Xanthine dehydrogenase/xanthine oxidase and oxidative stress

Springer Science and Business Media LLC - Tập 20 Số 3 - Trang 127-140 - 1997
Hae Young Chung1, Bong Sook Baek1, Sang Ho Song1, Myoung Sook Kim1, Jung Im Huh1, Kyung Hee Shim1, Kyu Won Kim2, Kyung Hee Lee1
1Department of Pharmacy, Pusan National University, Gumjung-ku, Pusan, 609-735, Korea
2Department of Molecular Biology, Pusan National University, Gumjung-ku, Pusan, 609-735, Korea

Tóm tắt

Từ khóa


Tài liệu tham khảo

Yu, B.P.: Aging and oxidative stress: Modulation by dietary restriction. Free Rad. Biol. Med., 21: 651–668, 1996.

Halliwell, B.: Oxidants and human disease: some new concepts. FASEB. J., 1: 358–364, 1987.

Oberley, L.W.: Superoxide dismutase, ed. 3, Pathological states. Boca Raton, FL; CRC press, 1985, p. 438.

Rotilio, G.: Superoxide and superoxide dismutase in chemistry, biology and medicine. Edited by Amsterdam, Elsevier Science Publishers, 1986, p. 749.

Ames, B.N: Endogenous oxidative DNA damage, aging, and cancer. Free Rad. Res. Comm., 7: 121–128, 1989.

Goldstein, B.D., and Witz, G.: Free radicals and carcinogenesis. Free Rad. Res. Comm., 11: 3–10, 1990.

Richter, C.: Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett., 241: 1–5, 1988.

Angermuller, S., Bruder, G., Völkl, A., Wesch, H., and Fahimi, H.D.: Localization of xanthine oxidase in crystalline cores of peroxysomes. A cytochemical and biochemical study. Eur. J. Cell Biol., 45: 137–144, 1987.

Freeman, B.A. and Crapo, J.D.: Biology of disease. Free radicals and tissue injury. Lab Invest., 47: 412–426, 1982.

Halliwell, B., and Gutteridge, J.M.C.: Role of free radicals and catalytic metal ions in human disease: An overview. Methods Enzymol., 186: 1–85, 1990.

Amaya, Y., Yamazaki, K., Sato, M., Noda, K., Nishino, T., and Nishino, T.: Proteolytic conversion of xanthine dehydrogenases from the NAD-dependent type to the O2-dependent type. J. Biol. Chem., 265: 14170–14175, 1990.

Della Corte, E., and Stripe, F.: The regulation of rat liver xanthine oxidase: Involvement of thiol groups in the conversion of the enzyme activity from dehydrogenase (type D) into oxidase (type O) and purification of the enzyme. Biochem. J., 126: 739–745, 1972.

Ames, B.N., Cathcart, R., Schwiers, E., and Hochstein, P.: Uric acid provides antioxidant defense in humans against oxidant and radical caused aging and cancer. Proc. Nat. Acad. Sci. USA, 78: 6858–6862, 1981.

Howell, R.R., and Wyngaarden, J.B.: On the mechanism of peroxidation of uric acid by homoproteins. J. Biol. Chem., 235: 3544–3549, 1960.

Kellogg, E.W., and Fridovich, I.: Liposome oxidation and erythrocyte lysis by enzymatically generated superoxide and hydrogen peroxide. J. Biol. Chem., 252: 6721–6727, 1977.

Davier, K.J., Seranian, A., Muakkassah-Kelly, S.F., and Hochstein, P.: Uric acid-iron ion complexes. Biochem. J., 235: 747, 1986.

Bray, R.C.: Molybdenum iron-sulfur flavin hydroxylases and related enzymes, in: Part B, The Enzymes, Vol. XII, edited by Boyer, P.D., 3rd ed., New York, Academic Press, 1975, pp. 299–419.

Hille, R., and Massey, V.: Molybdenum-containing hydroxylase: Xanthine oxidase, aldehyde oxidase, and sulfite oxidase in Molybdenum Enzymes Vol. 7, edited by Spiro, T.G., New York, Wiley-Interscience, 1985, pp. 443–518.

Waud, W.R., and Rajagopalan, K.V.: The mechanism of conversion of rat river xanthine dehydrogenase from an NAD-dependent form (type D) to an O2-dependent type (type O). Arch. Biochem. Biophys., 172: 354–364, 1976.

