin (DADLE), which mimics natural hibernation, or preperfusion with DADLE, administered for 15 min at 2 mmol, 25 min prior to cardioplegic ischemia. Hearts were then subjected to 18 hr of global ischemic storage at 4 degrees C. Isovolumic developed pressure, coronary flows, and myocardial oxygen consumption were significantly improved with DADLE pretreatment vs. all groups after storage and reflow. Furthermore, DADLE hearts demonstrated better histological ultrastructure preservation following prolonged storage ischemia. This study demonstrates that hibernation protection with DADLE is beneficial for prolonged cardiac storage. The use of hibernation induction triggers is promising for organ preservation and deserve further mechanistic study.

Glucose level and myocardial recovery after warm arrest.

BACKGROUND: During induced cold ischemia for cardiac operations, increasing glucose concentration is not thought to enhance myocardial protection and may detrimentally affect recovery. However, during "warm aerobic" arrest, increased glucose availability as substrate could enhance postischemic metabolic and functional recovery, as during and after ischemia, myocytes shift preference for substrate from fatty acids to glucose. Unfortunately, hyperglycemia may also increase patient susceptibility to neurologic injury. METHODS: This experiment was designed to study the optimal dose of glucose and its effect on function during warm arrest. Isolated, retrograde-perfused rabbit hearts received multidose cardioplegia containing increasing concentrations of glucose, from 0 to 88 mmol/L, and underwent 120 minutes of "warm" 34 degrees C global ischemia. Osmolarities were adjusted equivalently. RESULTS: After 34 degrees C ischemia, hearts treated with 5 to 88 mmol/L glucose showed significantly better functional recovery than those treated with 0 to 1 mmol/L glucose. However, the addition of 22 mmol/L glucose demonstrated optimal recovery with no further incremental enhancement with more glucose. Additional hearts receiving 0 or 22 mmol/L glucose had high-energy phosphates, lactate, CO2, and pH measured. The 22 mmol/L glucose hearts demonstrated active metabolism and significantly better recovery of high-energy phosphate levels than controls. CONCLUSIONS: Increasing glucose level modestly during warm arrest enhanced recovery, but profound hyperglycemia did not incrementally improve this effect, mandating a cautious use of glucose.

Perfluorocarbon supplementation and postischemic cardiac function.

BACKGROUND: During induced ischemia for cardiac surgery inefficient anaerobic energy mechanisms predominate. Sustaining aerobic metabolism with perfluorocarbon-supplemented blood cardioplegia theoretically could lead to improved postischemic recovery. Therefore we studied functional recovery after myocardial ischemia, comparing perflubron (C8F17Br) supplemented blood cardioplegia to standard blood cardioplegia. METHODS: Nineteen dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 90 minutes of cardioplegic arrest by use of blood cardioplegia with or without perflubron and then 30 minutes of 37 degrees C reperfusion. During ischemia myocardial oxygen tension, temperature, and pH were measured. Postischemic left ventricular recovery was assessed by means of preload recruitable stroke work, exponential end-diastolic stress-strain regression, and preservation of adenosine triphosphate and energy charge. RESULTS: The addition of perflubron, a new shorter half-life, lecithin-emulsified perfluorocarbon, provided superior myocardial protection when compared with standard blood cardioplegia. This benefit was evidenced by significantly increased recovery of preload recruitable stroke work slope (71% +/- 8% versus 42% +/- 9%), decreased myocardial edema, and enhanced end ischemic myocardial oxygen and pH levels. CONCLUSIONS: The reliable oxygen delivery system and endothelial-preserving properties of the perfluorocarbons may prove to be an invaluable asset in addition to standard blood cardioplegia in the preservation of postischemic ventricular function. These data support the further investigation of perfluorocarbon-enriched blood cardioplegia.

Dichloroacetate enhanced myocardial functional recovery post-ischemia : ATP and NADH recovery.

