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INFORMATION to USERS While the Most Advanced Technology Has INFORMATION TO USERS While the most advanced technology has been used to photograph and reproduce this manuscript, the quality of the reproduction is heavily dependent upon the quality of the material submitted. For example: • Manuscript pages may have indistinct print. In such cases, the best available copy has been filmed. • Manuscripts may not always be complete. In such cases, a note will indicate that it is not possible to obtain missing pages. • Copyrighted material may have been removed from the manuscript. In such cases, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, and charts) are photographed by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each oversize page is also filmed as one exposure and is available, for an additional charge, as a standard 35mm slide or as a 17”x 23” black and white photographic print. Most photographs reproduce acceptably on positive microfilm or microfiche but lack the clarity on xerographic copies made from the microfilm. For an additional charge, 35mm slides of 6”x 9” black and white photographic prints are available for any photographs or illustrations that cannot be reproduced satisfactorily by xerography. Order Number 8717696 The chemistry and pharmacological mechanism of sodium nitroprusside Park, Jeen-Woo, Ph.D. The Ohio State University, 1987 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V . 1. Glossy photographs or pages _____ 2. Colored illustrations, paper or print ______ 3. Photographs with dark background _____ 4. Illustrations are poor copy______ 5. Pages with black marks, not original copy ______ 6. Print shows through as there is text on both sides of p a g e _______ 7. Indistinct, broken or small print on several pages 8. Print exceeds margin requirements______ 9. Tightly bound copy with print lost in spine_______ 10. Computer printout pages with indistinct print _______ 11. Page(s) ____________ lacking when material received, and not available from school or author. 12. Page(s) ___________ seem to be missing in numbering only as text follows. 13. Two pages num bered . Text follows. 14. Curling and wrinkled pages ______ 15. Dissertation contains pages with print at a slant, filmed as received _________ 16. Other_______________________________________________________________________ University Microfilms International THE CHEMISTRY AND PHARMACOLOGICAL MECHANISM OF SODIUM NITROPRUSSIDE DISSERTATION Presented in Partial Fullfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jeen-Woo Park/ B.S., M.S. ★ * ★ * ★ The Ohio State University 1987 Reading Committee: Approved by Gary E. Means David H. Ives Richard P. Swenson Department of Biochemistry To My Parents, Wife and Daughter ii ACKNOWLEDGEMENTS With my deepest gratitude to my adviser, Dr. Gary E. Means, for his invaluable guidance, continuous encouragement and care. I wish to express my gratitude to Dr. David H. Ives, Dr. Edward J. Behrman and Dr. Richard P. Swenson for their encouragement and valuable help. I would also like to express my gratitude to Mr. David Chang of Campus Chemical Instrument Center for mass spectral data and Dr. George E. Billman of College of Medicine for help in animal experiment. Special thanks are due to my fellow graduate students for their helpful suggestion and assistance. iii VITA January 12, 1955 .... Born-Taegu, Korea 1978 .................. B.S., Seoul National University, Seoul, Korea 1980 .................. M.S. Biochemistry, Korea Advanced Institute of Science and Technology, Seoul, Korea 1980-1983 ............ Researcher, Korea Ginseng and Tobacco Research Institute, Seoul, Korea 1983-1984 ............ Graduate School Fellow, The Ohio State University, Columbus, Ohio 1984-1987 ............ Teaching and Research Associate, Department of Biochemistry, The Ohio State University, Columbus, Ohio PUBLICATIONS Park, J.W. and Means, G.E. (1987) Inactivation of Angiotensin Converting Enzyme by Sodium Nitroprusside. Biochem. Biophys. Res. Commun., in press. Monera, 0., Chang, M.K., Park, J.W., and Means, G.E. (1986) The Deamination of Lysine Residues of Proteins. Fed. Proc., 45. 