Amaya, Y., Yamazaki, K., Sato, M., Noda, K., Nishino, T., and Nishino, T.: Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. J. Biol. Chem., 265: 14170–14175, 1990.

Nagler, L.G., and Vartanyan, L.S.: Subunit structure of bovine milk xanthine oxidase. Biochim. Biophys. Acta., 427: 78–90, 1976.

Ichida, K., Amaya, Y., Noda, K., Minoshima, S., Hosoya, T., Sakai, O., Shimizu, N., and Nishino, T.: Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): Structural analysis of the protein and chromosomal location of the gene. Gene, 133: 279–284, 1993.

Terao, M., Cazzaniga, G., Ghezzi, P., Bianchi, M., Falciani, F., Perani, P., and Garattini, E.: Molecular cloning of a cDNA coding for mouse liver xanthine dehydrogenase. Biochem. J., 283: 863–870, 1992.

Nishino, T., Nishino, T., Sato, A., Page, T., and Amaya, Y.: Xanthine dehydrogenase: Structure and properties in Flavins and Flavoproteins, edited by Yagi, K., Berlin, Walter de Gruyter, 1984, p. 699.

Keith, R.P., Riley, M.J., Kreitman, M., Lewontin, R.C., Curtis, D., and Chambers, G.: Sequence of the structural gene for xanthine dehydrogenase (rosy locus) in Drosophila melanogaster. Genetics, 116: 67–73, 1987.

Nishino, T., and Nishino, T.: The nicotinamide adenine dinucleotide-binding site of chicken liver xanthine dehydrogenase. J. Biol. Chem., 264: 5468–5473, 1989.

Wooton, J.C., Nicolson, R.E., Cock, J.M., Walters, D.E., Burke, J.F., Doyle, W.A., and Bray, R.C.: Enzymes depending on the pterin molybdenum cofactor: Sequence families spectroscopic properties of molybdenum and possible cofactor-binding domains. Biochim. Biophys. Acta., 1057: 157–185, 1991.

Nakamura, M., and Yamazaki, I.: Preparation of bovine milk xanthine oxidase as a dehydrogenase form. J. Biochem., 92: 1279–1286, 1982.

Hunt, J., and Massey, V.: Purification and properties of milk xanthine dehydrogenase. J. Biol. Chem., 267: 21479–21485, 1992.

Saito, T.: The properties of sulfhydryl groups involved in the interconversion between the NAD+-dependent and O2-dependent types of rat liver xanthine dehydrogenase. Yokohama Med. Bull., 38: 151–168, 1987.

Saito, T., and Nishino, T.: Differences in redox and kinetic properties between NAD-dependent and O2-dependent types of rat liver xanthine dehydrogenase. J. Biol. Chem., 264: 10015–10022, 1989.

Nishino, T., and Nishino, T.: The mechanism of xanthine dehydrogenase to oxidase and the role of the enzyme in reperfusion injury, in: Part A, Purine and pyrimidine metabolism in man, Vol.VII, Edited by Harkness, R.A. et al., New York, Plenum Press, 1991, p. 327.

Amaya, Y., Yamazaki, K., Sato, M., Noda, K., Nishino, T., and Nishino, T.: Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. J. Biol. Chem., 265: 14170–14175, 1990.

Olson, J.S., Ballou, D.P., Palmer, G., and Massey, V.: The mechanism of action of xanthine oxidase. J. Biol. Chem., 249: 4363–4382, 1974.

Nishino, T., Nishino, T., Schopfer, L.M., and Massey, V.: The reactivity of chicken liver xanthine dehydrogenase with molecular oxygen. J. Biol. Chem., 264: 2518–2527, 1989.

Kooij, A., Bosch, K.S., Frederiks, W.M., and Vannoorden, C.J.F.: High levels of xanthine oxidoreductase in rat endothelial, epithelial and connective-tissue cells — A relation between localization and function. Virchows Archiv B-Cell Patholology including Molecular Pathology, 62: 143–150, 1992.

Reniers, J.J., Rupp, T., and Conti, C.J.: Modulation of xanthine dehydrogenase and oxidase activities during the hormonal induction of vaginal epithelial differentiation in ovariectomized mice. Differentiation, 47: 69–75, 1991.