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Isolated rabbit hearts were subjected to 120 min of mildly hypothermic (34 degrees C), cardioplegic arrest with multidose, modified St. Thomas' cardioplegia. Hearts were reperfused with either physiologic salt solution (PSS) as controls, (CON, n = 10) or PSS containing DCA (DCA, n = 6) at a concentration of 1 mM. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 min of reperfusion. In four DCA and four CON hearts, myocardial biopsies were taken at baseline, end-ischemia, 15 and 45 min for nucleotide levels. Functional recovery was significantly better in hearts reperfused with DCA as demonstrated by recovery of baseline developed pressure (DCA = 69 +/- 5%, CON = 45 +/- 9%) and dP/dt (DCA = 64% +/- 10% versus CON = 48% +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (79% +/- 20% of baseline vs 50% +/- 18%). Recovery of myocardial adenylate energy status was improved in the DCA versus CON hearts (ATP recovered to 45% +/- 20% versus 8% +/- 6% of baseline). Coronary sinus lactate concentration was decreased in DCA perfused hearts at 45 min of reperfusion. Percent of baseline NADH values was similar at 15 min of reperfusion, but at 45 min, DCA hearts showed a decrease in NADH levels, while CON hearts showed an increase (DCA = 48%; CON = 121%). The enhanced myocardial function and improved metabolic status noted with DCA may result from increased oxidative phosphorylation due to altered pyruvate dehydrogenase (PDH) activity.

Simultaneous detection of nucleotides, nucleosides and oxidative metabolites in myocardial biopsies.

A new simple, simultaneous matrix HPLC methodology was developed to facilitate better peak separability and resolution for the determination of levels of myocardial tissue nucleotides, nucleosides and oxidative metabolites. The components of interests were ATP, AMP, ADP, IMP, hypoxanthine, xanthine, adenosine, inosine, NAD, and NADH, which are used to establish myocardial cellular energy status and effectiveness of cardioprotection. Their detection was achieved using a 4-microns spherical bead, 300 x 3.9 mm I.D. Nova-Pak C18 column in a 12% methanol mobile phase solvent selection, ion-pairing reagents 1.47 mM TBAP (tetrabutylammonium phosphate) and 73.5 mM KH2PO4, at a pH of 4.0. The extraction method was modified for rapid determination to ensure diminished acid labile NADH effects. Comparisons of peak retention (k), resolution (Rs) of solvents of varying concentrations and pH adjustment facilitated this method. This isocratic single run determination allows for simple, simultaneous rapid quantification and identification of alterations in high-energy phosphates, nucleoside degradation products and NAD/NADH levels associated with myocardial ischemia, with excellent reliability.

The mechanism of amino acid loading in improving postischemic myocardial recovery.

During induced ischemia for cardiac surgery, myocardial stunning occurs and aerobic metabolism of glucose, fatty acids, and lactate is altered. Following reperfusion, stunned myocardium uses oxygen and substrate inefficiently, leading to poor functional recovery. However, amino acids may be used as anaplerotic metabolic substrates during and after ischemia, utilizing transamination of amino acids to form high-energy phosphates via the tricarboxylic acid cycle. We investigated if loading hearts with a physiologic spectrum of amino acids prior to ischemia could increase postischemic myocardial recovery. Isolated perfused rabbit hearts were subjected to 120 min of 34 degrees C cardioplegic ischemia. Hearts received cardioplegia alone as controls or were loaded with a 0.05, 0.1, 0.5, 1, 2, or 5% amino acid perfusion prior to cardioplegic ischemia. Following reperfusion, functional recovery revealed that hearts perfused with 0.05 and 0.1% amino acids had improved contractility and compliance vs untreated controls. To determine if the mechanism of amino acid loading in improving postischemic function was enhancement of high-energy phosphate resynthesis, nucleotides and nucleosides were measured. While all preischemic values were equivalent, amino-acid-loaded hearts had significantly greater high energy nucleotides at end ischemia and after reperfusion. These data demonstrate that metabolism, as well as function, is improved with amino acid loading prior to ischemia, which allowed for better internal reparative work during ischemia and external contractile work after ischemia. This strategy may have application in cardiac surgery.

