Professor Chris Fry
Director of the Institute of Biosciences and Medicine
Phone: Work: 01483 68 8505
Room no: 05 AW 01
- D.Sc. Physiology, London University 1991
- B.A. Mathematics. Class: First, The Open University 1981-1986
- Ph.D. Physiology, Leicester University, 1971-1974
- B.Sc. Biological Sciences. Class: Upper Second, Leicester University 1968-1971
The cell physiology of cardiac and smooth muscle, in particular the study of those factors that determine the contractility and excitability of these tissues. This has developed into investigations that seek to explain the pathophysiology of muscle dysfunction associated with organ disease. The two major organ systems I study are the heart and the smooth muscles of the lower urinary tract. Although these are two different organ systems, the fundamental cellular physiological control systems and derangements of function that occur in disease are not dissimilar so that valuable conclusions drawn from one tissue may be applied to another.
The experimental approach is to use electrophysiological and real-time fluorescence imaging techniques to record from isolated cells and multicellular preparations, coupled to immuno-histochemical analyses, tension measurements and molecular techniques. My laboratory has pioneered the use of human biopsy material (cardiac and lower urinary tract tissues) from patients with well-defined clinical conditions, to investigate the pathophysiology of these conditions.
Lower urinary tract cell physiology
1. The cell physiology of sub-urothelial myofibroblasts and urothelial epithelium.
The aim of the work is to understand the cellular basis of the sensations of bladder filling and pain. A heightened sense of bladder filling, termed bladder urgency, is an extremely prevalent condition, resulting in urinary incontinence in a proportion of patients; it is also related to other sensory disorders such as painful bladder syndrome. We study the role of urothelial cells and sub-urothelial myofibroblasts in initiating and modulating these sensations by their ability to release neurotransmitters that activate afferent nerve fibres.
2. The regulation of function in lower urinary tract smooth muscle.
This is concerned with identifying and characterising the cellular actions of neurotransmitters, identifying the importance of spontaneous activity in these tissues, and identifying the intracellular signalling pathways that mediate the action of extracellular modulators. Examples include: i) the role of purinergic signalling in determining normal and abnormal lower urinary tract function ii) the quantal subcellular release of intracellular Ca2+ in regulating spontaneous activity and iii) the role of intercellular coupling in determining normal and abnormal contractile function.
3. The development of functional activity in the fetal and neonatal lower urinary tract and the effect of congenital abnormalities on such development.
Human tissue from Great Ormond St has enabled my laboratory to investigate the effect that development abnormalities, such as bladder exstrophy and posterior urethral valves, have on lower urinary tract function. In concert we have developed animal (sheep) models of analogous anomalies to study in a more controlled environment not just the effects of these lesions, but also the extent of functional recovery when the anomalies are corrected. The aim is to develop optimal strategies to guide the timing of surgical intervention that correct these abnormalities to maximise the recovery of normal lower urinary tract function in later life.
Previous research highlights in lower urinary tract cell physiology
- Initial characterisation of a novel cell type in the bladder wall (myofibroblasts) and its potential role in bladder sensation, and pathologies such as urinary urgency and bladder pain.
- Demonstration that detrusor from fetal and neonatal human and animal bladders subjected to congenital or experimental abnormalities underlies bladder dysfunction
- Demonstration of the mechanisms whereby ATP acts as an additional parasympathetic neurotransmitter in human detrusor from patients with bladder disorders
- First description of the ionic basis of electrical activity in bladder (detrusor) smooth muscle and of the regulation of the intracellular [Ca2+] during contractile activation
- Development of techniques to use human biopsies of lower and upper urinary tract tissues for physiological measurements.
Cardiac muscle cell physiology
1. The role of gap junction remodelling in generating arrhythmias.
This uses hearts in failure, with compensated ventricular hypertrophy, with regional ventricular ischaemia or with atrial fibrillation and utilises electrophysiological mapping techniques, biophysical characterisation of the tissue and immunohistochemical analysis of the tissue. Tissue is derived from a number of animal models and human biopsy tissue. In particular we are investigating the role of intracellular kinases and phosphatases that regulate gap junction function.
2. The cellular basis of contractile and conduction failure in human myocardium from patients with cardiomyopathies.
Genetic analysis has identified specific genetic defects and the laboratory work aims to find how this leads to functional abnormalities.