Reniers, J.J., and Rupp, T.: Conversion of xanthine dehydrogenase to xanthine oxidase during keratinocyte differentiation: modulation by 12-O-tetradecanoylphorbol-13-acetate. J. Invest. Dermatol., 93: 132–135, 1989.

Allen, R.G., and Balin, A.K.: Oxidative influence on development and differentiation: An overview of a free radical theory of development. Free Rad. Biol. Med., 6: 631–661, 1989.

Yu, B.P.: Cellular defenses against damage from reactive oxygen species. Physiol. Rev., 74: 139–155, 1994.

Davies, K.J.A., Sevanian, A., Muakkassah-Kelly, S.F., and Hochstein, P.: Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid. Biochem J., 235: 747–754, 1986.

Groolveld, M., and Halliwell, B.: Measurement of allontoin and uric acid in human body fluids. A potential index of free radical reaction in vivo? Biochem. J., 243: 803–808, 1987.

Farber, J.L., Kyle, M.E., and Coleman, J.B.: Biology of disease. Mechanism of cell injury by activated oxygen species. Lab. Invest., 62: 670–679, 1990.

Dobashi, K., Asayama, K., Kato, K., Kobayash, M., and Kawaoi, A.: Immunohistochemical localization of copper-zinc and manganese superoxide dismutase in rat tissues. Acta. Histochem. Cytochem., 22: 351–365, 1989.

Oberley, T.D., Oberley, L.W., Slattery, A.F., Lauchner, L.J., and Elwell, J.H.: Immuno-histochemical localization of antioxidant enzymes in adult syrian hamster tissues and during kidney development. Am. J. Pathol., 137: 199–214, 1990.

Aruoma, O.I., and Halliwell, B.: Inactivation of α1-antiproteinase by hydroxyl radicals. The effect of uric acid. FEBS. Lett., 244: 76–80, 1989.

Terao, J., and Nagao, A.: Antioxidative effect of human saliva on lipid peroxidation. Agric. Biol. Chem., 55: 869–872, 1990.

Elsayed, N.M., and Tierney, D.F.: Hyperoxia and xanthine dehydrogenasel/oxidase activities in rat lung and heart. Arch. Biochem. Biophys., 273: 281–286, 1989.

Becker, B.F., Reinholz, N., Özçelik T., Leipert, B., and Gerlach, E.: Uric acid as radical scavenger and antioxidant in the heart. Pflügers. Arch., 415: 127–135, 1989.

Topham, R.W., Walker, M.C., and Calisch, M.P.: Liver xanthine dehydrogenase and iron mobilization. Biochem. Biophys. Res. Commun., 109: 1240–1246, 1982.

Topham, R.W., Walker, M.C., Calisch, M.P., and Williams, R.W.: Evidence for the participation of intestinal xanthine oxidase in the mucosal processing of iron. Biochemistry, 21: 4529–4535, 1982.

Esterbauer, H., Schaur, R.J., and Zollner, H.: Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde and related aldehydes. Free Rad. Biol. Med., 11: 81–128, 1991.

Chen, J.J., Bertrand, H., and Yu, B.P.: Inhibition of adenine nucleotide translocase by lipid peroxidation by products. Free Rad. Biol. Med., 19: 583–590, 1995.

Kristal, B.S., Park, B.K., and Yu, B.P.: 4-Hydroxyhexenal is a potent inducer of the mitochondrial transition. J. Biol. Chem. 271: 6033–6038, 1996.

Eckl, P., and Esterbauer, H.: Genotoxic effects of 4-hydroxyalkenals. Adv. Biosci., 76: 141–157, 1989.

Kato, S., Kawase, T., Alderman, J., Inatomi, N., and Lieber, C.S.: Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats. Gastroenterol., 98: 203–210, 1990.

Bailey, S.M., and Reinke, L.A.: Potential antioxidant function of xanthine oxidase in low flow ischemia-reperfusion. FASEB J., 10: 4280–4280, 1996.

Tan, S., Radi, R., Gaudier, F., Evans, R.A., Rivera, A., Kirk, K.A., and Parks, D.A.: Physiological levels of uric acid inhibit xanthine oxidase in human plasma. Pediatric Res., 34: 303–307, 1993.