Functional recovery after ischemia: warm versus cold cardioplegia.

Warm continuous retrograde cardioplegia has been introduced for myocardial protection during cardiac operations, particularly in the setting of acute myocardial ischemia because of its theoretical advantage of producing arrest without ischemia. To investigate the ability of warm continuous retrograde cardioplegia to provide myocardial protection after acute global ischemia, versus the more commonly used cold intermittent antegrade cardioplegia, 12 dogs were subjected to 15 minutes of normothermic global myocardial ischemia on cardiopulmonary bypass followed by 75 minutes of protected cardioplegic arrest using either warm continuous retrograde cardioplegia or cold intermittent antegrade cardioplegia. Standard blood cardioplegia at clinically used volumes and flow rates was used. Warm continuous retrograde cardioplegia animals received 30 mL/kg antegrade to induce arrest followed by 1.5 to 1.8 mL.kg-1.min-1 retrograde at 37 degrees C, whereas cold intermittent antegrade cardioplegia animals received 30 mL/kg antegrade to induce arrest followed by 15 mL/kg antegrade every 15 minutes at 10 degrees C. Load-insensitive left ventricular systolic function, diastolic function, high energy nucleotides, and edema formation were assessed before and after ischemia. Results showed that myocardial preservation using clinically reported flow rates and volumes of warm continuous retrograde cardioplegia was significantly inferior to that provided by clinically used cold intermittent antegrade cardioplegia, as demonstrated by decreased preload recruitable stroke work slope (28 +/- 11 versus 71 +/- 6), increased alpha constant of the end diastolic stress-strain relationship (14.2 +/- 3.0 versus 3.6 +/- 1.0), decreased total nondiffusable nucleotides (40.7 +/- 2.3 versus 57.4 +/- 2.3 microM/g wet weight) and increased water content (82.2% +/- 0.4% versus 80.4% +/- 0.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine's effect on myocardial functional recovery: substrate or signal?

During induced ischemia for cardiac surgery, nucleotides are degraded while being used to maintain myocyte integrity. The resulting nucleosides washout upon reperfusion, limiting nucleotide resynthesis resulting in poor postischemic cardiac function. We studied if the mechanism of the beneficial effect of adenosine, a nucleotide precursor, which is known to improve postischemic functional recovery is as a substrate for nucleotide resynthesis or by stimulation of adenosine A1 or A2 receptors. Isolated, retrograde-perfused rabbit hearts received cardioplegia as controls or cardioplegia containing 80 microM [R]-N6-[1-methyl-2-phenylethyl]-adenosine, an A1 receptor agonist, or 200 microM 5'-(N-ethylcarboxamido)adenosine, or 200 microM adenosine alone. To assess functional recovery developed pressure, max dP/dt, pressure-rate product, coronary flow, and myocardial oxygen consumption were compared after 120 min of 34 degrees C global cardioplegic ischemia. Following ischemia and reperfusion, adenosine alone had better developed pressure, dP/dt, and pressure-rate product, while heart rates, wet weights, %H2O, end-diastolic volumes/pressures, and oxygen extraction were not significantly different between groups. While adenosine receptor stimulation may play a role, in this model the beneficial effect of adenosine on functional recovery appears to be mediated more by adenosine's role as a substrate for nucleotide resynthesis.

Stunning, preconditioning, and functional recovery after global myocardial ischemia.