3. Identification of failed intracellular ion regulation in hearts with left ventricular hypertrophy
The rise of the intracellular [Na+] is the primary change that leads to electrophysiological and contractile disorders in these hearts. We aim to study the cause of this defect. The translational interest in this work is being extended to patients at the cardiac centres have end-stage heart failure. It is hypothesised that pharmacological regimes that aim to modulate the intracellular [Na+] will salvage myocardial function.
Previous research highlights in cardiac muscle cell physiology
- Demonstration of the central role of the intracellular [Na+] in determining electrophysiological and contractile dysfunction in left ventricular hypertrophy
- Measurement of the electrical properties of gap junctions in intact myocardium and their central role in generating conduction abnormalities in hypertrophied and failed myocardium.
- Demonstration that mitochondria play a crucial dynamic role in intracellular Ca2+ regulation in myocardium
- Development of multidimensional biophysical models of electrical current flow in myocardium.
- Original proposal of the concept of Ca2+-dependent outward currents in myocardium and its role in controlling action potential duration.
- 'Cytoplasm resistivity of mammalian atrial myocardium determined by dielectrophoresis and impedance methods'. Biophysical Journal, 103 (11), pp. 2287-2294. . (2012)
- 'The regulation of ATP release from the urothelium by adenosine and transepithelial potential.'. BJU Int, . (2012)
- 'Modulation of spontaneous activity in the overactive bladder – the role of P2Y agonists'. American Journal of Physiology, Renal Physiology, . (2012)
- 'Inhibition of stretching-evoked ATP release from bladder mucosa by anticholinergic agents'. British Journal of Urology International, . (2012)
- 'The passive and active contractile properties of the neurogenic, underactive bladder.'. BJU Int, England: 111 (2), pp. 355-361. . (2012)
- 'How does the urothelium affect bladder function in health and disease?'. Neurourology and Urodynamics, doi: 10.1002/nau.22195
- 'Randomized clinical trial of epidural, spinal or patient-controlled analgesia for patients undergoing laparoscopic colorectal surgery.'. Br J Surg, England: 98 (8), pp. 1068-1078.doi: 10.1002/bjs.7545
- 'Modeling the urinary tract-computational, physical, and biological methods.'. Neurourol Urodyn, United States: 30 (5), pp. 692-699.doi: 10.1002/nau.21131
- 'Intracellular Ca(2+) regulation and electrophysiolgical properties of bladder urothelium subjected to stretch and exogenous agonists.'. Elsevier Cell Calcium, Netherlands: 49 (6), pp. 395-399.Full text is available at: http://epubs.surrey.ac.uk/179646/
Intracellular Ca(2+) control and the electrophysiological properties of guinea-pig urothelium were measured during interventions encountered during bladder filling, including cell stretch and exposure to exogenous transmitters such as ATP and muscarinic agonists. Stretch, achieved by exposure to solutions of altered osmolality, generated intracellular Ca(2+)-transients that were attenuated by Gd(3+) in isolated cells. However ATP-induced intracellular Ca(2+)-transients were unaffected by Gd(3+) but blocked by thapsigargin. ATP-dependent Ca(2+)-transients were followed by a large inward current at a holding potential of -60mV. Carbachol was without significant effect, except for a small slowing of the rate of spontaneous intracellular Ca(2+)-transients that were recorded in about one-third of cells. With urothelial sheets the transepithelial potential (TEP) was increased by ATP applied to the baso-lateral (serosal) face, a similar change was achieved by reduction of the basolateral [Na]; carbachol was without significant effect. We propose that a rise of intracellular Ca(2+) may control ATP release as both mechanical stretch and exogenous ATP have been shown previously to release further ATP from isolated urothelium as part of a postulated signalling pathway for bladder filling. The similar increase of TEP by ATP and a raised transepithelial Na gradient is also consistent with a role for transepithelial ion transport as a regulator of ATP release. The lack of large effects with carbachol implies muscarinic agonists must exert any effects on the urothelium through other pathways.
