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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9201617 Metabolism of vasoactive peptides by aminopeptidase M Benter, Ibrahim Fadil, Ph.D. The Ohio State University, 1991 UMI 300 N. Zeeb RA Ann Arbor, MI 48106 METABOLISM OF VASOACTIVE PEPTIDES E« AMTNOPEPTIDASE M DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Ibrahim Fadil Benter, B.S. ***** The Ohio State University 1991 Dissertation Ocmmittee: Approved by P a tric k E. Ward John J. Enyeart Richard Fertel Gopi A. Tejwani Department of Pharmacology EEDICATED TO MY MDTHER, whose love and support kept me going over the years AND My EMHER, who guided my life with his uncarpranising principles **** ACKNOWLEDGEMENTS There are many that I owe a debt of gratitude far the help they have given me alcng the way. First, I express sy appreciation to Dr. Patrick Ward, for his guidance and instruction throughout sy graduate study. To Judy and Jack Enyeart for their help and friendship. To Dr. Gopi Tejwani for his help and encouragement over the years. To Dr. Richard Fertel, who helped me better understand where I am and where I am going to. Special thanks to sy friend and colleague, Dr. Saleem Ahmad, for being a good partner. To sy wife, I give sy deepest appreciation for her love, understanding and constant seaport throughout sy educational endeavors. Her personal sacrifices and unselfishness have helped to make t h is achivement p o ssib le. i i i VITA 1985 B.S. The University of Florida, Gainesville, Florida. Major: Chemistry. PUBLICATIONS Stier,C.T., I.F.Beriter and S.Levine Thrcntocxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats Stroke 1988; 19: 1145-1150 Stier,C.T., I.F.Benter and H.D.Itskovitz Enalapril protects against stroke and kidney dysfunction in stroke-prone spontaneously hypertensive rats Hypertension 1989? 13: 115-121 Ward,P.E, I.F.Benter and S.Wilk Metabolism of vasoactive peptides by plasma and purified renal aminopeptidase M Biochemical Pharmacology, 1990; 40: 1725-1732 B e n te r,I.F ., E.M.Hirsh, A.Tuchman and P.E.Ward N-Terminal degradation of lew molecular weight opioid peptides in human cerebrospinal fluid Biochemical Pharmacology, 1990; 40: 465-472 i v FIELDS OF STOEY Major Field: Riarmaoology Fhamaoology Departnent of Pharmacology faculty Biochemistry Dr. Ifetrick E. Hard Radioisotopes Drs. Feller, Malspeis and Brueggemeier v TABLE OF CONTENTS Page D edication .......................................................................................................... i i jmMEDGENENTS.............................................................................................i i i VITA..................................................................................................................... iv LEST OF TABLES.................................................................................................... X UST OF FIGURES................................................................................................ x i LEST OF ABBREVIATIONS................................................................................... xiv I . INTRODUCTION..................................................................................................1 A. CIRCULATING PEPTIDES............................................................................ 1 1. Renin-Angiotensin System ........................................................... 2 2. Kallitaein-Kinin System ............................................................. 7 3. Opioid System ...................... 9 B. METABOLISM OF CIRCULATING PEPTIDES................................................ 11 C. PEPTIDASES.............................................................................................12 D. AMINOEEPFIDASES....................................................................................18 1. AmincpFptidase-Medlated Angiotensin Metabolism ................ 20 2. Amincpeptidase-Mediated Kinin Metabolisn ........................... 21 3. Aminrpppt-.idase-MBdiated Cpioid Metabolism ......................... 22 4. Aminopeptida.se M ........... .......................................................... 24 E. HYPOTHESIS............................................................................................. 25 I I . MATERIALS AND METHODS...................... 26 A. MATERIALS............................................................................................... 26 B. ENZYME ASSAYS........................................................................................27 1. Synthetic Substrate Hydrolysis.. ............ ...........2 7 C. PEPTIDE METABOLISM (TLC and HPLC) .................................................. 29 1. Qualitative Analysis (TLC) .................... 29 2. Quantitative Analysis (HFLC) .................................................. 29 D. IMMUNOELECTROPHORESIS.........................................................................32 I I I . RESULTS.......................................................................................................34 A. HUMAN CSF AMINOPEPTIDASE M OPIOID PEPTIEE METABOLISM............. 34 1. CSF-Characterization of synthetic Substrate Hydrolysis.34 2. CSF-Imnunological Identification of AnM ............................. 36 3. CSF-AnM Mediated Opioid Peptide Metabolism ........................41 4. CSF-Suranary .................................................................................. 45 v i i B. HJQRE AnM FEFITEE METABOLISM............................................................. 47 1. Pure AnH-Qizyme U n i t y ... ....................................................... 47 2. Rrre Anti-Synthetic Substrate Hydrolysis ............................. 48 3. Pure AnM-Feptide Metabolism ....................................................54 3.1. Qialitative Analysis ....................................................54 3.2. Quantitative Analysis ..................................................54 3.2.1. Inhibition Profile and pH Optimum .............. 54 3.2.2. Relative Rates of N-terminal Metabolism. .54 3.2.3. Kinetics of Peptide Metabolism ....................58 4. Pure AnM-Sunmary ........................................................................ 62 C. HUMAN PLASMA Anti FEPTIEE METABOLISM.............................................. 62 1. Human Plasma-Synthetic Substrate Hydrolysis ...............63 2. Human Plasma-Inramoelectrcphoresis ................................63 3. Human Plasma-Peptide Metabolism ..................................... 68 3.1. Quantitative Analysis .................................................. 68 3.1.1. Inhibition Profile and pH Optimum .............. 68 3.1.2. Relative Rates of Peptide Hydrolysis 68 3 .1 .3 . C ontribution o f Anti to Plasma Enkephalin Metabolism .....................................72 3 .1 .4 . C ontribution o f Anti to Plasma Angiotensin Metabolism ...................................78 4. Human Plasma-Summary ..................................... 86 v i i i IV. ELSC05SICN............................................... 90 A. METABOLISM OF TOSCACUVE FEFT1UES BY AnM.................................... 90 B. AnM-MEDIAHD FEFTOE DEGRADATION IN HUMAN CSF ........................... 91 C. HJRIFTED AnM-MEDIAHD DEGRADATION OF VASOACTIVE PEPTIDES.. .95 D. METABOLISM OF ENKEFHALENS AND ANGIOHNSINS IN HUMAN PLASMA. .99 1. Opioid Peptide Metabolism ..................................................... 101 2. Angiotensin Metabolism ........................................................... 102 3. Kinin, Neurokinin and Somatostatin Metabolism ................ 104 E. FUNCTIONAL SFECTFTCnY OF AnM ....................................................... 107 LIST OF REFERENCES. ......... 110 i x LEST o f t a b u s Table Page 1. Synthetic substrate hydrolysis by human CSF .......................35 2. Metabolism of opioid peptides by human CSF ........................ 46 3. Synthetic substrate hydrolysis by pure AnM and plasma ............................................................................
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