Stunning (reversible myocardial ischemia without necrosis) occurs with induced global ischemia during cardiac operations and depresses the ability of the heart to utilize oxygen efficiently because less contractile work is developed per unit of oxygen utilized. Interestingly, regional studies have demonstrated dramatic infarct size reduction with stunning episodes before prolonged ischemia, a phenomenon known as myocardial preconditioning. It is postulated that the postischemic contractile dysfunction noted after stunning causes reduced energy demands, which "preconditions" myocardium to withstand a subsequent longer ischemic episode. Some evidence from regional studies suggests that preconditioning may improve functional recovery after ischemia. This study examined the complex relationship between stunning and preconditioning to functional recovery in a surgical setting of global ischemia. To study the effect of stunning, myocardial oxygen consumption, oxygen extraction, and functional indices of contractility were measured before and after isolated rabbit hearts were subjected to 10, 20, or 45 minutes of normothermic 37 degrees C global ischemic stun intervals. This demonstrated that while oxygen consumption and extraction quickly recover to prestun levels, contractility remains depressed well beyond the stun interval. To study the effect of preconditioning using stunning, isolated hearts were then subjected to 120 minutes of 34 degrees C cardioplegic-induced ischemia after preconditioning. Hearts received either modified St. Thomas cardioplegic solution as a control or cardioplegia administered after preconditioning with 37 degrees C ischemic stunning for 5, 10, 15, 20, or 45 minutes or multiple 5- or 10-minute stuns, with reperfusion before cardioplegic-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Dichloroacetate enhances myocardial functional and metabolic recovery following global ischemia.

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Sixteen isolated rabbit hearts were subjected to 120 minutes of mildly hypothermic (34 degrees C) cardioplegic arrest with multi-dose, modified St. Thomas' cardioplegia. Following ischemia, hearts were reperfused with either a physiologic salt solution (PSS) as controls, (CON, N = 10), or PSS containing DCA (DCA, N = 6) at a concentration of 1 mmol/L. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 minutes of reperfusion. Results were analyzed using analysis of variance (ANOVA, Sheffe F test) and significance was defined as P < 0.05. Functional recovery was significantly better in hearts reperfused with DCA. Developed pressure (DP) recovered to 62 +/- 4% of baseline in DCA hearts, compared to 37 +/- 8% in CON hearts. Recovery of dP/dt was also improved in DCA versus CON hearts (67 +/- 5 v 43 +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (71 +/- 10% of baseline, v 51 +/- 19%). Diastolic compliance during reperfusion was improved in those hearts receiving DCA, as was myocardial mechanical use efficiency (DP/MVO2). Correction of myocardial tissue pH to baseline values was similar in both groups, indicating that the beneficial effect on functional recovery seen with DCA was not solely related to amelioration of acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental differences in myocardial protection in response to 5'-nucleotidase inhibition.

Age-related differences in the activity of 5'-nucleotidase, an enzyme responsible for conversion of high-energy phosphates to their the diffusible precursors, may help to explain age-related differences in tolerance of global myocardial ischemia. Postischemic function and high-energy phosphate content were measured in the hearts of rabbits 7 to 10 days old (neonate), 30 to 40 days old (1 month), and 6 to 12 months old (adult). Hearts in each age group were subjected to 60 minutes of ischemia at 34 degrees C either with no cardioplegia, with unmodified St. Thomas' Hospital cardioplegic solution, or with St. Thomas' Hospital cardioplegic solution with pentoxifylline, a 5'-nucleotidase inhibitor. These groups were compared with one another and with control hearts that were continuously perfused for 1 hour. In adults, addition of pentoxifylline to St. Thomas' Hospital cardioplegic solution restored adenosine triphosphate and total nondiffusible nucleotide levels to control values and improved recovery of cardiac output and developed pressure compared with results with unmodified St. Thomas' Hospital cardioplegic solution. In contrast, biochemical and functional parameters in neonatal hearts were not affected by either unmodified St. Thomas' Hospital cardioplegic solution cardioplegia or St. Thomas' Hospital cardioplegic solution with pentoxifylline. Functional recovery in neonatal hearts subjected to unprotected ischemia was superior to that in the older age groups. In 1-month-old hearts, St. Thomas' Hospital cardioplegia improved recovery compared with recovery after unprotected ischemia, but no incremental improvement in function or high-energy stores was seen with addition of pentoxifylline. The lack of effect of pentoxifylline on neonatal hearts suggest that there is a relative deficiency of 5'-nucleotidase in this age group. This may contribute to the improved functional recovery observed in unprotected hearts. Furthermore, addition of pentoxifylline to adult hearts appears to confer the benefits of low 5'-nucleotidase activity occurring naturally in the neonate.