- 'Bladder Compliance What Does it Represent: Can We Measure it, and is it Clinically Relevant?'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, 30 (5), pp. 714-722.doi: 10.1002/nau.21129
- 'Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury.'. Wiley Journal of Cellular and Molecular Medicine, 16 (7), pp. 1533-1543.Full text is available at: http://epubs.surrey.ac.uk/179637/
Introduction Changes in the distribution of interstitial cells (IC) are reportedly associated with dysfunctional bladder. The present study investigated whether spinal cord injury (SCI) resulted in changes to IC subpopulations (vimentin-positive with the ultrastructural profile of IC), smooth muscle and nerves within the bladder wall and correlated cellular remodelling with functional properties. Methods Bladders from SCI (T8/9 transection) and sham-operated rats five-weeks post-injury were used for ex vivo pressure-volume experiments or processed for morphological analysis with transmission electron microscopy (TEM) and light/confocal microscopy. Results Pressure-volume relationships revealed low-pressure, hypercompliance in SCI bladders indicative of decompensation. Extensive networks of vimentin-positive IC were typical in sham lamina propria and detrusor but were markedly reduced post-SCI; semi-quantitative analysis showed significant reduction. Nerves labelled with anti-neurofilament and anti-vAChT were notably decreased post-SCI. TEM revealed lamina propria IC and detrusor IC which formed close synaptic-like contacts with vesicle-containing nerve varicosities in shams. Lamina propria and detrusor IC were ultrastructurally damaged post-SCI with retracted/lost cell processes and were adjacent to areas of cellular debris and neuronal degradation. Smooth muscle hypertrophy was common to SCI tissues. Conclusions IC populations in bladder wall were decreased five weeks post-SCI, accompanied with reduced innervation, smooth muscle hypertrophy and increased compliance. These novel findings indicate that bladder wall remodelling post-SCI affects the integrity of interactions between smooth muscle, nerves and IC, with compromised IC populations. Correlation between IC reduction and a hypercompliant phenotype suggests that disruption to bladder IC contribute to pathophysiological processes underpinning the dysfunctional SCI bladder.
- 'Researching Bladder Afferents-Determining the Effects of beta(3)-Adrenergic Receptor Agonists and Botulinum Toxin Type-A'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, 30 (5), pp. 684-691.doi: 10.1002/nau.21102
- 'The influence of age and bladder dysfunction on the contractile properties of isolated human detrusor smooth muscle.'. British Journal of Urology International,
[ Status: Accepted ]
- 'The physiological function of lower urinary tract smooth muscle.'. Elsevier Auton Neurosci, Netherlands: 154 (1-2), pp. 3-13.Full text is available at: http://epubs.surrey.ac.uk/179651/
The lower urinary tract is a muscular system composed of the urinary bladder and the outflow tract. During filling with urine the bladder is relaxed and the outflow tract offers a high resistance; during emptying the outflow resistance falls and the bladder wall generates a high wall tension to raise intravesical pressure. The coordination of these responses is organized in the brainstem and sacral spinal cord to control the activity of autonomic and somatic efferents to the smooth muscle of the bladder (detrusor) and the smooth and skeletal muscle of the bladder base and urethra. Detrusor contraction is predominantly controlled by parasympathetic fibres releasing acetylcholine and ATP; the outflow tract is controlled by parasympathetic and sympathetic fibres to the bladder base (trigone) and urethral smooth muscle (including a nitregic component) and somatic fibres to the urethral rhabdosphincter. The smooth muscles also develop spontaneous contractions that determine the tone of the musculature. The cellular signaling pathways that evoke contraction due to neurotransmitter release and the origin of spontaneous activity are discussed, as well as the electrical properties of the smooth muscle relevant to the propagation of electrical signals. Finally the interaction of muscle cells with other cell types (epithelium and interstitial cells) is considered, relevant to their ability to regulate muscle contractility. Throughout, the basic physiological processes are considered in relation to pathological developments that are prevalent in the human lower urinary tract, in particular the overactive bladder and urinary incontinence, and the identification of drug targets to manage these conditions.
