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J Thorac Cardiovasc Surg 1994;107:1222-1227
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Xanthine oxidoreductase release after descending thoracic aorta occlusion and reperfusion in rabbits

Birmingham, Ala., and Cambridge, Mass.

Partially supported by the National Institutes of Health grant HL 48676.

Received for publication June 17, 1993. Accepted for publication Sept. 14, 1993. Address for reprints: V. G. Nielsen, MD, Department of Anesthesiology, Research Division, University of Alabama at Birmingham, 845 Jefferson Tower, 619 S. 19th St., Birmingham, AL 35233-6810.

Abstract

Cardiopulmonary and other organ dysfunction often occurs after operation on the descending thoracic aorta. Though there are multiple causes of organ dysfunction in this setting, free radical injury may play a prominent role. Xanthine oxidoreductase, an enzyme that generates oxidants after exposure to ischemia, could be released from ischemic liver and intestine during reperfusion. To test this hypothesis, we created aortic occlusion in eight rabbits for 40 minutes by inflation of a 4F Fogarty balloon catheter in the descending thoracic aorta. Eight sham-operated rabbits served as a control group. Two hours of reperfusion followed removal of the balloon catheter. Hemodynamic and acid-base status were maintained near baseline values during reperfusion. Plasma samples were obtained for determination of the activity of the hepatocellular enzymes xanthine oxidoreductase, aspartate aminotransferase, alanine transferase, and lactate dehydrogenase. Plasma xanthine oxidoreductase activity increased significantly (p < 0.001) during reperfusion (729 ± 140µU/ml, mean ± standard error of the mean) compared with baseline (132 ± 18µU/mL). The other enzymes followed a similar pattern of release. We report the release of xanthine oxidoreductase in an animal model that simulates the situation of human thoracic aorta operations. The oxidants produced by the circulating xanthine oxidoreductase observed during reperfusion would likely be toxic to vascular endothelium, potentially contributing to multiple organ dysfunction. (J THORACCARDIOVASCSURG1994;107:1222-7)

Cardiopulmonary, neurologic, and other organ dysfunction often occurs after an otherwise uncomplicated descending thoracic aorta aneurysmectomy. ^1-8 When such complications occur, they are often associated with a high rate of permanent organ dysfunction or death. ^1-8 Though risk factors for multiple organ dysfunction in this setting include patient age ^1,3,4 and concurrent organ dysfunction, ^2,3,5-8 the role of oxygen radical injury during reperfusion may be of critical importance. The prevalence of paraplegia after descending thoracic aorta crossclamping in a dog model was reduced by administration of the enzymatic antioxidant superoxide dismutase, implicating oxidants as one cause of the injury. ⁹ Cellular or enzymatic sources of circulating oxidants released during reperfusion of formerly ischemic tissues could explain injury to a remote organ, such as the lung. Pulmonary oxidant injury mediated by neutrophils has been documented in the model of human abdominal aortic aneurysm repair ¹⁰ and in a model of hind limb ischemia in sheep. ¹¹ Administration of the enzymatic antioxidants superoxide dismutase ¹¹ and catalase, ¹¹ as well as the hydroxyl radical scavenger mannitol, ¹⁰ reduced lung injury in these models. These studies documented the involvement of neutrophils in the pulmonary injury remote from the tissues undergoing ischemia and reperfusion. The resultant hepatic and intestinal ischemia-reperfusion that occurs after thoracic aorta crossclamping may cause the systemic release of another oxidant generator, the hepatocellular enzyme xanthine oxidoreductase.

Xanthine oxidoreductase is an enzyme that catalyzes the purines, xanthine and hypoxanthine, to uric acid. ^12-14 Liver and intestine have the greatest tissue activity of xanthine oxidoreductase. ^12-14 Vascular endothelial cells contain the enzyme to a lesser extent. ^15,16 Typically, the enzyme exists in an innocuous form (xanthine dehydrogenase, XDH) with purine catabolism occurring via reduction of nicotinamide-adenine dinucleotide. ^13-16 However, if tissues are exposed to metabolic stress, such as hypoxia or ischemia, the enzyme converts to the oxidase form (xanthine oxidase, XO), which can, in the presence of adequate substrate and molecular oxygen, generate the oxidants O₂ – and H₂O₂. ^12-16 These data support the hypothesis that XO plays a role in the evolution of oxidant-mediated tissue injury observed after an ischemia-reperfusion event.

