Helen H. Young

Studies of hypoxemic/reoxygenation injury: Without aortic clamping:: VII. Counteraction of oxidant damage by exogenous antioxidants: Coenzyme Q10

Coenzyme Q10 (CoQ10) is a natural mitochondrial respiratory chain constituent with antioxidant properties. This study tests the hypothesis that CoQ10 administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass. The antioxidant properties of CoQ10 were confirmed by an in vitro study in which normal myocardial homogenates were incubated with the oxidant, t-butylhydroperoxide. Fifteen immature piglets (< 3 weeks old) were placed on 60 minutes of cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (oxygen tension about 400 mm Hg). Ten others became hypoxemic on cardiopulmonary bypass for 30 minutes by lowering oxygen tension to approximately 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 30 minutes. In five piglets, CoQ10 (45 mg/kg) was added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation, and five others were not treated (no treatment). Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter), oxidant damage (lipid peroxidation) was assessed by measuring conjugated diene levels in coronary sinus blood, and antioxidant reserve capacity was determined by measuring malondialdehyde in myocardium after cardiopulmonary bypass incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant damage and allowed complete functional recovery. Reoxygenated hearts (no treatment) showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation (2.3 +/- 0.6 A233 nm/0.5 ml plasma at 30 minutes after reoxygenation) and reduced antioxidant reserve capacity (malondialdehyde: 1219 +/- 157 nmol/g protein at 4.0 mmol/L t-butylhydroperoxide), resulting in severe postbypass dysfunction (percent end-systolic elastance = 38 +/- 6). Conversely, CoQ10 treatment avoided the increase in conjugated diene levels (2.1 +/- 0.6 vs 1.1 +/- 0.3, p < 0.05 vs no treatment), retained normal antioxidant reserve (896 +/- 76 nmol/g protein, p < 0.05 vs no treatment), and allowed nearly complete recovery of function (94% +/- 7%, p < 0.05 vs no treatment). We conclude that reoxygenation of the hypoxemic immature heart on cardiopulmonary bypass causes oxygen-mediated myocardial injury, which can be limited by CoQ10 treatment before reoxygenation. These findings imply that coenzyme Q10 can be used to surgical advantage in cyanotic patients, because therapeutic blood levels can be achieved by preoperative oral administration of this approved drug.

Endothelial stunning and myocyte recovery after reperfusion of jeopardized muscle: A role of l-arginine blood cardioplegia☆☆☆★★★

Ischemia and reperfusion may damage myocytes and endothelium in jeopardized hearts. This study tested whether (1) endothelial dysfunction (reduced nitric oxide release) exists despite good contractile performance and (2) supplementation of blood cardioplegic solution with nitric oxide precursor L-arginine augments nitric oxide and restores endothelial function. Among 30 Yorkshire-Duroc pigs, 6 received standard glutamate/aspartate blood cardioplegic solution without global ischemia. Twenty-four underwent 20 minutes of 37 degrees C global ischemia. Six received normal blood reperfusion. In 18, the aortic clamp remained in place 30 more minutes and all received 3 infusions of blood cardioplegic solution. In 6, the blood cardioplegic solution was unaltered; in 6, the blood cardioplegic solution contained L-arginine (a nitric oxide precursor) at 2 mmol/L; in 6, the blood cardioplegic solution contained the nitric oxide synthase inhibitor L-nitro arginine methyl ester (L-NAME) at 1 mmol/L. Complete contractile and endothelial recovery occurred without ischemia. In jeopardized hearts, complete systolic recovery followed infusion of blood cardioplegic solution and of blood cardioplegic solution plus L-arginine. Conversely, contractility recovered approximately 40% after infusion of normal blood and blood cardioplegic solution plus L-NAME. Postischemic nitric oxide production fell 50% in the groups that received blood cardioplegic solution and blood cardioplegic solution plus L-NAME but was increased in the group that received blood cardioplegic solution L-arginine. In vivo endothelium-dependent vasodilator responses to acetylcholine recovered 75% +/- 5% of baseline in the blood cardioplegic solution plus L-arginine group, but less than 20% of baseline in other jeopardized hearts. Endothelium-independent smooth muscle responses to sodium nitroprusside were relatively unaltered. Myeloperoxidase activity (neutrophil accumulation) was similar in the blood cardioplegic solution (without ischemia) and blood cardioplegic solution plus L-arginine groups (0.01 +/- 0.002 vs 0.013 +/- 0.003 microgram/gm tissue). Myeloperoxidase activity was raised substantially to 0.033 +/- 0.002 microgram/gm after exposure to normal blood and to 0.025 +/- 0.003 microgram/gm after infusion of blood cardioplegic solution and was highest at 0.053 +/- 0.01 microgram/gm with exposure to blood cardioplegic solution plus L-NAME in jeopardized hearts. The discrepancy between contractile recovery and endothelial dysfunction in jeopardized muscle can be reversed by adding L-arginine to blood cardioplegic solution.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping: III. Comparison of the magnitude of damage by hypoxemia/reoxygenation versus ischemia/reperfusion