Radi, R., Tan, S., Prodanov, E., Evans, R., and Parks, D.A.: Inhibition of xanthine oxidase by uric acid and its influence on superoxide radical production. Biochem. Biophys, Acta., 1122: 178–182, 1992.

Becker, B.F.: Towards the physiological function of uric acid. Free Rad. Biol. Med., 14: 615–631, 1993.

Askison, D., Hollwagth, M.E., Benoit, J.N., Parks, D.A., McCord, J.M., and Granger, D.N.: Role of free radicals in ischemia-reperfusion injury to the liver. Acta. Physiol. Scand., 548: 101–107, 1986.

Granger, D.N., Hollwarth, M.E., and Parks, D.A.: Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta. Physiol. Scand. Suppl., 548: 47–63, 1986.

Abe, K., Yuki, S., and Kogure, K.: Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke, 19: 480–485, 1988.

Asano, T., Johshita, H., Koide, T., and Takakkura, K.: Amelioration of ischaemic cerebral edema by a free radical scavenger, AVS; 1,2-bis(nicoti-amido)-propane. An experimental study using a regional ischaemia model in cats. Neurol. Res., 6: 163–168, 1984.

Hall, E.D., Pazara, K.E., and Braughler, J.M.: 21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Stroke, 19: 997–1002, 1988.

Johshita, H., Asano, T., Hanamura, T., and Takakura, K.: Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats. Stroke, 20: 788–794, 1989.

Liu, T.H., Beckman, S., Freeman, B.A., Hogan, E.L., and Hsu, C.Y.: Poluethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am. J. Physiol., 256: H589–H593, 1989.

Martz, D., Beer, M., and Betz, A.L.: Dimethylthiourea reduces ischemic brain edema without affecting cerebral blood flow. J.Cereb. Blood Flow Metab., 10: 352–357, 1990.

Martz, D., Rayos, G., Schielke, G.P., and Betz, A.L.: Allopurinol and dimethylthiou reduce brain infarction following middle cerebral artery occlusion in rats. Stroke, 20: 488–494, 1989.

Patt, A., Harken, H.A., Burton, L.K., Rodell, T.C., Piermattei, D., Schorr, W.J., Parker, N.B., Berger, E.M., Horesh, I.R., Terada, L.S., Linas, S.L., Cheronis, J.C., and Repine, J.E.: Xanthine oxidase-derived hydrogen peroxide contributes to ischemia reperfusion-induced edema in gerbil brains. J. Clin. Invest., 81: 1556–1562, 1988.

Watson, B.D., Busto, R., Goldberg, W.J., Santiso, M., Yoshida, S., and Ginsberg, M.D.: Lipid peroxidation in vivo induced by reversible global ischemia in rat brain. J. Neurochem., 42: 268–274, 1984.

Young, W., Wojak, J.C., and Decrescito, V.: 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke, 19: 1013–1019, 1988.

McCord, J.M.: Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med., 312: 159–163, 1985.

Grum, C.M., Ragsdale, R.A., Ketai, L.H., and Shlafer, M.: Absence of xanthine oxidase or xanthine dehydrogenase in the rabbit myocardium. Biochem. Biophys. Res. Commun., 141: 1104–1108, 1986.

Parks, D.A., Williams, T.K., and Beckman, J.S.: Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: a reevaluation. Am. J. Physiol., 254 (Gastrointest. Liver Physiol. 17): G768–G774, 1988.

Betz, A.L.: Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries. J. Neurochem., 44: 574–579, 1985.

Kanemitsu, H., Tamura, A., Kirino, T., Karasawa, S., Sano, K., Iwamoto, T., Yoshiura, M., and Iriyama, K.: Xanthine oxidase and uric acid levels in rat brain following focal ischmia. J. Neurochem., 51: 1982–1985, 1988.

Kanemitsu, H., Tamura, A., Kirino, T., Oka, H., Sano, K., Iwamoto, T., Yoshiura, M., and Iriyama, K: Allopuronol inhibits uric acid stimulation in the rat brain following focal cerebral ischemia. Brain Res., 49: 367–370, 1989.

Nihei, H., Kanemitsu, H., Tamura, A., Oka, H., and Sano, K.: Cerebral uric acid, xanthine, and hypoxanthine after ischemia: the effect of allopurinol. Neurosurgery, 25: 613–617, 1989.

