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Download The THE ISOLATION AND PHYSIOLOGICAL ACTIONS OF GASTRIC INHIBITORY POLYPEPTIDE BY RAYMOND ARNOLD PEDERSON B.ED.; UNIVERSITY OF CALGARY, 1964 a, I A THESIS SUBMITTED IN PARTIAL FULFILMENT OF ^ THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE DEPARTMENT OF PHYSIOLOGY WE ACCEPT THIS THESIS AS CONFORMING TO THE REQUIRED STANDARD SUPERVISOR EXTERNAL EXAMINER THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 1971 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of ~TA.y&j ¥ The University of British Columbia Vancouver 8, Canada Date 3^6/?/ ABSTRACT IT IS KNOWN THAT HUMORAL MECHANISMS FOR THE INHIBITION OF GASTRIC SECRETION AND MOTOR ACTIVITY OPERATE FROM THE DUODENUM. THE GASTROINTESTINAL HORMONES CHOLECYSTOKININ- PANCREOZYMIN (CCK-PZ) AND SECRETIN HAVE BEEN IMPLICATED AS THE HORMONES RELEASED IN SOME OF THESE PROPOSED MECHANISMS. DESPITE THE FACT THAT CCK-PZ AND SECRETIN ARE PROBABLY INVOLVED IN GASTRIC INHIBITORY MECHANISMS, THEY FALL SHORT OF FUL P LL L IN G THE ORIGINAL DEFINITION OF E N T E R 0 G A S T R 0 N E AS THE INHIBITORY PRINCIPLE RELEASED FROM THE DUODENUM BY THE PRESENCE THERE OF FAT. IMPURE PREPARATIONS OF CCK-PZ ARE KNOWN TO STIMULATE H+ SECRETION IN THE DOG WHEN GIVEN ALONE AND TO INHIBIT H+ SECRETION STIMULATED BY GASTRIN. INITIAL STUDIES IN - THIS THESIS COMPARING THE EFFECTS OF 2 PURITIES OF CCK-PZ ON GASTRIC SECRETION PROVIDED EVIDENCE FOR THE EXISTENCE OF A GASTRIC INHIBITOR DISTINCT FROM CCK-PZ AND SECRETIN IN PARTIALLY PURIFIED CCK-PZ PREPARATIONS. IT WAS CONCLUDED FROM THESE STUDIES THAT IN PARTIALLY PURIFYING CCK-PZ, AN INHIBITORY MATERIAL COULD HAVE BEEN REMOVED. THIS CONCLU• SION WAS SUPPORTED BY THE FINDING THAT A SIDE FRACTION FROM THE PURIFICATION OF CCK-PZ, WITH NO SIGNIFICANT CCK OR SECRETIN ACTIVITY, POSSESSED POTENT INHIBITORY ACTIVITY FOR GASTRIN PENTAPEPTIDE-STIMULATED H+ AND PEPSIN SECRETION IN THE DOG. THE SIDE FRACTION REFERRED TO IN THIS THESIS AS EG STAGE I BECAME THE STARTING POINT FOR SEVERAL PURIFI• CATION PROCEDURES. PURIFICATION OF THE INHIBITORY MATERIAL I I Ml LEO TO THE DISCOVERY THAT IT WAS A POLYPEPTIDE DISTINCT IN ITS CHEMICAL FEATURES FROM CCK-PZ, NOTABLY BY THE ABSENCE OF THE AMINO ACID PROLINE. THE PURE INHIBITORY MATERIAL, GASTRIC INHIBITORY POLY• PEPTIDE (G.I.P.), WHEN AVAILABLE, WAS SHOWN TO POSSESS NO SECRET IN ACT 1V ITY, NEGLIGIBLE CCK ACTIVITY, AND TO HAVE NO PYROGEN IC OR VAS0DEPRESSOR EFFECTS. G.I.P. WAS USED IN STUDIES TO DETERMINE ITS POTENCY AS AN INHIBITOR OF GASTRIC SECRET I ON AND MOTOR ACTIVITY IN THE DOG. STUDIES WERE CARRIED OUT IN WHICH.G.I.P. WAS SHOWN TO BE A HIGHLY POTENT INHIBITOR OF H+ AND PEPSIN SECRETION FROM BlCKEL POUCHES AND MOTOR ACTIVITY FROM VAGALLY DENERVATED ANTRAL POUCHES STIMULATED BY GASTRIN PENTAPEPTIDE AND THE WHOLE GASTRIN MOLECULE. ANOTHER OBJECTIVE WAS TO DETERMINE IF G.I.P. WAS EFFECTIVE AS AN INHIBITOR OF GASTRIC SECRETION AGAINST STIMULANTS THAT WERE RESISTANT TO INHIBITION BY CCK-PZ AND SECRETIN, E.G. HISTAMINE. RESULTS OF THESE EXPERIMENTS PROVED G.I.P. TO BE ABOUT