The immature heart is more tolerant to ischemia than the adult heart, yet infants with cyanosis show myocardial damage after surgical correction of congenital cardiac defects causing hypoxemia. This study tested the hypothesis that the hypoxemic developing heart is susceptible to oxygen-mediated damage when it is reoxygenated during cardiopulmonary bypass and that this hypoxemic/reoxygenation injury is more severe than ischemic/reperfusion stress. Fifteen Duroc-Yorkshire piglets (2 to 3 weeks old, 3 to 5 kg) underwent 60 minutes of 37 degrees C cardiopulmonary bypass. Five piglets (control) were not made ischemic or hypoxemic. Five underwent 30 minutes of normothermic ischemia (aortic clamping) and 25 minutes of reperfusion before cardiopulmonary bypass was discontinued. Five others underwent 30 minutes of hypoxemia (bypass circuit primed with blood with oxygen tension 20 to 30 mm Hg) and 30 minutes of reoxygenation during cardiopulmonary bypass. Functional (left-ventricular contractility) and biochemical (levels of plasma and tissue conjugated dienes and antioxidant reserve capacity) measurements were made before ischemia/hypoxemia and after reperfusion/reoxygenation. Cardiopulmonary bypass (no ischemia or hypoxemia) caused no changes in left-ventricular function or coronary sinus levels of conjugated dienes. The tolerance to normothermic ischemia was confirmed, inasmuch as left-ventricular function returned to 108% of control values and coronary sinus levels of conjugated dienes did not rise after reperfusion. Conversely, reoxygenation raised plasma levels of conjugated dienes in coronary sinus blood in the hypoxic group 57% compared with end-hypoxic levels (p < 0.05 versus end-hypoxic levels and versus ischemia, by analysis of variance). Antioxidant reserve capacity showed the lowest levels (highest production of malondialdehyde) in the hypoxemic group (51% higher than control values; p < 0.05 by analysis of variance). These biochemical changes were associated with a 62% depression of left-ventricular function after bypass because end-systolic elastance recovered only 38% of control levels (p < 0.05 by analysis of variance). These data confirm the tolerance of the immature heart to ischemia and reperfusion and document a hypoxemic/reoxygenation injury that occurs in immature hearts reoxygenated during bypass. Hypoxemia seems to render the developing heart susceptible to reoxygenation damage that depresses postbypass function and is associated with lipid peroxidation. These findings suggest that starting bypass in cyanotic immature subjects causes an unintended reoxygenation injury that may potentially be counteracted by adding antioxidants to the prime of the extracorporeal circuit.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping:: V. Role of the l-arginine–nitric oxide pathway: The nitric oxide paradox