Precursor trapping: a "neonatal" mechanism of myocardial protection.

During induced ischemia for cardiac surgery, 5'-nucleotidase (5NT) catalyzes nucleotide breakdown by dephosphorylating AMP and IMP to diffusible precursors--adenosine and inosine. These precursors become unavailable upon reperfusion washout limiting nucleotide resynthesis, resulting in poor postischemic function. Neonatal hearts, which are more resistant to ischemia than adults, have low 5NT activity, trapping available precursors. Adult rabbit hearts given cardioplegia with a 5NT inhibitor, pentoxifylline, demonstrated improved postischemic contractility, compliance, and myocardial oxygen consumption after 120 min of 34 degrees C ischemia. To determine if this improved function was a result of enhanced nucleotide precursor availability during or following ischemia, total nondiffusible nucleotides, ATP, ADP, AMP, and IMP, and total diffusible nucleotides, adenosine, inosine, hypoxanthine, and xanthine, were measured by HPLC at end ischemia, 1 and 15 min after reperfusion. While all preischemic values were equivalent, pentoxifylline-treated hearts had significantly greater total non-diffusible nucleotides at end ischemia, 1 and 15 min after reperfusion. Additionally, pentoxifylline-treated hearts had significantly greater total diffusible nucleosides at end ischemia and 1 min after reperfusion, but were equal to control at 15 min after reperfusion. Furthermore, coronary sinus effluent had a significantly higher release of total diffusible nucleosides in control vs pentoxifylline-treated hearts. The data indicate that precursor trapping with pentoxifylline prevented nucleotide catabolism to diffusible precursors and enhanced postischemic nucleotide availability. We postulate the increased precursor availability augmented myocardial nucleotide resynthesis and correlated with the improved functional recovery noted. This strategy may have application in adult cardiac surgery.

Flavone improves functional recovery after ischemia in isolated reperfused rabbit hearts.

The effects of flavone (2-phenyl-1,4-benzopyrone), a modulator of the cytochrome P-450 monooxygenase system, on myocardial postischemic reperfusion recovery were examined in the present study. Left ventricular functional recovery was evaluated in isolated, crystalloid-perfused rabbit hearts after 2 hours of modestly hypothermic (34 degrees C) global ischemia. Four groups (n = 8 in each group) were studied and compared: a vehicle control group, a second group pretreated with flavone (8 x 10(-6) mol/L) before ischemia, a third group pretreated with flavone followed by SKF 525-A (1.7 x 10(-5) mol/L), an inhibitor of cytochrome P-450, and a fourth group pretreated with flavone followed by indomethacin (1 x 10(-6) mol/L), an inhibitor of cyclooxygenase. At 15, 30, and 45 minutes after reperfusion, recovery of left ventricular developed pressure in the control group averaged (mean +/- standard deviation) only 2.60% +/- 12.7%, 35.5% +/- 15.0%, and 42.9% +/- 13.5% of baseline, respectively. In the flavone-treated group, recovery was significantly better, averaging 67.7% +/- 10.7%, 73.9% +/- 9.3%, and 73.6% +/- 7.6% of baseline at the same time periods. Recovery of peak positive rate of pressure rise in the control group averaged 27.4% +/- 15.2%, 38.6% +/- 19.2%, and 45.4% +/- 18.6% of baseline at 15, 30, and 45 minutes of reperfusion, respectively. In the flavone-treated group recovery values were significantly higher, averaging 67.8% +/- 9.6%, 77.3% +/- 8.5%, and 77.0% +/- 9.0% of baseline. End-diastolic pressures were significantly lower in the flavone-treated group compared with the control group at all reperfusion time points. Myocardial oxygen consumption was significantly higher in the flavone-treated group at 30 and 45 minutes of reperfusion, as well. The improvement resulting from flavone infusion was abolished completely by SKF 525-A, providing support for the interpretation that the effects of flavone were mediated through the cytochrome P-450 system. The cyclooxygenase inhibitor indomethacin midly attenuated the effects of flavone pretreatment, suggesting that the effects of flavone were only minimally related to metabolites of cyclooxygenase. We conclude that pretreatment with flavone represents a promising approach to myocardial protection that may be due to modulation of the myocardial cytochrome P-450 system.

