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Investigations Into the Role of Endothelin, Nitric Oxide And INVESTIGATIONS INTO THE ROLE OF ENDOTHELIN, NITRIC OXIDE AND PROSTAGLANDINS IN THE PATHOGENESIS OF DIABETIC CYSTOPATHY. A thesis presentedfor the degree o f Doctor o f Medicine in the Faculty o f Medicine of the University o f London Submitted By FAIZ HASSAN MUMTAZ, FRCS. Departments of Urology, Molecular Pathology and Clinical Biochemistry and Academic Surgery Royal Free and University College Medical School (University College London) and The Royal Free Hampstead NHS Trust, Pond Street London NW3 2QG ProQuest Number: 10014733 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10014733 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Endothelin-1 (ET- 1) and its receptors (ETa and ETb) have been identified on the urothelium and smooth muscle of the urinary bladder. ET-1 has potent smooth muscle contractile and mitogenic properties. In contrast, the nitric oxide (NO)-cyclic-guanine 3’5’ monophosphate (cGMP) pathway mediates bladder outlet smooth muscle relaxation. In addition, the prostaglandin (PG)-cyclic-adenosine 3’5’ monophosphate (cAMP) pathway regulates urinary tract smooth muscle tone. The role of these mediators in the pathogenesis of diabetic cystopathy has not been elucidated. Detrusor, bladder neck and urethral tissue fi*om control and six month alloxan-induced diabetic New Zealand White (NZW) rabbits were obtained. Using organ bath, autoradiographic, histochemical, biochemical and tissue culture techniques, the role of these mediators in the pathogenesis of diabetic cystopathy was investigated. These studies demonstrate: 1) Impaired bladder neck and urethral smooth muscle responses to ET-1 and NO in diabetes mellitus (DM) despite a significantly increased expression of ETb receptors and NO synthase (NOS) binding sites. This upregulation may be a compensatory pathophysiological response to smooth muscle dysfunction and/or to alterations in the bioactivity of ET-1 and NO in DM. 2) Decreased formation of cGMP and cAMP by the diabetic smooth muscle that may be a consequence of a decrease in NO and PG bioactivity, respectively. 3) Increased muscarinic receptor-linked PGE2 and PGI2 production by the diabetic detrusor and bladder outlet. This may be a compensatory response to a hypotonic bladder and impaired bladder outlet relaxation in response to NO. 4) Inhibited diabetic smooth muscle cell proliferation by ETa and ETb receptor antagonists indicating a mitogenic role for ET-1 in detrusor hyperplasia. The ET, NO and PG pathways may contribute to the pathogenesis of diabetic cystopathy. The experimental model described may be useful for the evaluation of pharmacological interventions in diabetic cystopathy. TABLE OF CONTENTS Pase Number Title Page 1 Abstract 2-3 Table o f Contents 4-8 List of Figures 9-10 List of Tables 11 Abbreviations 12-14 Acknowledgement 15-16 Publications 17-18 Statement of Originality 19 Hypothesis 20 Chapters 21-158 References 159-220 CHAPTER 1: INTRODUCTION 1.1 Diabetic cystopathy: definition and prevalence 22 1.2 Physiology o f micturition 23-27 1.3 Endothelin in the lower urinary tract 27-33 1.3.1. Synthesis and localisation o f endothelin receptors 1.3.2. Effect o f endothelin on smooth muscle tone 1.3.3. Mechanisms o f endothelin-mediated smooth muscle contraction 1.3.4. Effects o f endothelin on cell proliferation 1.3.5 Pathophysiological role o f endothelin 1.4. Nitric oxide in the lower urinary tract 33-49 1.4.1. The discovery o f nitric oxide 1.4.2. Synthesis, release and degradation o f nitric oxide 1.4.3 Distribution o f nitric oxide synthase in the lower urinary tract 1.4.4. Role o f nitric oxide in the prenatal development o f the lower urinary tract 1.4.5 Evidence o f nitric oxide-dependent smooth muscle relaxation 1.4.6 Mechanism o f nitric oxide-mediated effects in the lower urinary tract 1.4.7 Pathophysiological role o f nitric oxide 1.5 Prostaglandins and the lower urinary tract 50-54 1.5.1 Synthesis and distribution o f prostaglandins 1.5.2 Factors modulating prostaglandins release 1.5.3 Effects o f prostaglandins on smooth muscle tone 1.5.4 Prostaglandins and diabetes mellitus 1.6. Pathophysiology o f lower urinary tract dysfunction in diabetes mellitus 54-60 1.6.1. Autonomic neuropathy 1.6.2. Autonomic receptor andfunctional changes 1.6.3. Structural changes o f the bladder smooth muscle CHAPTER 2: INDUCTION OF DIABETES MELLITUS AND GENERAL BIOCHEMISTRY 2.1 Methods 61-65 2.1.1 Animals, diet and animal weights 2.1.2 Alloxan administration and validation o f the diabetic state 2.1.3 Blood collection and analysis o f samples 2.1.4 Materials 