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Suppressors of Oxygen Metabolites Fail to Reduce Vein Graft Intimal Hyperplasia

Suppressors of Oxygen Metabolites Fail to Reduce Vein Graft Intimal Hyperplasia Abstract Objective: To evaluate the role of reactive oxygen metabolites in the initiation of intimal hyperplasia of vein grafts inserted into the arterial circulation. Setting: University pathologic research laboratory. Animals: Sprague-Dawley rats. Intervention: Animals were randomized to receive either the xanthine oxidase inhibitor allopurinol, the iron chelating agent starch-conjugated deferoxamine, or the free-radical scavenger 21-aminosteroid U74389G. Control animals were included for each group. The epigastric vein was inserted into the right common femoral artery. Vein grafts were harvested 30 days postoperatively. The degree of intimal hyperplasia at the two anastomoses as well as at the midgraft was calculated. Main Outcome Measures: The vein grafts were divided into three sections designated proximal anastomosis, midgraft, and distal anastomosis. Intimal and medial areas were determined in an observer-blind fashion and expressed as intimal area–medial area ratios. Results: Pretreatment of the animals with any of these agents resulted in no significant reduction in the degree of intimal hyperplasia in any treated groups compared with the control animals 30 days postoperatively. Conclusions: Arterial reconstruction often involves interposition of vein segments into the arterial circulation. These veins are subject to ischemia and reperfusion, with the potential for generation of reactive oxygen metabolites and subsequent vein graft injury, resulting in intimal hyperplasia. We hypothesized that perioperative pharmacologic intervention either to scavenge or to reduce the production of reactive oxygen metabolites would attenuate the initial vein graft injury and thus limit the subsequent development of intimal hyperplasia. These data create doubt as to the influence of reactive oxygen metabolites in the initiation of intimal hyperplasia in the vein graft.(Arch Surg. 1995;130:976-980) References 1. Kent KC, Whittemore AD. What's new in small-caliber arterial substitution . Surg Rounds . 1991;14:557-566. 2. Imparato AM, Bracco A, Kim GE, Zeff RZ. Intimal and neointimal fibrous proliferation causing failure of arterial reconstruction . Surgery . 1972;72:1107-1117. 3. Hirsch GM, Karnovsky MJ. Inhibition of vein graft intimal proliferative lesions in the rat by heparin . Am J Pathol . 1991;139:581-587. 4. Cambria RP, Ivarsson BL, Fallon JT, Abbott WM. Heparin fails to suppress intimal proliferation in experimental vein grafts . Surgery . 1992;111:424-429. 5. McCord JM. Oxygen derived free-radicals in postischemic tissue injury . N Engl J Med . 1985;312:159-163.Crossref 6. Roys RS, McCord JM. Superoxide and ischemia: conversion of xanthine dehydrogenase to xanthine oxidase . In: Greenwald R, Cohen G, eds. Oxyradicals and Their Scavenger Systems: Cellular and Molecular Aspects . New York, NY: Elsevier Science Publishing Co Inc; 1983;2:145-153. 7. Saugstad OD. Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production . Pediatr Res . 1988;23:143-150.Crossref 8. Reilly PM, Schiller HJ, Bulkley GB. Reactive oxygen metabolites in shock . In: Wilmore DW, Brennan MF, eds. Care of the Surgical Patient . New York, NY: Scientific American Inc; 1991:1-30. 9. Vickers S, Hildreth J, Kuhajda F, et al. Immunohistoaffinity localization of xanthine oxidase in the microvascular endothelial cells of porcine and human organs . Circ Shock . 1990:31:42. Abstract. 10. Babbs CF, Cregor MD, Turek JJ, Badylak SF. Endothelial superoxide production in the isolated rat heart during early reperfusion after ischemia . Am J Pathol . 1991;139:1069-1080. 11. Jarasch ED, Bruder G, Heid HW. Significance of xanthine oxidase in capillary endothelial cells . Acta Physiol Scand Suppl . 1986;548:39-46. 12. Michiels C, Arnould T, Remade J, Houbion A. Human umbilical vein endothelial cells: implication of free radicals, xanthine oxidase, and energy deficiency . J Cell Physiol . 1992;153:53-61.Crossref 13. Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells . J Clin Invest . 1986; 77:757-761.Crossref 14. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s . Nature . 1993;1362:801-809.Crossref 15. Braughler JM, Chase RL, Neff GL, et al. A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells . J Pharmacol Exp Ther . 1988;244:423-427. 16. Ratych RE, Chuknyiska RS, Bulkley GB. The primary localization of free-radical generation after anoxia/reoxygenation in isolated endothelial cells . Surgery . 1987;102:122-131. 17. Hung CT, Zoest AR, Perrier DG. Analysis of allopurinol and oxypurinol in plasma by RP-HPLC . J Liquid Chromatogr . 1986;9:2471-2483.Crossref 18. Fridovich I. Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase . J Biol Chem . 1970;245:4053-4057. 19. Emmerson BT, Gordon RB, Cross M, Thomson DB. Plasma oxipurinol concentrations during allopurinol therapy . Br J Rheumatol . 1987;26:445-449.Crossref 20. Puig JG, Casas EA, Ramos H, Michan AA, Mateos FA. Plasma oxypurinol concentration in a patient with allopurinol sensitivity . J Rheumatol . 1989;16:842-844. 21. Charlat ML, O'Neill PG, Egan JM, et al. Evidence for a pathogenic role of xanthine oxidase in the 'stunned' myocardium . Am J Physiol . 1987;252:H566-H577. 22. Zager RA, Gmur DJ. Effects of xanthine oxidase inhibition on ischemic acute renal failure in the rat . Am J Physiol . 1989;257:F953-958. 23. Megison SM, Horton JW, Chao H, Walker PB. High-dose versus low-dose enteral allopurinol for prophylaxis in mesenteric ischemia . Circ Shock . 1990;30: 323-329. 24. Flower RJ, Moncada S, Vane JR. Drug therapy of inflammation . In: Goodman AG, Gilman LS, eds. The Pharmacologic Basis of Therapeutics . New York, NY: Macmillan Publishing Co Inc; 1980:682-729. 25. Moorhouse PC, Grootveld M, Halliwell B, Quinlan JG, Gutteridge JM. Allopurinol and oxypurinol are hydroxyl radical scavengers . FEBS Lett . 1987;213:23-28.Crossref 26. Zimmerman BJ, Parks DA, Grisham MB, Granger DN. Allopurinol does not enhance antioxidant properties of extracellular fluid . Am J Physiol . 1988;255: H202-H206. 27. Hagen PO, Davies MG, Schuman RW, Murray JJ. Reduction of vein graft intimal hyperplasia by ex vivo treatment with desferrioxamine manganese . J Vasc Res . 1992;29:405-409.Crossref 28. Darr DJ, Yanni S, Pinnell SR. Protection of chinese hamster ovary cells from paraquat-mediated cytotoxicity by a low molecular weight mimic of superoxide dismutase (DF-Mn) . Free Radic Biol Med . 1988;4:357-363.Crossref 29. Hallaway PE, Eaton JW, Panter SS, Hedlund BE. Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers . Proc Natl Acad Sci U S A . 1989;86:10108-10112.Crossref 30. Braughler JM, Burton PS, Chase RL, et al. Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation . Biochem Pharmacol . 1988;37:3853-3860.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Surgery American Medical Association