- 'Animal Models and Their Use in Understanding Lower Urinary Tract Dysfunction'. WILEY-LISS NEUROUROLOGY AND URODYNAMICS, 29 (4), pp. 603-608.doi: 10.1002/nau.20903
- 'Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and Treatment of Urinary Incontinence, Pelvic Organ Prolapse, and Fecal Incontinence'. WILEY-LISS NEUROUROLOGY AND URODYNAMICS, 29 (1), pp. 213-240.doi: 10.1002/nau.20870
- 'Is the Urothelium Intelligent?'. WILEY-LISS NEUROUROLOGY AND URODYNAMICS, 29 (4), pp. 598-602.doi: 10.1002/nau.20914
- 'Measurement of PO(2) during vitrectomy for central retinal vein occlusion, a pilot study'. SPRINGER GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 247 (8), pp. 1019-1023.Full text is available at: http://epubs.surrey.ac.uk/179648/
- 'Characteristics of Spontaneous Activity in the Bladder Trigone'. ELSEVIER SCIENCE BV EUR UROL, 56 (2), pp. 346-353. . (2009)
- 'Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment'. ELSEVIER SCIENCE BV EUROPEAN UROLOGY, 55 (6), pp. 1440-1449.Full text is available at: http://epubs.surrey.ac.uk/285473/
- 'Aberrant Ca2+ oscillations in smooth muscle cells from overactive human bladders'. CHURCHILL LIVINGSTONE CELL CALCIUM, 45 (5), pp. 456-464.Full text is available at: http://epubs.surrey.ac.uk/25595/
- 'ORIGIN AND MODULATION OF SPONTANEOUS ACTIVITY IN THE BLADDER TRIGONE'. ELSEVIER SCIENCE BV EUR UROL SUPPL, 8 (4), pp. 174-174. . (2009)
- 'The Function of Suburothelial Myofibroblasts in the Bladder'. ELSEVIER SCIENCE INC J UROLOGY, 181 (2), pp. 915-916.doi: 10.1002/nau.20483
- 'Adreno-muscarinic synergy in the bladder trigone: Calcium-dependent and -independent mechanisms'. CHURCHILL LIVINGSTONE CELL CALCIUM, 45 (1), pp. 11-17.Full text is available at: http://epubs.surrey.ac.uk/179636/
- 'Clinical and Experimental Aspects of Adreno-Muscarinic Synergy in the Bladder Base and Prostate'. WILEY-LISS NEUROUROLOGY AND URODYNAMICS, 28 (8), pp. 938-943.doi: 10.1002/nau.20742
- 'Modulation of bladder myofibroblast activity: implications for bladder function'. AMER PHYSIOLOGICAL SOC AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 295 (3), pp. F688-F697. . (2008)
- 'Changes to the contractile function of ureter smooth muscle after partial infravesical obstruction in fetal sheep'. BLACKWELL PUBLISHING BJU INTERNATIONAL, 102 (4), pp. 490-494. . (2008)
- 'Selective P2Y(6)-Receptor Antagonism as a Putative Treatment for Detrusor Overactivity'. FEDERATION AMER SOC EXP BIOL FASEB JOURNAL, 22 . (2008)
- 'Synergistic effects in neuromuscular activation and calcium-sensitization in the bladder trigone'. WILEY-BLACKWELL BJU INTERNATIONAL, 101 (5), pp. 610-614. . (2008)
- 'The function of suburothelial myofibroblasts in the bladder.'. Neurourol Urodyn, United States: 26 (6 Suppl), pp. 914-919.doi: 10.1002/nau.20483
- 'Radiotelemetered urodynamics of obstructed ovine fetal bladders: correlations with ex vivo cystometry and renal histopathology'. BLACKWELL PUBLISHING BJU INTERNATIONAL, 99 (6), pp. 1517-1522. . (2007)
- 'Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists'. AMER PHYSIOLOGICAL SOC AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 292 (3), pp. F1065-F1072. . (2007)
- 'Ion-selective electrodes as a tool for measuring urinary NH4+concentration'. ELSEVIER SCIENCE BV EUROPEAN UROLOGY SUPPLEMENTS, 6 (2), pp. 115-115. . (2007)
- 'Ca2+ regulation in detrusor smooth muscle from ovine fetal bladder after in utero bladder outflow obstruction.'. J Urol, United States: 177 (2), pp. 776-780.Full text is available at: http://epubs.surrey.ac.uk/179639/
We characterized intracellular Ca(2+) regulation in fetal bladders following outflow obstruction by examining the Ca(2+) response to agonists in smooth muscle cells.