2.1.5. Statistical analysis 2.2 Results 66-72 CHAPTER 3: LOCALISATION OF ETa AND ETb RECEPTOR BINDING SITES AND PHARMACOLOGICAL CHARACTERISATION OF ENDOTHELIN RECEPTORS IN THE RABBIT LOWER URINARY TRACT: EFFECT OF EXPERIMENTAL DIABETES 3.1 Introduction 74- 75 3.2 Methods 76-79 3.2.1 Saturation binding analysis 3.2.3 Quantitative assessment o f ET-1,ET a cmd ETb receptors 3.2.3 In-vitro organ bath studies 3.2.4 Statistical analysis 3.3. Results 80-93 3.4 Discussion 94-9 7 CHAPTER 4: LOCALISATION OF NITRIC OXIDE SYNTHASE AND IN VITRO FUNCTIONAL RESPONSES TO NITRIC OXIDE IN THE RABBIT LOWER URINARY TRACT: IDENTIFICATION OF DIABETES-INDUCED CHANGES 4.1 Introduction 99-100 4.2 Materials and methods 101-103 4.2.1 Autoradiographic localisation and quantification o f nitric oxide synthase binding sites 4.2.2 Histochemical localisation o f nitric oxide synthase. 4.3.3 In vitro organ bath studies 4.2.4 Statistical analysis 4.3 Results 104-115 4.4. Discussion 116-119 CHAPTER 5: PROSTACYCLIN AND CYCLIC NUCLEOTIDE SYNTHESIS BY THE RABBIT LOWER URINARY TRACT: DIABETES INDUCED CHANGES 5.1 Introduction 121 5.2 Material and methods 122-124 5.2.1 Preparation o f tissues 5.2.2 PGh and PGE 2 formation 5.2.3 Assessment of cyclic nucleotide formation 5.2.4 Statistics analysis 5.3 Results 125-129 5.4 Discussion 130-133 CHAPTER 6: INHIBITION OF DIABETIC BLADDER SMOOTH MUSCLE CELL PROLIFERATION BY ENDOTHELIN RECEPTOR ANTAGONISTS, 6.1 Introduction 135-136 6.2 Material and methods 137-138 6.2.1 Proliferation assay with detrusor and bladder neck smooth muscle cells 6.2.2 Statistical analysis 6.3 Results 139-145 6.4 Discussion 146-148 CHAPTER 7 GENERAL DISCUSSION 149-158 FURTHER WORK COMPLETED 159 FUTURE WORK 159 REFERENCES 160-220 LIST OF FIGURES 1 - Low-resolution autoradiographs of ETa and ETb radioligand binding sites in the control and diabetic detrusor. 2 - Low-resolution autoradiographs of ETa and ETb radioligand binding sites in the control and diabetic bladder neck. 3- Higb-resolution autoradiograph of ETa receptor binding sites in the control detrusor. 4- Higb-resolution autoradiograph of ETb receptor binding sites in the control and diabetic bladder neck. 5- Higb-resolution autoradiograph of ETa receptor binding to the blood vessels within the detrusor. 6 - Concentration response curves to ET-1 in the control detrusor and bladder neck. 7- Concentration response curves to ET-1 in the control detrusor in the presence of BQ123andBQ788. 8 - Concentration response curves to ET-1 in the control and diabetic detrusor. 9- Concentration response curves to ET-1 in the control and diabetic bladder neck. 10-Low resolution autoradiographs of [^H]-L-NOARG binding to a transverse section from the detrusor. 11-Low resolution autoradiographs of [^H]-L-NOARG binding to a transverse section from the control and diabetic bladder neck. 12- Low resolution autoradiographs of [^H]-Z-NOARG binding to a transverse section from the control and diabetic urethra. 13-Photograph showing the distribution of NADPH-d activity in the control and diabetic detrusor and bladder neck. 14-Photograph demonstrating NADPH-d activity in the diabetic bladder neck at a higher magnification. 15-Photograph showing neuronal NADPH-d activity in control and diabetic urethra. 16-Concentration response curves to exogenous NO in control and diabetic bladder neck and urethral smooth muscle. 17-NANC-mediated responses in control and diabetic urethral smooth muscle. 18-Arachidonic acid-stimulated prostaglandin E 2 formation by the detrusor, bladder neck and urethra from control and diabetic rabbits. 19- Acetylcholine-stimulated prostaglandin E 2 formation by the detrusor, bladder neck and urethra from control and diabetic rabbits. 20- Forskolin-stimulated cAMP formation by the detrusor, bladder neck and urethra from control and diabetic rabbits. 21- Sodium nitroprusside-stimulated cGMP formation by the detrusor, bladder neck and urethra from control and diabetic rabbits. 22-Effect of ETa (BQ123) and ETb (BQ788) antagonists on the level of BrdU incorporation by the control and diabetic detrusor SMC in the presence of diabetic rabbit serum. 23-Effect of ETa (BQ123) and ETb (BQ788) antagonists on the level of BrdU incorporation by the control and diabetic bladder neck SMC in the presence of diabetic rabbit serum. 10 LIST OF TABLES 1. Body weights in control and diabetic animals. 2. Haematological variables in control and diabetic rabbits. 3. Urea & electrolytes, phosphate, magnesium, calcium and glucose variables in control and diabetic rabbits. 4. Urate, amylase and liver function test variables in control and diabetic rabbits.
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