Suppressors of Oxygen Metabolites Fail to Reduce Vein Graft Intimal Hyperplasia

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Publisher
American Medical Association
Copyright
Copyright © 1995 American Medical Association. All Rights Reserved.
ISSN
0004-0010
eISSN
1538-3644
DOI
10.1001/archsurg.1995.01430090062020
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Abstract

Abstract Objective: To evaluate the role of reactive oxygen metabolites in the initiation of intimal hyperplasia of vein grafts inserted into the arterial circulation. Setting: University pathologic research laboratory. Animals: Sprague-Dawley rats. Intervention: Animals were randomized to receive either the xanthine oxidase inhibitor allopurinol, the iron chelating agent starch-conjugated deferoxamine, or the free-radical scavenger 21-aminosteroid U74389G. Control animals were included for each group. The epigastric vein was inserted into the right common femoral artery. Vein grafts were harvested 30 days postoperatively. The degree of intimal hyperplasia at the two anastomoses as well as at the midgraft was calculated. Main Outcome Measures: The vein grafts were divided into three sections designated proximal anastomosis, midgraft, and distal anastomosis. Intimal and medial areas were determined in an observer-blind fashion and expressed as intimal area–medial area ratios. Results: Pretreatment of the animals with any of these agents resulted in no significant reduction in the degree of intimal hyperplasia in any treated groups compared with the control animals 30 days postoperatively. Conclusions: Arterial reconstruction often involves interposition of vein segments into the arterial circulation. These veins are subject to ischemia and reperfusion, with the potential for generation of reactive oxygen metabolites and subsequent vein graft injury, resulting in intimal hyperplasia. We hypothesized that perioperative pharmacologic intervention either to scavenge or to reduce the production of reactive oxygen metabolites would attenuate the initial vein graft injury and thus limit the subsequent development of intimal hyperplasia. These data create doubt as to the influence of reactive oxygen metabolites in the initiation of intimal hyperplasia in the vein graft.(Arch Surg. 1995;130:976-980) References 1. Kent KC, Whittemore AD. What's new in small-caliber arterial substitution . Surg Rounds . 1991;14:557-566. 2. Imparato AM, Bracco A, Kim GE, Zeff RZ. Intimal and neointimal fibrous proliferation causing failure of arterial reconstruction . Surgery . 1972;72:1107-1117. 3. Hirsch GM, Karnovsky MJ. Inhibition of vein graft intimal proliferative lesions in the rat by heparin . Am J Pathol . 1991;139:581-587. 4. Cambria RP, Ivarsson BL, Fallon JT, Abbott WM. Heparin fails to suppress intimal proliferation in experimental vein grafts . Surgery . 1992;111:424-429. 5. McCord JM. Oxygen derived free-radicals in postischemic tissue injury . N Engl J Med . 1985;312:159-163.Crossref 6. Roys RS, McCord JM. Superoxide and ischemia: conversion of xanthine dehydrogenase to xanthine oxidase . In: Greenwald R, Cohen G, eds. Oxyradicals and Their Scavenger Systems: Cellular and Molecular Aspects . New York, NY: Elsevier Science Publishing Co Inc; 1983;2:145-153. 7. Saugstad OD. Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production . Pediatr Res . 1988;23:143-150.Crossref 8. Reilly PM, Schiller HJ, Bulkley GB. Reactive oxygen metabolites in shock . In: Wilmore DW, Brennan MF, eds. Care of the Surgical Patient . New York, NY: Scientific American Inc; 1991:1-30. 