- 'The role of angiotensin receptor-1 blockade on electromechanical changes induced by left ventricular hypertrophy and its regression'. ELSEVIER SCIENCE BV CARDIOVASC RES, 73 (3), pp. 539-548.Full text is available at: http://epubs.surrey.ac.uk/179650/
Objective: The aims of this study were to: i) investigate the role of angiotensin in mediating changes to myocardial electromechanical properties during the development and regression of left ventricular hypertrophy (LVH) generated by constriction of the thoracic aorta; ii) identify any role of angiotensin-1 receptor blockade on ameliorating changes to these electromechanical properties. Methods: LVH was induced in guinea-pigs by constricting the ascending aorta (AC groups). After 42±3 days, the constriction was either removed or left in place. Following the second operation animals were fed losartan (10 mg·kg−1·day−1) or saline for 42±3 days. Sham-operated animals served as controls. In other groups, LVH was generated by subcutaneous angiotensin II (200 ng·kg−1·min−1) infusion for 42±3 days with or without losartan administration (AT groups), and compared to animals undergoing aortic constriction for a similar period. Electromechanical changes were recorded in isolated left ventricular myocardial preparations. Results: Wet and dry heart-to-body weight ratios (HBR) increased significantly in the AC and AT models compared to control. Losartan prevented the increase of HBR in the AT group. Removal of the constriction allowed LVH to regress to control. The force–frequency relationship was reduced in both models and recovered fully on regression. However, the two models generated different electrophysiological changes: in the AC group, longitudinal conduction velocity was reduced and transverse conduction increased, with a consequent reduction of the anisotropic conduction ratio. On regression recovery was only partial; action potential duration was prolonged and did not recover. In the AT group, electrophysiological changes were limited: only an increase of transverse conduction and a reduction of the anisotropic conduction ratio were observed. Losartan had no effect on HBR or electromechanical variables in the aortic constricted animals, nor did it affect the extent of recovery in animals with regression of LVH. Conclusions: The electromechanical changes to hypertrophied myocardium are different in these two models of LVH. Moreover, losartan was ineffective in modulating the consequences of hypertrophy induced by constriction of the thoracic aorta.
- 'The association between T-type Ca(2+) current and outward current in isolated human detrusor cells from stable and overactive bladders'. WILEY-BLACKWELL BJU INTERNATIONAL, 99 (2), pp. 436-441. . (2007)
- 'Bisphosphonates: Novel inhibitors of calcium oxalate crystallisation'. MARY ANN LIEBERT INC JOURNAL OF ENDOUROLOGY, 20, pp. A72-A72. . (2006)
- 'T-type Ca2+ channels in non-vascular smooth muscles'. Elsevier CELL CALCIUM, 40 (2), pp. 231-239.Full text is available at: http://epubs.surrey.ac.uk/338632/
T-type Ca2+ current has been recorded in smooth muscle myocytes, and associated interstitial cells, from smooth muscle cells isolated from the gastro-intestinal tract, urinary bladder, urethra, prostate gland, myometrium, vas deferens, lymphatic vessels and airways smooth muscle. By contrast, current through such channels has not been recorded from other tissues, such as the ureter. Whilst the properties of this Ca2+ current are similar in most of these cells, with respect to their voltage-dependence, ion selectivity and response to channel modulators, some differences have been recorded, most notably in the gastro-intestinal tract, and may demand a reappraisal of how a T-type Ca2+ current is characterised. The functions of such a current in different tissues remains uncertain. In most of smooth muscles discussed in this review, it is hypothesised that it underlies rhythmic or spontaneous electrical activity, especially in concert with other current-carrying systems, such as Ca2+-activated outward currents. Of equal interest is that the T-type Ca2+ channel may be a target for agents that modulate tissue function, especially in pathological conditions, or are the site of secondary effects of agents used in clinical medicine. For example, T-type Ca2+ channel modulators have been proposed to reduce overactive muscular activity in the gastro-intestinal or urinary tract, or function as tocolytic agents: and the action of volatile anaesthetics on them in airways smooth muscle requires consideration in their overall action.