HALF AS EFFECTIVE AN INHIBITOR OF H+, PEPSIN AND FUNDIC MOTOR ACTIVITY DURING HISTAMINE INFUSION AS COMPARED WITH EXPERIMENTS IN WHICH GASTRIN PENTAPEPTIDE WAS THE STIMULANT. THE RANGE OF EFFECTIVENESS OF G.I.P. AS A GASTRIC INHIBITOR WAS EXTENDED TO VAGALLY— STIMULATED H+ AND PEPSIN SECRETION WITH POTENCY OF INHIBITION EQUALLING THAT FOUND IN HISTAMINE STUDIES. AS A RESULT OF STRUCTURAL SIMILARITIES BETWEEN G.I.P. AND GLUCAGON, STUDIES WERE CARRIED OUT TO DETERMINE IF G.I.P. MIMICKED THE HYPERGLYCEMIC OR PANCREATIC INHIBITORY I V ACTIONS KNOWN TO BE POSSESSED BY GLUCAGON. THIS WAS FOUND NOT TO BE THE CASE. IN ADDITION TO INHIBITING STIMULATED GASTRIC SECRETION AND MOTOR ACTIVITY, G.I.P. WAS SHOWN TO INHIBIT FUNDIC POUCH H+ SECRETION, PEPSIN SECRETION AND MOTOR ACTIVITY IN THE UNSTIMULATED CONDITION. IT IS CONCLUDED THAT SINCE G.I.P. FULFILLS THE PHYSIO• LOGICAL REQUIREMENTS AS AN EFFICIENT GASTRIC INHIBITOR AND MIMICS THE ACTIONS OF FAT IN THE DUODENUM, IT IS AN EXCEL• LENT CANDIDATE FOR THE HUMORAL AGENT RELEASED FROM THE DUODENUM BY FAT AND PERHAPS BY HYDROCHLORIC ACID AND HYPER• TONIC SOLUTIONS* HOWEVER, RESERVATIONS MUST BE HELD AS TO ITS STATUS AS A HORMONE UNTIL IT IS DETECTED IN BLOOD AND TISSUES. TABLE OF CONTENTS PAGE ABSTRACT . I I LIST OF TABLES vi I I LIST OF FIGURES xi ACKNOWLEDGEMENTS xiv INTRODUCTION .... 1 METHODS 18 OPERATIVE PROCEDURES 18 I CHRON ICDOGS 18 I I ACUTE CATS 21 III ACUTE GUINEA PIGS 22 IV ACUTE RABBITS 23 COLLECTION AND ANALYSES OF SAMPLES 23 I COLLECTION OF GASTRIC SECRETION .... 23 A. BICKEL POUCH COLLECTION - DOG .... 23 B. GASTRIC REMNANT COLLECTION - DOG . 24 C. WHOLE STOMACH COLLECTION - CAT ... 24 D. PERFUSION OF ANTRAL POUCH ANO MEASUREMENT OF ANTRAL MOTOR ACTIVITY IN THE DOG 24 E. MEASUREMENT OF FUNOIC POUCH MOTOR ACTIVITY IN THE DOG 26 F. MEASUREMENT OF GALL BLADDER ACTIVITY IN THE DOG 26 I I ANALYSES OF SAMPLES 27 A. GASTRIC SECRETION 27 A) ESTIMATION OF H+ CONCENTRATION . 27 B) ESTIMATION OF PEPSIN ....... 27 B. PANCREATIC SECRETION ........ 28 A) VOLUME 28 B) PROTEIN OUTPUT 28 C. ESTIMATION OF BLOOD GLUCOSE ..... 28 ASSAY METHODS 28 I ASSAY OF CHOLECYSTOKININ ACTIVITY IN GASTRIC INHIBITORY PREPARATIONS .... 28 II ASSAY OF ENTEROGASTRONE ACTIVITY .... 32 III ASSAY OF SECRETIN ACTIVITY • • 32 IV A. ASSAY FOR BLOOO PRESSURE CHANGES • • 34 B. ASSAY FOR PYROGENIC EFFECTS 34 SOURCE OF HORMONE PREPARATIONS 34 ANALYSIS OF DATA 36 v V I PAGE RESULTS 38 I MULTIPARAMETER STUDY ON THE EFFECTS OF THE INTRAVENOUS INFUSION OF TWO PREPARATIONS CONTAINING CHOLECYSTOKININ- PANCREOZYMIN (CCK-PZ) 38 A. THE EFFECT OF CCK-PZ ON INTRA-GALL BLADDER PRESSURE 39 B. THE EFFECT OF CCK-PZ ON ANTRAL MOTOR ACTI VI TY 39 C. THE EFFECT OF CCK-PZ ON PEPSIN OUTPUT FROM BlCKEL POUCHES ........ 39 D. THE EFFECT OF CCK-PZ ON H+ SECRETION FROM BlCKEL POUCHES . 44 II COMPARISON OF TWO PREPARATIONS CONTAIN• ING CCK-PZ IN TERMS OF GASTRIC SECRETORY INHIBITION 44 III PREPARATION, ASSAY AND GASTRIC INHIBITORY ACTIONS OF EG STAGE I 51 A. EFFECTS OF EGI ON GASTRIC SECRETION AND MOTOR ACITVITY . 57 A) BICKEL POUCH H+ SECRETION . ... 