This study tests the hypothesis that nitric oxide, which is endothelial-derived relaxing factor, produces reoxygenation injury via the L-arginine-nitric oxide pathway in hypoxemic immature hearts when they are placed on cardiopulmonary bypass. Twenty 3-week-old piglets undergoing 2 hours of hypoxemia (oxygen tension about 25 mm Hg) on a ventilator were reoxygenated by initiating cardiopulmonary bypass (oxygen tension about 400 mm Hg). Five animals were not treated, whereas the pump circuit was primed with the nitric oxide-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg) in five piglets. L-Arginine, the substrate for nitric oxide, was administered in a fivefold excess (20 mg/kg), together with L-NAME in five piglets (L-NAME and L-arginine), and given alone in five other piglets (L-arginine). Five normoxemic, instrumented piglets served as a control group, and five others underwent 30 minutes of cardiopulmonary bypass without preceding hypoxemia. Left ventricular contractility was determined as end-systolic elastance by pressure-dimension loops. Myocardial conjugated dienes were measured as a marker of lipid peroxidation, and the antioxidant reserve capacity (malondialdehyde production in tissue incubated with t-butylhydroperoxide) was measured. Nitric oxide level was determined in coronary sinus plasma as its spontaneous oxidation product, nitrite. Cardiopulmonary bypass per se did not alter left ventricular contractility, cause lipid peroxidation, or lower antioxidant capacity. Reoxygenation without treatment depressed cardiac contractility (end-systolic elastance 38% +/- 12% of control*), raised nitric oxide (127% above hypoxemic values), increased conjugated dienes (1.3 +/- 0.2 vs 0.7 +/- 0.1, control*), and reduced antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30, control*). Inhibition of nitric oxide production by L-NAME improved end-systolic elastance to 84% +/- 12%,** limited conjugated diene elution (0.8 +/- 0.1 vs 1.3 +/- 0.2, no treatment**), and improved antioxidant reserve capacity (679 +/- 69 vs 910 +/- 59, no treatment**). Conversely, L-arginine counteracted these beneficial effects of L-NAME, because left ventricular function recovered only 24% +/- 6%,* conjugated dienes were 1.2 +/- 0.1,* and antioxidant reserve capacity was 826 +/- 70.* L-Arginine alone caused the same deleterious biochemical changes as L-NAME/L-arginine and resulted in 60% mortality. The close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardial conjugated diene production (r = 0.752) provides in vivo evidence that lipid peroxidation contributes to myocardial dysfunction after reoxygenation.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies of hypoxemic/reoxygenation injury: Without aortic clamping: IX. Importance of avoiding perioperative hyperoxemia in the setting of previous cyanosis

This study of an in vivo infantile piglet model of compensated hypoxemia tests the hypothesis that reoxygenation on hyperoxemic cardiopulmonary bypass produces oxygen-mediated myocardial injury that can be limited by normoxemic management of cardiopulmonary bypass and the interval after cardiopulmonary bypass. Twenty-five immature piglets (< 3 weeks old) were placed on 120 minutes of cardiopulmonary bypass and five piglets served as a biochemical control group without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Twenty others became hypoxemic on cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg. The study was terminated in five piglets at the end of hypoxemia, whereas 15 others were reoxygenated at an oxygen tension about 400 mm Hg or about 100 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level to avoid metabolic acidosis and lactate production. Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde after cardiopulmonary bypass in myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation at an oxygen tension about 400 mm Hg raised myocardial conjugated diene level and creatine kinase production (CD: 3.5 +/- 0.7 A233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g, p < 0.05 vs cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4.0 mmol t-butylhydroperoxide, p < 0.05 vs control), and produced severe postbypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 vs cardiopulmonary bypass control). Lowering oxygen tension to about 100 mm Hg during reoxygenation avoided conjugated diene production and creatine kinase release, retained normal antioxidant reserve, and improved functional recovery (80% +/- 11%, p < 0.05 vs oxygen tension about 400 mm Hg). These findings show that conventional hyperoxemic cardiopulmonary bypass causes unintended reoxygenation injury in hypoxemic immature hearts that may contribute to myocardial dysfunction after cardiopulmonary bypass and that normoxemic management may be used to surgical advantage.

The effect of glutamate on hypoxic newborn rabbit heart

Effects of glutamate on myocardial mechanical function and energy metabolism during 120 min of hypoxia and subsequent reoxygenation were studied in the isolated arterially perfused newborn and adult rabbit hearts. The muscle was perfused with a Krebs-Henseleit (KH) solution or KH solution which contained 1 mM glutamate. Glutamate attenuated the effects of hypoxia on mechanical function and tissue ATP concentration, and enhanced the recovery of mechanical function and tissue ATP during reoxygenation. During hypoxia, glutamate increased tissue succinate and GTP with no change in total lactate and pyruvate production. Trace studies using 14C-glutamate and the tissue homogenate showed that hypoxia increased tissue succinate and inhibited TCA cycle. Additional glutamate produced more CO2 and TCA intermediates in both oxygenated and hypoxic mediums. These data indicate that glutamate increased the rate of ATP production in the hypoxic and reoxygenated heart. This study shows that the improvement of mechanical function and ATP formation in the hypoxic myocardium by glutamate was due to an increase in both oxidative phosphorylation and substrate level phosphorylation. The effect of glutamate on the ATP and GTP production in the newborn heart was not different from the adult.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping: VI. Counteraction of oxidant damage by exogenous antioxidants: N-(2-mercaptopropionyl)-glycine and catalase

