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Ann Arbor, MI 48106 ANTIULCER ACTIVITY OF THE CALCIUM ANTAGONIST FROPYL-METHYLENEDIOXYINDENE DISSERTATION Presented In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Wai-shiu Fred Wong, U.S. P h arm ., M.S. t\t ijt >Jt >{r The Ohio State University 1990 Dissertation Committee: Approved By Dr. Ralf G. Rahwan Dr. Robert L. Stephens Jr. Dr. Norman J. Uretsky A dvisor Dr. Lane J. Wallace College of Pharmacy To God for giving me wisdom to explore the physical nature of man whom He creates, and to my parents for their sacrifices, and their unceasing love, support and encouragement, and to Amanda for her love, concern and understanding. 11 ACKNOWLEDGMENTS I want to express my sincere appreciation and gratitude to: Dr. Ralf G. Rahwan for his guidance and encouragement, and his persistent enthusiasm and confidence in my research works. Drs. Robert L. Stephens, Jr., Norman J. Uretsky, and Lane J. Wallace for their helpful suggestions and constructive criticisms, and special thanks to Dr. Wallace for his excellent advice in statistics and computer instructions, and to Dr. Stephens for his active participation in my experiments. Dr. McKay for his guidance in taking photomicrographs from microscopic s lid e s . Drs. Dennis R. Feller, Popat N. Patil and Allan M. Burkman for their constant concerns and suggestions. iii VITA November 16, 1961 .............................. Born - Kowloon, Hong Kong 1985 ......................................... ............. B.S, in Pharmacy, The St. John's University, Jamaica, New York 1985 - 1990 ................................................. Graduate Teaching Associate, College of Pharmacy, The Ohio State University, Columbus, Ohio 1988 .................................................................. M.S . in Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio PUBLICATIONS Wong, W.S.F.: Intracellular actions of calcium antagonists in saponin­ skinned vascular smooth muscle. M.Sc. Thesis, The Ohio State University, Columbus, Ohio, 1988. Wong, W.S.F. and Rahwan, R.G.: Pharamcolglcal actions of the calcium antagonist propyl-methylenedioxylndene in skinned vascular smooth muscle. Can. J, Physiol. Pharmacol. 66: 1041-1047, 1988. Rahw an, R.G. and Wong, W.S.F. : Site of action of the calcium antagonist propyl-methylenedioxylndene (pr-MDI) in skinned vascular smooth muscle. 4th Int. Congr. Cell Biol. Abst. P10.1.2, 1988. Wong, W.S.F. and Rahwan, R.G.: Examination of the potential antiepileptic activity of calcium antagonists with different sites of action. Gen. Pharmacol. 20: 309-312, 1989. Wong, W.S.F. and Rahwan, R.G. : Anti ulcer activity of the calcium antagonist propyl-methylenedloxyindene. Pharmacologist. Abst. 149, 1989. iv Wong, W.S.F. and Rahwan, R.G.: Antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. I. Effect on cold-restraint stress-induced ulcers in rats. Gen. Pharmacol. 21: 321-325, 1990. Wong, W.S.F. and Rahwan, R.G.: Antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. II, Effects on acid secretion and gastric emptying in rats. Gen. Pharmacol. 21: 327-331, 1990. FIELDS OF STUDY Major Field: Pharmacology Smooth Muscle Pharmacology - Dr. R.G. Rahwan Pharmacology of Calcium - Dr. R.G. Rahwan Gastrointestinal Pharmacology - Dr. R.G. Rahwan and D r. R.L. Stephens, Jr. v TABLE OF CONTENTS PAGE DEDICATION ..................................................................................................................... ii ACKNOWLEDGMENTS ................................................................................................... iil VITA ....................................................................................................................................... Iv LIST OF TABLES ............................................................................................................ x LIST OF FIGURES .......................................................................................................... xi CHAPTER I INTRODUCTION ................................................................................. 1 1.1 Anatomy of the Stomach and the Duodenum ............................ 1 1.2 Histophysiology of the Gastric Glands ..................................... 12 1.3 Regulations of Gastric Acid Secretion .......... 17 1.4 Pathogenesis of Peptic Ulcer Disease ................................................. 26 1.4.1 Experimental models of gastric ulcers ......................................... 32 1.4.1.1 Cold-restraint stress ulcers............... 33 1.4.1.2 TRH-lnduced gastric ulcerations ............................................ 35 1.4.1.3 Cysteamlne-induced duodenal ulcers ...................................... 38 1.5 Pharmacology of Antiulcer Drugs .......................................................... 41 1.5.1 Antisecretory agents ............................................................................. 41 1.5.1.1 Hz-receptor antagonists ....................... 41 1.5.1.2 Antimuscarinic agents ............... 46 1.5.1.3 Anti gastrin agents ............................................................................ 49 vl 1.5.1.4 H+/K+-ATPase inhibitors ............................................................... 51 1.5.1.5 A ntacids .................................................................................................. 57 1.5.2 Mucosal protective agents ..................................................................... 58 1.5.2.1 Prostaglandins ...................................................................................... 58 1.5.2.2 Sucralfate ................................................................................................ 61 1.5.2.3 Colloidal bismuth subcitrate .................... 64 1.6 Calcium Antagonists and Peptic Ulcer Disease .............................. 66 1.6.1 Calcium channel blockers ..................................................................... 67 1.6.2 Intracellular calcium antagonists ..................................................... 71 1.6.3 Effects of calcium antagonists on experimental ulcers ...................... 75 CHAPTER II RATIONALE AND AIMS OF THIS STUDY ..............................79 CHAPTER III ANTIULCER ACTIVITY OF THE CALCIUM ANTAGONIST PROPYL-METHYLENEDIOXYINDENE. EFFECTS ON COLD-RESTRAINT STRESS-INDUCED ULCERS, ACID SECRETION, MAST CELL DEGRANULATION AND GASTRIC EMPTYING IN RATS .............................................................................................. 83 3.1 Introduction .................. 83 3.2 Methods and Materials ........................................................... 86 3.2.1 Effect of pr-MDI on cold-restralnt stress-indi .ied ulcers .............................................................................. 86 3.2.2 Effect of pr-MDI on gastric acid secretion .............................. 87 3.2.3 Effect of pr-MDI on mast cell degranulation .......... 88 3.2.4 Effect of pr-MDI on gastric emptying ...................... 89 vii 3,2.5 Materials and data analysis ............................................................... 91 3.3 Results ......................................................................................................... 92 3.3.1 Effect of pr-MDI on cold-restralnt stress-induced ulcers .................. 92 3.3.2 Effect of pr-MDI on gastric acid secretion ............................... 96 3.3.3 Effect of pr-MDI on mast cell degranulation ...................... 98 3.3.4 Effect of pr-MDI on gastric emptying ........................................ 101 3.4 Discussion .......................................................................................................... 101 CHAPTER IV ANTIULCER ACTIVITY OF THE CALCIUM ANTAGONIST PROPYL-METHYLENEDIOXYINDENE,