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Cell Biology Committee 2 Cell Biology Chairman C.H FRY (U.K) Members A.J KANAI (USA), A. ROOSEN (Germany), M. TAKEDA (Japan), D.N WOOD (U.K) 113 ABBREVIATIONS AND NOMENCLATURE α,β ABMA -methylene ATP NiCl2 nickel chloride ACE angiotesin converting enzyme NIH National Institutes of Health ACh acetylcholine NK receptor neurokinin receptor α-, β-actin isoforms of actin NMDA n-methyl-D-aspartate AITC allyl-isothiocyanate NO nitric oxide AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole- NOS nitric oxide synthase propionate nNOS neuronal nitric oxide synthase 3-APMPA 3-aminopropyl(methyl)phosphinic acid OAB overactive bladder 3-APPA 3-aminopropylphosphinic acid P pressure A—receptor adenosine- receptor P2-receptor receptors to ATP, subtype X/Y α -receptor alpha adrenoreceptor pA2 negative logarithm of dissociation constant AT angiotensin PACAP pituitary adenylate cyclase activating peptide ATP adenosine triphosphate 4-PBA 4-phenylbutyrate BOO bladder outlet obstruction PDE phosphdiesterase B-receptor bradykinin receptor PE phenylephrine β-receptor beta adrenoreceptor PG prostaglandin + BKCa large conductance K channel PKA protein kinase-A BSMC bladder-derived smooth muscle cell PLC phospholipase-C C bladder compliance PT pressure threshold Ca2+ calcium ion RAR recto-anal reflex CA trans-cinnamaldehyde ROK/ROCK rho-associated kinase cAMP cyclic adenosine monophosphate RT-PCR reverse transcriptase polymerase chain reaction CaM kinase Ca-mitogen kinase S1 first sacral spinal level cGK cGMP-dependent protein kinase SCI spinal cord injury cGMP cyclic guanosine monophosphate SCT spinal cord transection (transected) CICR Ca2+-induced Ca2+ release SERCA sarcoplasmic reticulum Ca2+-pump c-kit (kit)a protein-tyrosine kinase receptor sGC soluble guanylate cyclase Cl- chloride ion SHR spontaneous hypertensive rat CNS central nervous system SIS small intestine submucosa CO carbon monoxide slo-gene encoding the BK channel α-subunit + Cx gap junction protein, connexin SKCa small conductance K channel CPI-17 an MLCP inhibitor SM smooth muscle myosin DAG diacylglycerol SMPP-1M a smooth muscle myosin phosphatase 4-DAMP N-2-chloroethyl-4-piperidinyl diphenylacetate SUI stress urinary incontinence E elastic (Young’s) modulus T wall tension EAG ether-à-go-go-related gene T10 tenth thoracic spinal level ENaC epithelial Na+ channel 7TM receptor 7-transmembrane helix receptor eNOS endothelial nitric oxide synthase TMB-8 an IP receptor blocker 3 + EP receptor prostaglandin E2 (PGE2) receptor TREK channel TWIK-related K channel ER endoplasmic reticulum TRPA transient receptor potential, ankyrin ET endothelin TRPM transient receptor potential, melastatin G-protein guanosine phosphate binding protein TRPML transient receptor potential, mucolipin GABA γ-amino butyric acid TRPP transient receptor potential, polycystin G-I tract gastrointestinal tract TRPV transient receptor potential, vanilloid GRK G-protein coupled receptor kinase TTFA thenoyltrifluoroacetone HA-1077 a rho-kinase inhibitor TTX tetrodotoxin HERG human ether-a-go-go related gene TUNEL terminal deoxynucleotidyl transferase biotin- 5-HT 5-hydroxytryptamine dUTP nick end labeling ICC interstitial cell of Cajal TX thromboxane IC-MY ICC in longitudinal muscle layer UP uroplakin IC-SM ICC in circular muscle layer UPEC uropathogenic Escherichia coli iNOS inducible nitric oxide synthase UPR unfolded protein response IL-6 interleukin-6 UTP uridine triphosphate IMI inter-micturition interval VEGF vascular endothelial growth factor IP3 inositol trisphosphate VIP vasoactive intestinal peptide IPSS international prostate symptom score Y-27632 a rho-kinase inhibitor k stiffness K+ potassium ion Throughout SI (Systeme Internationale) units have been used, in particular + KATP intracellular ATP-gated K channel based on units of length, metre (m); mass, kilogramme (kg); time, second KCl potassium chloride (s); electric current, ampere (A); amount of substance (mol, M): prefixes KCNQ voltage-gated K+ channel, KQT-like superfamily are k (103), m (10-3), µ (10-6), n (10-9). Derived units are combinations 2 -3 -1 L0 optimal resting length for a muscle of SI units and include those for: voltage (V, = kg m s A ); resistance L2 second lumbar spinal level (Ω = V.A-1); conductance (S = Ω-1); force (Newton, N = kg.m.s-2); LUT lower urinary tract frequency (Hz, s-1). Some non-SI units, derived from SI units include m receptor muscarinic receptor (gene level) gram (g), minute (min), hour (hr). Some non-SI units without a precise M receptor muscarinic receptor (protein level) definition are used on occasion: these include litre (l, approximating to 3 mGluR metabotropic glutamate receptor dm ) and cm.H2O as a unit of pressure. The molar unit of concentration MLCK myosin light chain kinase (moles per dm3 solvent) is