This study tests the hypothesis that antioxidants administered before reoxygenation can reduce oxygen-mediated damage and improve myocardial performance. Of 25 Duroc-Yorkshire piglets (2 to 3 weeks, 3 to 5 kg) five underwent 60 minutes of cardiopulmonary bypass without hypoxemia (control group), and five others underwent 30 minutes of hypoxemia on cardiopulmonary bypass with a circuit primed with oxygen tension about 25 mm Hg blood followed by reoxygenation on cardiopulmonary bypass (no treatment). In vitro studies were performed to obtain the optimal dosage of the antioxidants N-(2-mercaptopropionyl)-glycine and and catalase to be used in subsequent in vivo experimental studies; cardiac homogenates were incubated in 0 to 5 mmol/L concentrations of the oxidant t-butylhydroperoxide and malondialdehyde production was measured. Fifteen piglets were made hypoxemic on cardiopulmonary bypass for 30 minutes, and the antioxidants N-(2-mercaptopropionyl)-glycine at either 30 or 80 mg/kg body weight or N-(2-mercaptopropionyl)-glycine, 30 mg/kg body weight, and catalase, 50,000 U/kg body weight, were added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation. Left ventricular contractility, which was expressed as end-systolic elastance, was measured by conductance catheter before hypoxemia and after reoxygenation. Myocardial antioxidant reserve capacity was determined after reoxygenation by incubating cardiac homogenates in the oxidant t-butylhydroperoxide and measuring subsequent malondialdehyde elution. The in vitro bioassay studies showed a dose-dependent reduction of lipid peroxidation with N-(2-mercaptopropionyl)-glycine, with maximal benefits of a 40% decrease and malondialdehyde elaboration occurring with N-(2-mercaptopropionyl)-glycine and catalase compared with untreated cardiac homogenates. Cardiopulmonary bypass (no hypoxemia) caused no oxidant damage or changes in contractile function after cardiopulmonary bypass. Reoxygenation without treatment raised conjugated diene levels 57%,* lowered antioxidant reserve capacity 51%,* and was associated with only 38%* recovery of contractile function (p < 0.05 vs control). In contrast, treatment with antioxidants avoided lipid peroxidation, maintained antioxidant reserve capacity, and resulted in a dose-dependent improvement in left ventricular contractility with complete recovery occurring in N-(2-mercaptopropionyl)-glycine and catalase-treated piglets (*p < 0.05 vs no treatment). This study confirms the occurrence of hypoxemic/reoxygenation injury in immature hearts placed on cardiopulmonary bypass and shows that biochemical and functional damage can be counteracted by adding antioxidants to the cardiopulmonary bypass priming fluid. Contractile function improved in a dose-dependent manner, and oxygen-mediated damage could be avoided by mercaptopropionyl glycine/catalase treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies of hypoxemic/reoxygenation injury with aortic clamping ☆ ☆☆ ★ ★★ ♢ ♢♢: XI. Cardiac advantages of normoxemic versus hyperoxemicmanagement during cardiopulmonary bypass