- 'Ammonium ion-selective electrodes for urinalysis'. MARY ANN LIEBERT INC JOURNAL OF ENDOUROLOGY, 20, pp. A87-A87. . (2006)
- 'EXPERIMENTAL SHORT-TERM PARTIAL OBSTRUCTION OF THE FETAL SHEEP
BLADDER OUTFLOW: II. COMPLIANCE AND CONTRACTILITY ASSOCIATED
WITH URINARY FLOW IMPAIRMENT'. Elsevier Journal of Paediatric Urology, 2 (4), pp. 254-260.Full text is available at: http://epubs.surrey.ac.uk/285494/
Purpose Posterior urethral valves (PUV) is the commonest cause of congenital bladder outlet obstruction. Despite valve ablation in the neonatal period, up to 70% of patients develop renal failure by their teenage years, and progressive bladder dysfunction. This study forms part of a continuing project examining the relationship between severity and duration of obstruction and urinary tract dysfunction. Here is the assessed result of short-term (9-day) obstruction. Materials and methods Fourteen male fetal lambs at 75 days' gestation were assigned to one of three groups: urachal ligation, urachal ligation with partial urethral obstruction, sham-operated controls. Pregnancy proceeded for 9 days. At autopsy, filling cystometry was performed with the urinary tract in situ and the bladder harvested for nerve counts using PGP 9.5 immunohistochemistry, or in vitro measurement of contractile function. Results Obstruction was associated with an increase in bladder:fetal weight ratio. Compliance was variable in the obstructed bladders, but the calculated wall stress per unit strain was either similar or less than controls. Nerve-mediated or agonist-induced contraction magnitude in tissue from obstructed bladders and nerve counts did not differ from controls. Conclusions Nine days of outflow obstruction at mid-gestation generated a bladder of increased weight but without evidence of contractile failure. An increase in bladder compliance as a function of bladder growth was observed even at this stage, and represents one of the initial responses to outflow tract obstruction.
- 'EXPERIMENTAL SHORT-TERM FETAL BLADDER OUTFLOW OBSTRUCTION: I. MORPHOLOGY AND CELL BIOLOGY ASSOCIATED WITH URINARY FLOW IMPAIRMENT'. Journal of Paediatric Urology, 2, pp. 243-253. . (2006)
- 'Characterization of the purinergic receptor subtype on guinea-pig suburothelial myofibroblasts.'. BJU Int, England: 97 (6), pp. 1327-1331. . (2006)
- 'The influence of changes in extracellular and intracellular sodium concentration on detrusor contractility'. WILEY-BLACKWELL BJU INTERNATIONAL, 97 (5), pp. 1083-1086. . (2006)
- 'Symposium report on urothelial dysfunction: Pathophysiology and novel therapies'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, 175 (5), pp. 1624-1629. . (2006)
- 'Ca2+ regulation in detrusor smooth muscle from developing fetal sheep bladders.'. Elsevier Cell Calcium, Scotland: 39 (4), pp. 367-374.Full text is available at: http://epubs.surrey.ac.uk/338631/
Sheep fetus is a useful model to study in utero bladder outflow obstruction but little is known about cell physiology of fetal bladders. To remedy this defect we have characterised intracellular Ca(2+) regulation in fetal sheep myocytes of different developmental ages. Fetal detrusor myocytes had a similar resting [Ca(2+)](i) to adult cells and exhibited transient [Ca(2+)](i) increases in response to carbachol, ATP, high-K, caffeine and low-Na. The carbachol transients were abolished by atropine and caffeine; the ATP response was blocked by alpha,beta-methylene ATP; high-K-evoked [Ca(2+)](i) rises were antagonised by verapamil. The maximal responses to carbachol, high-K, caffeine and low-Na in fetal cells were similar to those of adult counterparts, whilst the ATP response was smaller (p < 0.05). These variables were largely similar between the three gestational groups with the exception of ATP-induced response between early fetal and adult bladders (p < 0.05). Dose-response curves to carbachol demonstrated an increase of potency between mid-gestation and early adulthood (p < 0.05). These data show that muscarinic receptors coupled to intracellular Ca(2+) release, P2X receptor-linked Ca(2+) entry, depolarisation-induced Ca(2+) rise via L-type Ca(2+) channels, Na(+)/Ca(2+) exchange and functional intracellular Ca(2+) stores are all operational in fetal bladder myocytes. Whilst most of Ca(2+) regulators are substantially developed and occur at an early fetal age, a further functional maturation for cholinergic sensitivity and purinergic efficacy continues throughout to adulthood.