Werns, S.W., Shea, M.J., Mitsos, S.E., Dysko, R.C., Fantone, J.C., Schork, M.A., Abrams, G.D., Pitt, B., and Lucchesi, J.C.: Reduction of the size of infarction by allopurinol in the ischemic-reperfused canine heart. Circulation, 73: 518–524, 1988.

Krenitsky, T.A., Tuttle, J.V., Cattau, E.L., Jr., and Wang, P.: A comparison of the distribution and electron acceptor specificities of xanthine oxidase and aldehyde oxidase. Comparative Biochem. Physiol. B, 49: 687–703, 1974.

Wajner, M., and Harkness, R.A.: Distribution of xanthine dehydrogenase and oxidase activities in human and tissues. Biochim. Biophys. Acta., 991: 79–84, 1989.

Godin, D.V., and Bhimji, S: Effects of allopurinol on myocardial ischemic injury produced by coronary artery ligation and reperfusion. Biochem. Pharmacol., 36: 2101–2107, 1987.

Myers, C.L., Weiss, S.J., Kirsh, M.M., Shepard, B.M., and Shlafer, M.: Effects of supplementing hypothermic crystalloid carioplegic solution with catalase, superoxide dismitase, allopurinol, or deferoxamine on functional recovery of globally ischemic and reperfused isolated hearts. J. Thorac. Cardiovasc. Surg., 91: 281–289, 1986.

Terada, L.S., Leff, J.A., and Repine, J.E.: Measurement of xanthine oxidase in biological tissues. Methods Enzymol., 186: 651–656, 1990.

Granger, D.N.: Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am. J. Physiol., 255: H1269–H1275, 1988.

Suzuki, M., Inauen, W., Kvietys, P.R., Grisham, M.B., Meininger, C., Scheling, M.E., Granger, H.J., and Granger, D.N.: Superoxide mediates reperfusion-induced leukocyte-endothelial cell interaction. Am. J. Physiol., 257: H1740–H1745, 1989.

Maliski, T., Tah, Z., Grinfeel, D.S., Patton, S., Kaptruczak, M., and Tomboulian, P.: Diffusion of nitric oxide in the wall monitored in situ by porphyrinic microsensors. Biochem Biophys. Res. Commun., 193: 1076–1082, 1993.

Blough, N.V., and Zafiriou, O.C.: Reaction of superoxide with nitric oxide to form peroxynitrite in alkaline aqueous solution. Inorg. Chem., 24: 3502–3504, 1985.

Moreno, J.J., and Pryor, W.A.: Inactivation of α-1-proteinase inhibitor by peroxynitrite. Chem. Res. Toxicol., 5: 425–431, 1992.

Ischiropoulos, H., Zhu, L., and Beckman, J.S.: Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys., 298: 446–451, 1992.

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A., and Freeman, B.A.: Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA, 87: 1620–1624, 1990.

Radi, R., Beckman, J.S., Bush, K.M., and Freeman, B.A.: Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Archiv. Biochem. Biophys., 288: 481–487, 1991.

Stamler, J.S., Simon, D.I., Osborne, J.A., Mullins, M.E., Jaraki, O., Michel, T., Single, D.J., and Loscalzo, J.S.: Nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc. Natl. Acad. Sci. USA, 89: 444–448, 1992.

Radi, R., Beckman, J.S., Bush, K.M., and Freeman, B.A.: Peroxynitrite oxidation of sulfhydryls. J. Biol. Chem., 266: 4244–4250, 1991.

Moncada, S., Palmer, R.M.J., and Higgs, E.A.: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol. Rev., 43: 109–142, 1991.

Marletta, M.A.: Nitric oxide; Biosynthesis and biological significance. Trends Biochem. Sci., 14: 488–492, 1989.

Dawson, V.L., Dawson, T.M., London, E.D., Nredt, D.S., and Snyder, S.H.: Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA, 88: 6368–6371, 1991.

Matheis, G., Sherman, M.P., Buckberg, G.D., Haybron, D.M., Young, H.H., and Ignarro, L.J.: Role of L-arginine-nitric oxide pathway in myocardial reoxygenation injury. Am. J. Physiol., 262: H616–H620, 1992.