Animal studies have implicated circulating XO as a potent intravascular source of tissue injury. ^17-19 XO release into the circulation has been documented in a rat model of hemorrhagic shock, with significant elevation of other hepatocellular enzyme activity also noted. ¹⁷ XO has been implicated as a cause of pulmonary injury after intestinal ischemia-reperfusion in a rat model. ¹⁸ Pretreatment with the XDH + XO inhibitor, allopurinol, decreased gastric ulceration in a baboon model of thoracic aorta crossclamping. ¹⁹ In human studies an increase in plasma XO activity, as well as a concurrent increase in the concentration of plasma oxidation products, has been documented during reperfusion of an upper extremity undergoing an orthopedic procedure. ²⁰ Additionally, human plasma concentrations of hypoxanthine and xanthine have been documented to increase after reconstructive aortic operations. ^21,22 Though both animal and human studies suggest that circulating XO and substrate can be observed after an ischemia-reperfusion injury, an animal model had yet to be proposed that simulated the situation of human thoracic aorta crossclamping with concurrent monitoring of plasma XDH + XO activity.

The present study tests the hypothesis that XDH + XO is released into the systemic circulation after descending thoracic aorta occlusion and reperfusion in a rabbit model that closely simulates the situation of human thoracic aorta crossclamping. We also hypothesized that a concurrent systemic release of other hepatocellular enzymes would follow descending thoracic aorta occlusion and reperfusion, implicating the liver as a source of XDH + XO.

MATERIALS AND METHODS

Rabbit model
Male New Zealand White rabbits (Myrtle's Rabbits, Thompson Station, Tenn.) weighing 1.8 to 2.5 kg were anesthetized with intravenous fentanyl (100 µg/kg per hour) and droperidol (5 mg/kg per hour) via a marginal ear vein. Arterial pressure was monitored by placement of a 22-gauge catheter in a central ear artery. After tracheostomy, mechanical ventilation of the lungs (inspired O₂ fraction = 1.0) with a Harvard Apparatus ventilator (model 661, Millis, Mass.) was done with the arterial carbon dioxide tension maintained between 32 and 40 torr. Pancuronium bromide (Elkins-Sinn, Inc., Cherry Hill, N.J.) 0.1 mg/kg was administered intravenously to ensure relaxed chest wall muscle tone during ventilation. Central venous access was obtained via the right internal jugular vein with a 5F double-lumen catheter (Cook Critical Care, Bloomington, Ind.) for pressure monitoring, fluid administration, and blood sampling. A right femoral arterial catheter was also placed to verify complete aortic occlusion in the experimental group. All rabbits received an infusion of lactated Ringer's solution at 20 ml/kg per hour, and esophageal temperatures were maintained between 38° and 39° C with a heating pad.

Experimental protocol
Rabbits were randomly assigned to either the control (n = 8) or descending thoracic aorta occlusion (n = 8) group. Control (sham-operated) animals had the left femoral artery exposed, with sham thoracic aorta occlusion beginning with ligation of the artery. The experimental group also underwent a left femoral cutdown, with insertion of a 4F Fogarty embolectomy catheter (American Edwards Laboratory, Irvine, Calif.) into the thoracic aorta with the balloon placed 1 to 2 cm above the diaphragm. Balloon position was predetermined by measuring the distance between the surface anatomy landmarks of the xiphoid process and the inguinal ligament. Catheter insertion to this length (usually 18 to 19 cm) at the inguinal ligament invariably placed the balloon at the appropriate site as confirmed by postmortem examination. Thoracic aorta occlusion was achieved by inflation of the catheter balloon with 750 µl of saline solution, with subdiaphragmatic ischemia confirmed by a nonpulsatile femoral arterial pressure, which typically measured 0 to 10 torr. After 40 minutes of occlusion, the balloon was deflated and the catheter removed from the aorta. The ensuing postocclusion shock was treated with intravenous lactated Ringer's solution and phenylephrine (Elkins-Sinn, Inc.), with maintenance of hemodynamic parameters within 15% of preocclusion values. Acid-base status was similarly maintained with intravenous sodium bicarbonate 8.4% (Abbott Laboratories, North Chicago, Ill.). Blood samples were removed before induction of anesthesia; after 40 minutes of thoracic aorta occlusion; and at 5, 30, 60, and 120 minutes of reperfusion. The baseline sample was taken from the ear artery, whereas all subsequent samples were removed from the right atrium via the central line. All samples were heparinized and centrifuged, with the plasma assayed as described in the biochemical analysis section herein. After 2 hours of reperfusion, the rabbits were killed with an overdose of pentobarbital (The Butler Company, Columbus, Ohio) 65 mg/kg intravenously.