used throughout and is donated by the letter MLCP myosin light chain phosphatase M. Thus the non-standard form of concentration mol/L is avoided, as it MPEP 6-methyl-2-(phenylethynyl)pyridine has no meaning in the SI system of units. mRNA messenger ribose nucleic acid Symbols for ions in solution, eg Ca2+, Na+, etc, refer to the species that MS mechanosensitive are presumed to take part in chemical reactions. No assumptions are made mtNOS mitochondrial nitric oxide synthase about the activity coefficient of the species in solution. Symbols for Na+ sodium ion metals, Ca, Na, etc, refer to chemical moieties and this makes no statement NA noradrenaline as to the sub-fraction that will take part in a biological process, eg Na- NANC non-adrenergic, non-cholinergic pump. 114 CONTENTS I. INTRODUCTION VI. BIOMECHANICAL PROPERTIES OF THE BLADDER WALL II. THE UROTHELIUM AND 1. ACTIVE AND PASSIVE CONTRACTILE SUBUROTHELIUM PROPERTIES OF THE BLADDER WALL 2. COMPLIANT PROPERTIES OF THE 1. INTRODUCTION BLADDER AND BLADDER WALL 2. THE UROTHELIUM: CHANGES IN DISEASE 3. BIOMECHANICAL PROPERTIES OF AND BACTERIAL INFECTIONS LOWER URINARY TRACT TISSUES AND 3. SECRETORY AND SIGNALING COLLAGEN SUBTYPES PROPERTIES OF THE UROTHELIUM/ 4. PROPERTIES OF THE PELVIC FLOOR AND SUBUROTHELIUM GENUINE STRESS INCONTINENCE 4. INTERACTIONS BETWEEN 5. THE ACTIVE PROPERTIES OF MUSCLE IN UROTHELIUM/ SUBUROTHELIUM AND THE LOWER URINARY TRACT DETRUSOR 6. TENSION AND PRESSURE III. CELL PHYSIOLOGY OF MUSCLE VII. THE LOWER CONTRACTION: DETRUSOR GASTRO-INTESTINAL TRACT 1. THE NORMAL PHYSIOLOGY OF THE 1. CONTRACTILE MECHANISMS RECTUM AND ANUS 2. ELECTRICAL ACTIVITY AND ION 2. INNERVATION CHANNELS 3. SMOOTH MUSCLE TISSUES 3. DETRUSOR ACTIVATION AND 4. INTERSTITIAL CELLS RELAXATION 5. FUTURE DIRECTIONS 4. SPONTANEOUS ACTIVITY 5. TRIGONE VIII. NOVEL MOLECULAR TARGETS IV. THE URETHRA 1. INTRODUCTION 2. METABOTROPIC RECEPTORS 1. INTRODUCTION 3. ION-CHANNELS 2. URETHRAL SMOOTH MUSCLE IX. TISSUE REPLACEMENT AND 3. URETHRAL SKELETAL MUSCLE TRANSLATIONAL RESEARCH V. CELL PHYSIOLOGY OF 1. INTRODUCTION NEUROACTIVE AGENTS IN THE 2. INJECTABLE THERAPY LOWER URINARY TRACT 3. TISSUE REPLACEMENT 1. MUSCARINIC CHOLINERGIC 4. APPROACHES TO GRAFT GENERATION TRANSMISSION 5. CONCLUSION 2. ADRENERGIC TRANSMISSION X. RECOMMENDATIONS FOR LOWER 3. PURINERGIC TRANSMISSION URINARY TRACT AND LOWER 4. NITRERGIC MECHANISMS GASTRO-INTESTINAL TRACT 5. NICOTINE AND NICOTINIC RECEPTORS RESEARCH 6. ADENOSINE RECEPTORS 7. NEUROPEPTIDES REFERENCES 115 Cell Biology C.H FRY, A.J KANAI, A. ROOSEN, M. TAKEDA, D.N. WOOD be applied to the G-I tract. Equally, our understanding I. INTRODUCTION of the mode of action of some useful drugs and a greater understanding of their molecular targets has This aim of this report is to describe the cell and tissue been radically altered, which should enable the physiology and biochemistry of the lower urinary tract development of better-targeted drugs. Figure 1 shows that will help to understand the pathophysiology of a diagrammatic representation of the bladder wall the overactive bladder and lower gastrointestinal (G- with some of the structures and receptors that will be I) tract and to highlight potential avenues whereby described in the following sections. the conditions may be better managed. The report Increased understanding of these tissues has also will attempt to explain the most important features of facilitated tissue-engineering approaches to develop the lower urinary and G-I tracts, and describe important functional implants and recent advances will be changes that are associated with functional disorders. described. This report has attempted to reflect these It is not always possible to differentiate between advances. It will refer to the previous report when primary and secondary changes to tissue that are basic principles were described, and when some associated with tract dysfunction but this is not aspects were discussed in depth and re-examination necessarily important if potentially useful targeted might be repetitious. All referenced material is from models are identified that may be used to develop peer-reviewed publications, most of which have new therapeutic and other approaches to manage appeared after the previous consultation [1]. urinary and faecal incontinence. Since the previous consultation [1] there has been II. THE UROTHELIUM AND considerable advance in our understanding of the SUBUROTHELIUM lower urinary and G-I tract, particularly with respect to the bladder. In particular the urothelium has emerged 1. INTRODUCTION as an important tissue in mediating lower urinary tract sensations, and the principles learnt may in the future The previous report [1] concentrated on the structure Figure 1: Schematic representation of the bladder wall and its
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