9. Vickers S, Hildreth J, Kuhajda F, et al. Immunohistoaffinity localization of xanthine oxidase in the microvascular endothelial cells of porcine and human organs . Circ Shock . 1990:31:42. Abstract. 10. Babbs CF, Cregor MD, Turek JJ, Badylak SF. Endothelial superoxide production in the isolated rat heart during early reperfusion after ischemia . Am J Pathol . 1991;139:1069-1080. 11. Jarasch ED, Bruder G, Heid HW. Significance of xanthine oxidase in capillary endothelial cells . Acta Physiol Scand Suppl . 1986;548:39-46. 12. Michiels C, Arnould T, Remade J, Houbion A. Human umbilical vein endothelial cells: implication of free radicals, xanthine oxidase, and energy deficiency . J Cell Physiol . 1992;153:53-61.Crossref 13. Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells . J Clin Invest . 1986; 77:757-761.Crossref 14. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s . Nature . 1993;1362:801-809.Crossref 15. Braughler JM, Chase RL, Neff GL, et al. A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells . J Pharmacol Exp Ther . 1988;244:423-427. 16. Ratych RE, Chuknyiska RS, Bulkley GB. The primary localization of free-radical generation after anoxia/reoxygenation in isolated endothelial cells . Surgery . 1987;102:122-131. 17. Hung CT, Zoest AR, Perrier DG. Analysis of allopurinol and oxypurinol in plasma by RP-HPLC . J Liquid Chromatogr . 1986;9:2471-2483.Crossref 18. Fridovich I. Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase . J Biol Chem . 1970;245:4053-4057. 19. Emmerson BT, Gordon RB, Cross M, Thomson DB. Plasma oxipurinol concentrations during allopurinol therapy . Br J Rheumatol . 1987;26:445-449.Crossref 20. Puig JG, Casas EA, Ramos H, Michan AA, Mateos FA. Plasma oxypurinol concentration in a patient with allopurinol sensitivity . J Rheumatol . 1989;16:842-844. 21. Charlat ML, O'Neill PG, Egan JM, et al. Evidence for a pathogenic role of xanthine oxidase in the 'stunned' myocardium . Am J Physiol . 1987;252:H566-H577. 22. Zager RA, Gmur DJ. Effects of xanthine oxidase inhibition on ischemic acute renal failure in the rat . Am J Physiol . 1989;257:F953-958. 23. Megison SM, Horton JW, Chao H, Walker PB. High-dose versus low-dose enteral allopurinol for prophylaxis in mesenteric ischemia . Circ Shock . 1990;30: 323-329. 24. Flower RJ, Moncada S, Vane JR. Drug therapy of inflammation . In: Goodman AG, Gilman LS, eds. The Pharmacologic Basis of Therapeutics . New York, NY: Macmillan Publishing Co Inc; 1980:682-729. 25. Moorhouse PC, Grootveld M, Halliwell B, Quinlan JG, Gutteridge JM. Allopurinol and oxypurinol are hydroxyl radical scavengers . FEBS Lett . 1987;213:23-28.Crossref 26. Zimmerman BJ, Parks DA, Grisham MB, Granger DN. Allopurinol does not enhance antioxidant properties of extracellular fluid . Am J Physiol . 1988;255: H202-H206. 27. Hagen PO, Davies MG, Schuman RW, Murray JJ. Reduction of vein graft intimal hyperplasia by ex vivo treatment with desferrioxamine manganese . J Vasc Res . 1992;29:405-409.Crossref 28. Darr DJ, Yanni S, Pinnell SR. Protection of chinese hamster ovary cells from paraquat-mediated cytotoxicity by a low molecular weight mimic of superoxide dismutase (DF-Mn) . Free Radic Biol Med . 1988;4:357-363.Crossref 29. Hallaway PE, Eaton JW, Panter SS, Hedlund BE. Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers . Proc Natl Acad Sci U S A . 1989;86:10108-10112.Crossref 30. Braughler JM, Burton PS, Chase RL, et al. Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation . Biochem Pharmacol . 1988;37:3853-3860.Crossref

Journal

Archives of SurgeryAmerican Medical Association

Published: Sep 1, 1995

References