The study was approved by the Animal Review Committee of the University of Alabama at Birmingham. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and with the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 809-23, revised 1978).

Biochemical analysis
Plasma samples were kept on ice until assay on the day of experimentation or, in the case of xanthine oxidoreductase and protein, samples were immediately stored at –85° before analysis. Specific methods used for each assay are given below.

Xanthine oxidoreductase (XDH + XO).
Plasma samples were subjected to size exclusion chromatography with a G-25 column (Pharmacia, Piscataway, N.J.) to remove low-molecular-weight inhibitors of XDH + XO. Total plasma XDH + XO activity was determined by monitoring the production of uric acid in the presence of xanthine (75 µmol/L) and nicotinamide-adenine dinucleotide (0.5 mmol/L). Allopurinol (100 µmol/L), an inhibitor of XDH + XO, was used in parallel assay samples to confirm that urate formation was due to XDH + XO activity. Oxonic acid (0.01 mmol/L) was added to inhibit uricase, an enzyme found in rabbits that oxidizes urate to allantoin, thus preventing underestimation of XDH + XO activity. After 60 minutes of incubation at 37° C, the reaction was terminated by deproteinization. Deproteinized plasma was then assayed for uric acid with a high-performance liquid chromatography–based electrochemical technique developed by Tan and colleagues. ^22a

Aspartate aminotransferase (AST), alanine transferase (ALT), lactate dehydrogenase (LDH).
Fresh plasma samples were allowed to come to room temperature before spectrophotometric assay. Levels of ALT and AST were measured with a method based on a modification of the procedure of Henry and colleagues. ²³ The plasma LDH level was measured according to a modification of the procedure of Wacker, Ulmer, and Vallee. ²⁴

Protein assay.
Plasma samples were spectrophotometrically assayed for protein concentration by a modification of the method of Bradford. ²⁵ Values obtained were used to determine original plasma XDH + XO activities by comparison of precolumn and postcolumn sample protein concentrations.

Statistical analysis
All variables are expressed as mean ± standard error of the mean. Analysis of the effect of ischemia-reperfusion on the circulating enzyme activities was conducted by repeated-measures analysis of variance. Comparison between groups for the change with each time point was done with the use of the contrast statement of the repeated-measures analysis of variance. All analysis was done with SAS system for personal computers, release 6.03 (SAS, Inc., Cary, N.C.). An -error of less than 0.05 was considered significant.

RESULTS

Xanthine oxidoreductase (Fig 1).
Xanthine oxidoreductase activity was noted in the baseline state of the control (sham; 88.1 ± 14.3 µU/ml) and experimental (132 ± 18.1 µU/ml) groups. This XDH + XO activity did not increase significantly over the course of the experiment in the control group. No increase in XDH + XO activity was noted during ischemia in the experimental animals. Circulating XDH + XO activity in the ischemic group during reperfusion was significantly greater than baseline and corresponding control (sham) group values. A plateau in plasma XDH + XO activity was seen after 60 minutes of reperfusion (727 ± 141 µU/ml, p < 0.001), and this elevated plasma activity persisted throughout the 2 hours of reperfusion.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Plasma XDH + XO activity increased significantly during 2 hours of reperfusion after 40 minutes of descending thoracic aorta occlusion (AoO).*p < 0.05;**p < 0.01;***p < 0.001.

View larger version (28K): [in this window] [in a new window]   Fig. 2. Plasma ALT activity increased significantly during 2 hours of reperfusion in fashion similar to that of XDH + XO, implicating liver as likely source of circulating XDH + XO. AoO, Aortic occlusion;***p < 0.001.

View larger version (27K): [in this window] [in a new window]   Fig. 3. Plasma AST activity increased markedly throughout 2 hours of reperfusion in fashion similar to that of XDH + XO, implicating liver as likely source of circulating XDH + XO. AoO, Aortic occlusion; ***p < 0.001.