- 'Alterations in cardiac connexin expression in cardiomyopathies'. KARGER CARDIOVASCULAR GAP JUNCTIONS, 42, pp. 228-242.doi: 10.1159/000092572
- 'Evidence that inward rectifier K(+) channels mediate relaxation by the PGI(2) receptor agonist cicaprost via a cyclic AMP-independent mechanism'. OXFORD UNIV PRESS CARDIOVASCULAR RESEARCH, 69 (1), pp. 107-115. . (2006)
- 'Structural characterization of myofibroblasts in the bladder'. WILEY-BLACKWELL BJU INTERNATIONAL, 97 (1), pp. 29-32. . (2006)
- 'THE EFFECT OF HEATING (37-41 degrees C) ON DETRUSOR CONTRACTILE FUNCTION IN RABBIT MUCOSA-INTACT AND DENUDED PREPARATIONS.'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Beijing, PEOPLES R CHINA: 42nd Annual Meeting of the International-Continence-Society (ICS) 31 (6), pp. 1027-1028. . (2012)
- 'DISSECTING THE NON-PURINERGIC PARACRINE MEDIATORS IN THE UROTHELIUM-MEDIATED BLADDER HYPERACTIVITY'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Beijing, PEOPLES R CHINA: 42nd Annual Meeting of the International-Continence-Society (ICS) 31 (6), pp. 1022-1023. . (2012)
- 'CHARACTERISATION OF SPONTANEOUS CONTRACTILITY OF THE MUCOSAL LAYER OF GUINEA PIG BLADDER: COMPARISON WITH THE DETRUSOR AND INTACT BLADDER LAYERS'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Beijing, PEOPLES R CHINA: 42nd Annual Meeting of the International-Continence-Society (ICS) 31 (6), pp. 1025-1026. . (2012)
- 'Outcomes From Remote Monitoring Technology for Bradycardia-Pacemaker Follow-Ups'. LIPPINCOTT WILLIAMS & WILKINS CIRCULATION, Dubai, U ARAB EMIRATES: World Congress of Cardiology Scientific Sessions 125 (19), pp. E852-E852. . (2012)
- 'MUSCARINIC MODULATION OF UROTHELIAL ATP RELEASE AND ITS PARACRINE ACTION'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Glasgow, SCOTLAND: 41st Annual Meeting of the International-Continence-Society (ICS) 30 (6), pp. 1179-1181. . (2011)
- 'THE PHYSIOLOGICAL PROPERTIES OF THE DECOMPENSATED, SPINAL CORD INJURED BLADDER'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Glasgow, SCOTLAND: 41st Annual Meeting of the International-Continence-Society (ICS) 30 (6), pp. 932-934. . (2011)
- 'MUSCARINIC RECEPTORS INHIBIT PURINERGIC NEUROTRANSMISSION IN RAT'. WILEY-LISS NEUROUROLOGY AND URODYNAMICS, Phoenix, AZ: 8th Annual Winter Meeting of the Society-for-Urodynamics-and-Female-Urology 30 (2), pp. 237-238. . (2011)
- 'THE CONTRACTILE AND HISTOLOGICAL PROPERTIES OF HUMAN BLADDER SAMPLES OBTAINED FROM CHILDREN WITH NORMAL AND PATHOLOGICAL BLADDERS'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Glasgow, SCOTLAND: 41st Annual Meeting of the International-Continence-Society (ICS) 30 (6), pp. 1189-1190. . (2011)
- 'ELECTROPHYSIOLOGICAL PROPERTIES AND INTRACELLULAR CA2+REGULATION IN UROTHELIUM SUBJECTED TO STRETCH'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Glasgow, SCOTLAND: 41st Annual Meeting of the International-Continence-Society (ICS) 30 (6), pp. 1178-1179. . (2011)
- 'Statins modify connexin expression in activated human macrophages'. ELSEVIER IRELAND LTD ATHEROSCLEROSIS, 213 (1), pp. E10-E10. . (2010)
- 'DIFFERENTIAL EXPRESSION AND TRANSLATION OF ADENOSINE RECEPTOR AGONISTS IN HUMAN DETRUSOR FROM STABLE AND OVERACTIVE BLADDERS AND ITS CONSEQUENCE IN REGULATING DETRUSOR CONTRACTILITY'. Springer International Urogynecology Journal, 21 (Suppl 1), Toronto, Canada: Joint Meeting of the International Continence Society and the International Urogynecological Association, pp. S130-S131.Full text is available at: http://epubs.surrey.ac.uk/179645/