Koppenol, W.H., Pryor, W.A., Moreno, J.J., Ischiropoulos, H., and Beckman, J.S.: Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem. Res. Toxicol., 5: 834–842, 1992.

Moncada, C., Lekieffre, D., Arvin, B., and Meldrum, B.: Effect of NO synthase inhibition on NMDA-induced and ischemia-induced hippocampal-lesions. Neuroreports, 3: 530–532, 1992.

Nagafuji, T., Matsui, T., Koide, T., and Asano, T.: Blockade of nitric-oxide formation by N-ω-Nitro-L-arginine Mitigates ischemic brain edema and subsequent cerebral infarction in rats. Neurosci. Lett., 147: 159–162, 1992.

Galea, E., Feinstein, D.L., and Reis, D.J.: Induction of calcium-independent nitric-oxide synthase activity in primary rat glial cultures. Proc. Natl. Acad. Sci. USA, 89: 10945–10949, 1992.

Buisson, A., Plotkine, M., and Boulu, R.G.: The neuroprotective effect of a nitric-oxide inhibitor in a rat model of focal cerebral-ischemia. Br. J. Pharmacol., 106: 766–767, 1992.

Beckman, J.S.: The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J. Dev. Physiol., 15: 53–59, 1991.

Morikawa, E., Huang, Z., and Moskowitz, M.A.: L-arginine decreases infarct size caused by middle cerebral arterial-occlusion in SHR. Am. J. Physiol., 263: H1632–H1635, 1992.

Padmaja, S., and Huie, R.E.: The reaction of NO with superoxide. Free Rad. Res. Comms., 18: 195–199, 1993.

Siegfried, M.R., Erhardt, J., Rider, T., Ma, X.L., and Lefer, A.M.: Cardioprotection and attenuation of endothelial dysfunction by organic nitric-oxide donors in cyocardial ischemia-reperfusion. J. Pharmacol. Exp. Ther., 260: 668–675, 1992.

Gambassi, F., Pistelli, A., Dibello, V.G., Lupini, M., Mannaioni, P.F., and Masini, E.: Ischemia-reperfusion injury and histamine-release in isolated perfused guinea-pig heart. — Effects of nitric-oxide generators. Pharmacol. Res., 25: 11–12, 1992.

Linz, W., Wiemer, G., and Scholkens, B.A.: ACE-inhibition induces NO-formation in cultured bovine endothelial-cells and protects isolated ischemic rat hearts. J. Mol. Cell Cardiol., 24: 909–919, 1992.

McDonald, L.J., and Murad, F.: Nitric oxide and cyclic GMP signaling. Proc. Soc. Exp. Biol. Med., 211: 1–6, 1996.

Ulrich, F., and Hartmut, K.: Nitric oxide synthase: expression and expressional control of the three isoforms. Naunyn-Schmiedeberg’s Arch Pharmacol., 352: 351–364, 1995.

Pollock, J.S., Förstermann, U., Tracey, W.R., and Nakane, M.: Nitric oxide synthase isozymes antibodies. Histochemical Journal, 27: 738–744, 1995.

Bredt, D.S., Hwang, P.M., Glatt, C.E., Lowenstein, C., Reed, R.R., and Snyder, S.H.: Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature, 351: 714–718, 1991.

Nathan, C., and Xie, Q.: Nitric oxide synthase: role, tolls, and controls. Cell, 78: 915–918, 1994.

Bredt, S., and Synder, S. H.: Nitric oxide a novel neuronal messenger. Neuron, 8: 3–11, 1992.

Nathan, C.: Nitric oxide as a secretory product of mammalian cells. FASEB J., 6: 3051–3064, 1992.

Bredt, D.S., Hwang, P.M., and Synder, S.H.: Localization of nitric oxide synthase indicating a neuronal role for nitric oxide. Nature, 347: 768–769, 1990.

Pollock, J.S., Fostermann, U., Mitchell, J.A., Warner, T.D., Schmidt, H., Nakang, M., and Murad, F.: Purification and characterization of particulate EDRF synthase from cultured and native bovine aortic endothelial cells. Proc. Natl. Acad. Sci. USA., 88: 10480–10484, 1991.