View larger version (29K): [in this window] [in a new window]   Fig. 4. Plasma LDH activity increased significantly during 2 hours of reperfusion. Reperfused liver and intestine are likely sources of significant amount of this circulating LDH activity. AoO, Aortic occlusion; *p < 0.05; **p < 0.01; ***p < 0.001.

The present study documents the novel observation that xanthine oxidoreductase is released into the systemic circulation after thoracic aorta occlusion and reperfusion. The concurrent release of the hepatocellular enzymes ALT, AST, and LDH suggests that one of the sources of XDH + XO in this model is the ischemic liver. It is also likely that the reperfused intestine may contribute to plasma XDH + XO and LDH activity, although a specific marker of intestinal cell injury is not available. These experiments also document the pattern of XDH + XO release, demonstrating prolonged, elevated plasma XDH + XO activity during reperfusion. The plasma XDH + XO activity is likely due to continuous release from reperfused tissue, because the plasma half-life is currently believed to be approximately 10 minutes. ²⁶ The organ distribution and tissue-specific activity of XDH + XO are similar in human beings and rabbits ¹²; therefore it is likely that human beings, in clinical settings that involve hepatic and intestinal ischemia-reperfusion (for example, trauma, major vascular operations), will have elevated circulating XDH + XO activity. Finally, vascular endothelium may be a significant source of circulating XDH + XO in human beings, inasmuch as upper limb ischemia-reperfusion in patients undergoing orthopedic procedures resulted in increased plasma activity of XDH + XO. ¹⁸

XO binds avidly to the glycocalyx of porcine ²⁷ and bovine ¹⁷ vascular endothelial cells in culture and has also been found to bind to human ²⁷ and rat ¹⁷ vascular endothelium in vivo. XO has also been shown to concentrate on the endothelial surface in the rat. ¹⁷ The vascular endothelium in the rabbit model presented was exposed to significantly elevated XDH + XO activity throughout the 2-hour reperfusion period, with concentration of XDH + XO activity at the endothelial surface a likely event. Though it has been shown that a single 5 mU/ml bolus of XO and substrate causes significant endothelial cell death in culture, ¹⁴ it is likely that continuous exposure to the XDH + XO activities seen during reperfusion in our model may be similarly toxic to vascular endothelium, especially if XO is concentrated on the cell surface. Consequently, tissues with very low endogenous XDH + XO activity, such as the heart, ²⁸ may be injured after hepatic and intestinal ischemia-reperfusion. Endothelial cell injury may be further amplified by the release of chemoattractants and resultant neutrophil-mediated damage, as seen in other animal models. ²¹ We reported the plasma activities of xanthine oxidoreductase, inasmuch as it is likely XDH may convert to the oxidant-generating XO. This could occur during reperfusion by several mechanisms, including ongoing tissue hypoxia or neutrophil-mediated proteolysis. ¹⁵ The endothelium-bound XO, in the presence of elevated plasma purine levels, could cause oxidant-mediated tissue injury. The microvascular compromise resulting from these events could ultimately lead to the scenario of multiple organ dysfunction often seen after thoracic aorta crossclamping.

In conclusion, we have presented a clinically relevant rabbit model of thoracic aorta occlusion and reperfusion, with documented release of the oxidant-generating enzyme XO. The efficacy of pretreatment with specific XDH + XO inhibitors (for example, allopurinol, tungsten, pterin aldehyde) may be accurately assessed by monitoring the reduction of plasma XDH + XO activity. Once circulating XDH + XO activity is reduced or completely inhibited, the contribution of plasma or cytosolic XO-mediated oxidant injury after thoracic aorta occlusion and reperfusion can be determined. The period of thoracic aorta occlusion required to cause XDH + XO release can also be determined by varying the duration of ischemia. Ultimately, a reduction in morbidity and mortality after thoracic aorta operation may be realized by decreasing the prevalence of multiple organ dysfunction mediated by circulating XDH + XO.

Footnotes

From the Departments of Anesthesiology, ^a Pediatrics, ^b and Physiology and Biophysics, ^d the University of Alabama at Birmingham, and the Department of Anesthesiology, ^c Brigham and Women's Hospital, Harvard University, Cambridge, Mass.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nielsen, V. G. Articles by Parks, D. A. Search for Related Content PubMed PubMed Citation Articles by Nielsen, V. G. Articles by Parks, D. A.