- 'DIFFERENTIAL EXPRESSION AND TRANSLATION OF ADENOSINE RECEPTOR AGONISTS IN HUMAN DETRUSOR FROM STABLE AND OVERACTIVE BLADDERS AND ITS CONSEQUENCE IN REGULATING DETRUSOR CONTRACTILITY'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Toronto, CANADA: Joint Meeting of the International-Continence-Society/International-Urogynecological-Association 29 (6), pp. 934-935. . (2010)
- 'The Relationship Between Gap Junction Conductance and Conduction Velocity in Intact Myocardium'. LIPPINCOTT WILLIAMS & WILKINS CIRCULATION, Orlando, FL: 82nd Scientific Session of the American-Heart-Association 120 (18), pp. S621-S621. . (2009)
- 'Bisphosphonates: effective inhibitors of calcium oxalate crystallisation'. WILEY-BLACKWELL PUBLISHING, INC BJU INTERNATIONAL, Glasgow, SCOTLAND: Annual Meeting of the British-Association-of-Urological-Surgeons 103, pp. 34-34. . (2009)
- 'M2 receptor activation modulates human and guinea pig detrusor contractions via cAMP inhibition'. WILEY-BLACKWELL BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Brighton, ENGLAND: Meeting of the Clinical Pharmacology Section of the British-Pharmacological-Society 65 (6), pp. 978-978. . (2008)
- 'A study of the relation between gap junction expression, conductance and conduction velocity in intact myocardium'. B M J PUBLISHING GROUP HEART, Glasgow, SCOTLAND: Annual Scientific Conference of the British-Cardiovascular-Society 93, pp. A1-A1. . (2007)
- 'Cholinergic control of prostate contractility mediated through smooth muscle M3 receptors'. WILEY-BLACKWELL BJU INTERNATIONAL, Glasgow, SCOTLAND: Annual Meeting of the British-Association-of-Urological-Surgeons 99, pp. 12-12. . (2007)
- 'Prostacyclin synthase activity regulates the adipose depot specific IL-6 secretion'. NATURE PUBLISHING GROUP INTERNATIONAL JOURNAL OF OBESITY, Budapest, HUNGARY: 15th European Congress on Obesity 31, pp. S69-S69. . (2007)
- 'Interstitial cells drive overactivity in pathological bladders-determined using optical imaging'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Rotterdam, NETHERLANDS: 37th Annual Meeting of the International-Continence-Society 26 (5), pp. 670-671. . (2007)
- 'The mechanism of atropine resistance in human detrusor muscle'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Rotterdam, NETHERLANDS: 37th Annual Meeting of the International-Continence-Society 26 (5), pp. 673-674. . (2007)
- 'Modulation of sub-urothelial myofibroblast responses to sensory modulators'. WILEY-BLACKWELL NEUROUROLOGY AND URODYNAMICS, Rotterdam, NETHERLANDS: 37th Annual Meeting of the International-Continence-Society 26 (5), pp. 669-670. . (2007)
- 'Intracellular and gap-junction conductance correlates with connexin43 quantity in left ventricular septal myocardium in patients with hypertrophic obstructive cardiomyopathy'. OXFORD UNIV PRESS EUROPEAN HEART JOURNAL, Barcelona, SPAIN: 28th Congress of the European-Society-of-Cardiology/World Congress of Cardiology 27, pp. 413-413. . (2006)
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Imperial College London, Professor of Cardiac Electrophysiology; National Heart and Lung Institute
University College London, Professor of Physiology; Department of Neuroscience, Physiology and Pharmacology
External Examiner Posts
Cambridge University, Tripos (medicine and veterinary sciences) examinations
Bristol University, BSc physiology programme
Royal College of Surgeons, Court of examiners for MRCS.
Journal Editorial Posts
Neurourology and Urodynamics, section editor biochemistry and physiology
Surgery, basic science editor
Physiological Society; American Physiological Society; International Continence Society; British Cardiovascular Society
Pfizer, Astellas (lower urinary tract disorders)
Tri-services ethical review panel member, Ministry of Defence