Sessa, W.C., Harrison, J.K., Luthin, D.R., Pollock, J.S., and Lynch, K.R.: Genomic analysis and expression patterns reveal distinct genes for endothelial and brain nitric oxide synthase. Hypertension, 21: 934–938, 1993.

Marsden, P.A., Heng, H.H.Q., Scherer, S.W., Stewart, R.J., Hall, A.V., Shi, X.M., Tsui, L.C., and Schappert, K.T.: Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J. Biol. Chem., 268: 17478–17488, 1993.

Kaoru, M., Takeshi, K., Kazuhiro, S., Yoshiki, Y., Katsumi, T., Li-Xia, Y., Ryuichi, H., Takeshi, A., Yasutake, Y., Yoshinori, D., Shohei, O., Kozo, H., Chuichi, K., Shigetake, S., and Yutaka, S.: Cloning and structure characterization of the human endothelial nitric oxide synthase gene. FEBS, EJB 94: 719–726, 1994.

Sessa, W.C., Harrision, J.K., Barber, C.M., Zeng, D., Durieux, M.E., D’Angelo, D.D., Lynch, K.R., and Peach, M.J.: Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthse. J. Biol. Chem., 267: 15274–15276, 1992.

Janssens, S.P., Shimouchi, A., Quertermous, T., Block, D.B., and Block, K.D.: Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J. Biol. Chem., 267: 14519–14522, 1992.

David, S.B., and Solomon, H.S. Isolation of nitric oxide synthase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A., 87: 682–685, 1990.

Cras, T.D., Xue, C., Rengasamy, A., and Johns, R.A.: Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung. Am. J. Physiol-Lung Cell. Mol. Physiol., 270: L164–L170, 1996.

Kumura, E., Yoshimine, T., Iwatsuki, K., Yamanaka, K., Tanaka, S., Hayakawa, T., Shiga, T., and Kosaka, H.: Generation of nitric oxide and superoxide during reperfusion after focal cerebral-ischemia in rats. Am. J. Physiol-Cell Physiol., 39: C748–C752, 1996.

Cazevielle, C., Muller, A., Meynier, F., and Bonne, C.: Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury. Free Rad. Biol. Med. 14: 389–395, 1993.

Synder, S.H., and Bredt, D.S.: Nitric oxide as a neuronal messenger. Trends Pharmacol. Sci., 12: 125–128, 1991.

Garthwaite, G., and Garthwaite, J.: Cyclic GMP and cell death in rat cerebellar slices. Neurosci., 26: 321–326, 1988.

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A., and Freeman, B.A.: Apparent hydroxyl radical production by peroxynitrite; Implication for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA, 87: 1620–1624, 1990.

Radi, R., Beckman, J.S., Bush, K.M., and Freeman, B.A.: Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. Biol. Chem., 266: 4244–4250, 1991.

Radi, R., Beckman, J.S., Bush, K.M., and Freeman, B.A.: Peroxynitrite-induced membrane lipid peroxidation; The cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys., 288: 481–487, 1991.

Hogg, N., Darley-Usmer, V.M., Wilson, M.T., and Moncada, S.: Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide. Biochem. J., 281: 419–424, 1992.

Blough, N.V., and Zafiriou, O.C.: Reaction of superoxide with nitric oxide to form peroxynitrite in alkaline aqueous solution. Inorg. Chem., 24: 3502–3504, 1985.

Slater, T.F.: Chemical reactions of free radicals, in Free Radical Mechanisms in Tissue Injury, edited by Slater, T.F., London, Pion Limited, 1972, p. 21–33.

Harman, D.: The aging process. Proc. Natl. Acad. Sci. USA, 78: 7124–7128, 1981.

Haining, J.L., Leagan, J.S., and Lovell, W.J.: Synthesis and degradation of rat liver xanthine oxidase as a function of age and protein deprivation. J. Gerontol., 25: 205–209, 1970.

Janssen, M., Dejong, J.W., Pasini, E., Ferrari, R.: Myocardial xanthine oxidoreductase activity in hypertensive and hypercholesterolemic rats. Cardioscience, 4: 25–29, 1993.

Chung, H.Y., and Yu, B.P.: Regulation of the rat xanthine dehydrogenase/oxidase and uric acid formation by aging and dietary restriction. AGE, 18: 218, 1995 (Abstract).