57 B) BICKEL POUCH PEPSIN SECRETION . 60 B. EFFECTS OF EGI (G25) ON GASTRIC SECRETION AND MOTOR ACTIVITY STIMU• LATED BY ENDOGENOUS GASTRIN .... 64 A) BICKEL POUCH H"*" SECRETION .... 64 B) BICKEL POUCH PEPSIN SECRETION . 64 c) ANTRAL MOTOR ACTIVITY ...... 64 IV PREPARATION AND ASSAY OF EG STAGE II • 69 V PURIFICATION OF EG STAGE II TO EG STAGE Ml 73 VI EFFECT OF PURE GASTRIC INHIBITORY POLY• PEPTIDE ON BICKEL POUCH ACID AND PEPSIN SECRETION AND ANTRAL MOTILITY STIMU• LATED BY GASTRIN PENTAPEPTIDE 73 A) BICKEL POUCH H+ SECRETION .... 74 B) BICKEL POUCH PEPSIN SECRETION . 74 c) ANTRAL MOTOR ACTIVITY 81 VII EFFECT OF GASTRIC INHIBITORY POLYPEP• TIDE ON GASTRIC SECRETION AND MOTOR ACTIVITY STIMULATED BY SYNTHETIC HUMAN GASTRIN (SHG-I) 81 A) BICKEL POUCH H+ SECRETION .... 87 B) BICKEL POUCH PEPSIN SECRETION • . 87 c) ANTRAL MOTOR ACTIVITY 92 VIII EFFECT OF G.I.P. ON GASTRIC SECRETION AND MOTOR ACTIVITY STIMULATED BY HISTAMINE DIHYDROCHLORIDE 92 V I I PAGE VIII (CONT.) A) BICKEL POUCH H+ SECRETION .... 96 B) BICKEL POUCH PEPSIN SECRETION . 100 c) BICKEL POUCH MOTOR ACTIVITY . 100 IX EFFECT OF G.I.P. ON INSULIN-STIMULATED GASTRIC SECRETION 104 A) GASTRIC REMNANT H* SECRETION . 109 B) GASTRIC REMNANT PEPSIN SECRETION. 109 X EFFECT OF G.I.P. ON H+ SECRETION AND VOLUME OF PANCREATIC JUICE IN THE ANAESTHETIZED CAT DURING THE INFUSION OF GASTRIN PENTAPEPTIDE 109 A) EFFECT OF G.I.P. ON H+ SECRETION FROM THE CAT STOMACH STIMULATED BY GASTRIN PENTAPEPTIDE 115 B) EFFECT OF G.I.P. ON VOLUME OF PANCREATIC JUICE DURING THE INFUSION OF GASTRIN PENTAPEPTIDE. 115 XI EFFECT OF GASTRIC INHIBITORY POLYPEPTIDE ON FASTJNG BLOOD GLUCOSE LEVELS .... 117 A) BLOOD GLUCOSE LEVELS IN EXPERIMENTS INVOLVING THE INHIBITION OF GASTRIN PENTAPEPTIDE—STIMULATED H+ SECRE• TION . 117 B) COMPARISON OF EQUIMOLAR INJECTIONS OF GLUCAGON AND G.I.P. ON BLOOD GLUCOSE LEVELS IN THE DOG AND THE RABBIT 117 XII EFFECT OF GASTRIC INHIBITORY POLYPEPTIDE ON BICKEL POUCH PEPSIN OUTPUT STIMULATED BY SECRETIN ..... 119 XIII EFFECT OF GASTRIC INHIBITORY POLYPEPTIDE ON GASTRIC SECRETION AND MOTOR ACTIVITY IN THE UNSTIMULATED DOG 124 A) BICKEL POUCH H+ OUTPUT 124 B) BICKEL POUCH PEPSIN OUTPUT ... 124 c) ANTRAL AND BICKEL POUCH MOTOR ACTIVITY 124 DISCUSSION 127 BIBLIOGRAPHY 153 LIST OF TABLES TABLE PAGE I. EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON INTRA-GALL BLADDER PRESSURE 4-0 II. EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON ANTRAL MOTILITY 4-2 III. EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON PEPSIN SECRETION 45 IV. EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON H+ OUTPUT 47 V. EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON H+ OUTPUT STIMULATED BY GASTRIN PENTAPEPTIDE . 52 VI. EFFECT OF INTRAVENOUS INFUSION OF EGI ON H+ OUTPUT STIMULATED BY GASTRIN PENTAPEPTIDE ... 58 VII. EFFECT OF INTRAVENOUS INFUSION OF EGI ON PEPSIN OUTPUT STIMULATED BY GASTRIN PENTAPEPT I OE 61 VIII. EFFECT OF INTRAVENOUS INFUSION OF EGI (G25) ON H+ OUTPUT STIMULATED BY PERFUSION OF ANTRAL POUCHES WITH 0.1$ ACH • 65 IX.
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