1540. Abstract of the ASBC/DBC-ACS Meeting, Washington D.C. Park, J.W. and Means, G.E. (1985) Formation of N-Nitrosamines from Sodium Nitroprusside and Secondary Amines. New Engl. J. Med., 313, 1547. Park, J.W., Kim, S.J., and Lee, H.J. (1983) Active Site Functional Residues of Urokinase as a plasminogen Activator. Korean Biochem. J. 16, 100. iv Kwon, B.M. and Park, J.W. (1983) Study of Hydantoin III. Mass Spectrometric Behavior in the Electron Impact of 2- Imino-4-thiazolidinone Derivatives. J. Heterocyclic Chem., 20, 1725. Kwon, B.M., Oh, D.Y., and Park, J.W. (1983) Mass Spectra of Organophosphorus Compounds II. Unimolecular Reactions of 2- Phenyl-l,3,2-dioxaphosphoran 2-oxide Derivatives in the Gas Phase. Phosphorus and Sulfur 16, 271. Park, J.W. (1982) Analysis of Phenolics in Cigaret Smoke by GC/MS with Multiple Ion Selection Technique. Arch. Pharmacal. Res. 5., 71. Kim, K.R., Zlatkis, A., Park, J.W., and Lee, U.C. (1982) Isolation of Essential Oils from Tobacco by Gas Co- Distillation/Solvent Extraction. Chromatographia 15, 559. Park, J.W. (1982) Direct Analysis of Nicotelline from Tobacco by MS with DADI/MIKE Spectrometry. Arch. Pharmacal. Re3. 5., 25. Park, J.W., Lee, H.J., and Kim, S.J. (1980) Studies on the Anticoagulation Process (Fibrinolysis) by Urokinase. I. Purification and Characterization of Urokinase from Human Urine. Korean Biochem. J. 13. 127. FIELDS OF STUDY Major Field: Biochemistry Studies in Molecular Biology. Professors George A. Marzluf and Lee F. Johnson Studies in Carcinogenesis. Professors George E. Milo and Dorothy E. Schumm Studies in Biophysical Chemistry. Professor Alan G. Marshall v TABLE OF CONTENTS page DEDICATION .................................................. ii ACKNOWLEDGEMENTS ........................................... iii VITA .......................................................... iv LIST OF TABLES .............................................. viii LIST OF FIGURES ............................................ ix INTRODUCTION ................................................ 1 MATERIALS .................................................... 14 METHODS ...................................................... 16 Preparation of N-nitroso derivatives of amines ................................................ 16 Colorimetric method for the detection of N-nitrosamines ...................................... 18 Kinetic studies for nitrosation reactions ........ 19 Effect of blocking agents on the N-nitrosation of piperazine by SNP ................ 19 Modification of angiotensin I, II and ACE by SNP ........................................... 20 Assay of ACE activity .............................. 21 Reaction of SNP with thiols ......................... 21 Sulfhydryl group determination by Ellman reaction.. .................................... 22 Identification of GSNO by ion-exchange column ................................................ 22 vi Preparation of S-nitrosothiols ................... 23 Homololysis of S-nitrosothiols ................... 24 Nitrite determination .............................. 24 Identification of gas product .................... 24 Heterolysis of S-nitrosothiols ................... 25 Transnitrosation of S-nitrosothiols ............. 25 Effect of GSNO on the ADH activity .............. 26 Reaction of GSNO with hemoglobin ................. 27 Reaction of GSNO with HSA ......................... 27 Animal experiments .................................. 28 Gas chromatography .................................. 29 High-performance liquid chromatography .......... 29 Mass spectrometry ................................... 30 Other analytical methods .......................... 30 RESULTS ...................................................... 32 N-Nitrosamines from the reaction of SNP with amines .......................................... 32 Modification of angiotensin I, II and ACE by SNP ........................................... 49 Reaction of SNP with thiols ....................... 52 Preparation and characterization of S-nitrosothiols ..................................... 59 Chemical reactions of S-nitrosothiols ........... 70 Animal experiments ............................... 89 DISCUSSION ................................................... 97 LIST OF REFERENCES ......................................... 129 vii LIST OF TABLES Table page 1. Products obtained from the reactions of SNP with physiologically and pharmacologically important amines .......................... 43 2. Pseudo-first order rate constants for the nitrosation of secondary amines by SNP ............................................... 46 3. Effects of glutathione, cysteine and ascorbate on the reaction of SNP with piperazine .................................... 48 4. Effects of modification of ACE with SNP in the presence of competitive inhibitors.......... 54 5. S-Nitrosothiols from the reaction of thiols with sodium nitrite at pH 1.5 ................... 63 6. Homolysis of 20 mM S-nitrosothiols at pH 7.4 and 37° ..................................... 74 7. Reaction of thiols with S-nitrosothiols ...... 82 8. Equilibria for the
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