The conventional way to start cardiopulmonary bypass is to prime the cardiopulmonary bypass circuit with hyperoxemic blood (oxygen tension about 400 mm Hg) and deliver cardioplegic solutions at similar oxygen tension levels. This study tests the hypothesis that an initial normoxemic oxygen tension strategy to decrease the oxygen tension-dependent rate of oxygen free radical production will, in concert with normoxemic blood cardioplegia, limit reoxygenation damage and make subsequent hyperoxemia (oxygen tension about 400 mm Hg) safer. Thirty-five immature (3 to 5 kg, 2 to 3 week old) piglets underwent 60 minutes of cardiopulmonary bypass. Eleven control studies at conventional hyperoxemic oxygen tension (about 400 mm Hg) included six piglets that also underwent 30 minutes of blood cardioplegic arrest. Of 25 studies in which piglets were subjected to up to 120 minutes of ventilator hypoxemia (reducing fraction of inspired oxygen to 5% to 7%; oxygen tension about 25 mm Hg), 11 underwent either abrupt (oxygen tension about 400 mm Hg, n = 6) or gradual (increasing oxygen tension from 100 to 400 mm Hg over a 1-hour period, n = 5) reoxygenation without blood cardioplegia. Fourteen others underwent 30 minutes of blood cardioplegic arrest during cardiopulmonary bypass. Of these, nine were reoxygenated at oxygen tension about 400 mm Hg, and five others underwent normoxemic cardiopulmonary bypass and blood cardioplegia (oxygen tension about 100 mm Hg) with systemic oxygen tension raised to 400 mm Hg after aortic unclamping. Measurements of lipid peroxidation (conjugated dienes and antioxidant reserve capacity) and contractile function (pressure-volume loops, conductance catheter, end-systolic elastance) were made before and during hypoxemia and 30 minutes after reoxygenation. Hyperoxemic cardiopulmonary bypass did not produce oxidant damage or reduce functional recovery after cardiopulmonary bypass in nonhypoxemic controls. In contrast, abrupt and gradual reoxygenation without blood cardioplegia produced significant lipid peroxidation (84% increase in conjungated dienes), lowered antioxidant reserve capacity 68% +/- 5%, 44% +/- 8%, respectively, and decreased functional recovery 75% +/- 6% (p < 0.05), 66% +/- 4% (p < 0.05). Similar impairment followed abrupt reoxygenation before blood cardioplegic myocardial management, because conjungated diene production increased 13-fold, antioxidant reserve capacity fell 40%, and contractility recovered only 21% +/- 2% (p < 0.05). Conversely, normoxemic induction of cardiopulmonary bypass and blood cardioplegic myocardial management reduced conjungated diene production 73%, avoided impairment of antioxidant reserve capacity, and resulted in 58% +/- 11% recovery of contractile function.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies of hypoxemic/reoxygenation injury: Without aortic clamping: IV. Role of the iron-catalyzed pathway: deferoxamine

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping: VIII. Counteraction of oxidant damage by exogenous glutamate and aspartate

Previous studies show that (1) hypoxemia depletes immature myocardium of amino acid substrates and their replenishment improves ischemic tolerance, (2) reoxygenation on cardiopulmonary bypass causes oxygen-mediated damage without added ischemia, and (3) this damage may be related to the nitric oxide-L-arginine pathway that is affected by amino acid metabolism. This study tests the hypothesis that priming the cardiopulmonary bypass circuit with glutamate and aspartate limits reoxygenation damage. Of 22 immature Duroc-Yorkshire piglets (< 3 weeks old), five were observed over a 5-hour period (control), and five others underwent 30 minutes of CPB without hypoxemia (cardiopulmonary bypass control). Twelve others became hypoxemic by reducing ventilator inspired oxygen fraction to 6% to 7% (oxygen tension about 25 mm Hg) before reoxygenation on cardiopulmonary bypass for 30 minutes. Of these five were untreated (no treatment), and the cardiopulmonary bypass circuit was primed with 5 mmol/L glutamate and aspartate in seven others (treatment). Left ventricular function before and after bypass was measured by inscribing pressure-volume loops (end-systolic elastance). Myocardial conjugated diene levels were measured to detect lipid peroxidation, and antioxidant reserve capacity was tested by incubating cardiac muscle with the oxidant t-butylhydroperoxide to determine the susceptibility to subsequent oxidant injury. CPB (no hypoxemia) allowed complete functional recovery without changing conjugated dienes and antioxidant reserve capacity, whereas reoxygenation injury developed in untreated hearts. This was characterized by reduced contractility (elastance end-systolic recovered only 37% +/- 8%*), increased conjugated diene levels (1.3 +/- 0.1 vs 0.7 +/- 0.1*), and decreased antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30 malondialdehyde nmol/g protein at 2 mmol/L t-butylhydroperoxide*). In contrast, priming the cardiopulmonary bypass circuit with glutamate and aspartate resulted in significantly better left ventricular functional recovery (75% +/- 8% vs 37% +/- 8%*), minimal conjugated diene production (0.8 +/- 0.1 vs 1.3 +/- 0.1*), and improved antioxidant reserve capacity (726 +/- 27 vs 910 +/- 59 malondialdehyde nmol/g protein*) (*p < 0.05 vs cardiopulmonary bypass control). We conclude that reoxygenation of immature hypoxemic piglets by the initiation of cardiopulmonary bypass causes myocardial dysfunction, lipid peroxidation, and reduced tolerance to oxidant stress, which may increase vulnerability to subsequent ischemia (i.e., aortic crossclamping). These data suggest that supplementing the prime of cardiopulmonary bypass circuit with glutamate and aspartate may reduce these deleterious consequences of reoxygenation.