Amino acid substrate preloading and postischemic myocardial recovery.

During induced myocardial ischemia for cardiac surgery, myocardial stunning occurs and aerobic metabolism of glucose, fatty acids, and lactate is inhibited as anaerobic pathways predominate. Even following reperfusion, stunned myocardium uses oxygen and substrate inefficiently leading to poor functional recovery as less mechanical work is developed per oxygen utilized. Amino acids potentially can act as cardiac metabolic substrates during and after ischemia, utilizing the transamination of amino acids by the malate-aspartate shuttle to form high energy phosphates via the tricarboxylic acid cycle. We investigated if "preloading" hearts with a physiologic spectrum of amino acids could increase postischemic myocardial recovery. Isolated perfused rabbit hearts were subjected to 120 min of 34 degrees C cardioplegic ischemia. Hearts received cardioplegia alone as controls or were "preloaded" with a 0.05% amino acid perfusion for 30 min prior to cardioplegic ischemia. Following reperfusion, analysis of functional recovery revealed that contractility and cardiac efficiency were improved with amino acids substrate preloading. The mechanism of this may be due to uptake of amino acids prior to ischemia, which are later utilized for internal reparative work during ischemia and external contractile work after ischemia.

Enhanced myocardial protection during global ischemia with 5'-nucleotidase inhibitors.

Depletion of adenosine triphosphate precursors, such as myocardial adenosine, during global ischemia results in poor postischemic adenosine triphosphate repletion and functional recovery. Neonatal hearts may be more resistant to this deleterious effect of ischemia, because they are characterized by low 5'-nucleotidase activity, which may result in higher sustained endogenous myocardial adenosine triphosphate precursor levels during ischemia. Adult hearts, however, have high levels of 5'-nucleotidase activity leading to depleted precursors during ischemia and poor postischemic functional recovery. Augmenting myocardial adenosine exogenously during ischemia in adult hearts has a beneficial effect on recovery. The present study tested if preservation of nucleotide precursors, better adenosine triphosphate repletion, and enhanced postischemic myocardial recovery in adult hearts could be achieved with a "neonatal" strategy. Therefore 5'-nucleotidase inhibitors were administered to isolated, perfused adult rabbit hearts subjected to 120 minutes of ischemia (at 34 degrees C) to determine if this improved functional recovery. Hearts received St. Thomas' Hospital cardioplegic solution (control hearts) or cardioplegic solution containing 5'-nucleotidase inhibitors: pentoxifylline, thioinosine, [s-(p-nitrophenyl)-4-thioinosine], or thioinosine's dimethyl sulfoxide vehicle alone. After ischemia and reperfusion, recovery of systolic function, diastolic function, and myocardial oxygen consumption was significantly better with 5'-nucleotidase inhibition. No changes in coronary flow were noted. We speculate and are pursuing the theory that the mechanism of 5'-nucleotidase inhibition's favorable action is due to preventing the catabolism, transport, and loss of nucleotide precursors during ischemia, maintaining adenosine triphosphate precursor availability.