Clinical Characteristics and Mortality of Old and Very Old Patients Hospitalized for Hip Fracture or Acute Medical Conditions.

BACKGROUND: There is increasing interest in healthcare quality and economic implications for hip fracture patients of very old age. However, results are limited by access to comparable control groups. OBJECTIVES: We examined healthcare quality measures including mortality and length of stay (LOS) in hospital of adults aged 60-107 years undergoing hip operations, compared to an age-matched group admitted for acute general medical conditions. DESIGN: Monocentric cross-sectional study. SETTING: Ashford and St Peter's Hospitals NHS Foundation Trust, Surrey, United Kingdom. PARTICIPANTS: A total of 3972 consecutive admissions for hip operation from 1st April 2009 to 30th June 2019 (dataset-1) and 6979 for acute general medical conditions from 1st April 2019 to 29th February 2020 (dataset-2). Respective ages, mean (±standard deviation), were 83.5 years (±9.1) and 79.8 years (±9.8). MEASUREMENTS: Mortality and LOS were assessed with each group divided into five- year age bands and those ≥95 years. RESULTS: There were proportionally more (P <0.001) females admitted for hip operations (72.8%) than for acute general medical conditions (53.8%). Amongst patients admitted with general medical conditions, the frequency of the most serious recorded conditions - including congestive heart failure, stroke, and pneumonia - increased with age. Amongst patients undergoing hip operations, 5.7% died in hospital and 29.3% had a LOS ≥3 weeks. Corresponding values for acute general medical conditions were 10.4% and 11.8%. For those undergoing hip operations in all age categories, the risk of death was lower than for acute general medical group: sex-adjusted odds ratios ranged between 0.27 and 0.67, but the risk of LOS ≥3 weeks was greater: odds ratios ranged between 2.46 and 2.95. CONCLUSIONS: Compared to those admitted with acute general medical conditions, patients admitted for hip operations had a lower risk of death, but a longer hospital LOS. .

Targeting neurotrophin and nitric oxide signaling to promote recovery and ameliorate neurogenic bladder dysfunction following spinal cord injury - Mechanistic concepts and clinical implications.

This review summarizes the presentations made to a workshop entitled "Targeting Neurotrophin and Nitric Oxide Signaling to Promote Recovery and Ameliorate Neurogenic Bladder Dysfunction following Spinal Cord Injury - Mechanistic Concepts and Clinical Implications" at the International Continence Society (ICS) 2022 Vienna Meeting. Spinal cord injury (SCI; T8-T9 contusion/transection) causes impaired mobility, neurogenic detrusor overactivity (NDO), detrusor sphincter dyssynergia (DSD) and subsequent decreased quality of life. This workshop discussed the potential of future therapeutic agents that manage the lesion and its consequences, in particular possibilities to reduce the lesion itself and manage pathophysiological changes to the lower urinary tract (LUT). Attenuation of the spinal cord lesion itself was discussed with respect to the potential of a trio of agents: LM11A-3, a p75 neurotrophin receptor modulator to counter activation of local apoptotic pathways; LM22B-10 to promote neuronal growth by targeting tropomyosin-related kinase (Trk) receptors; and cinaciguat, a soluble guanylate cyclase (sGC) activator as an agent promoting angiogenesis at the injury site. The workshop also discussed targets on the bladder to block selectivity sites associated with detrusor overactivity and poor urinary filling profiles, such as purinergic pathways controlling excess contractile activity and afferent signaling, as well as excess fibrosis. Finally, the importance of increased mechanosensitive signaling as a contributor to DSD was considered, as well as potential drug targets. Overall, an emphasis was placed on targets that help restore function and reduce pathological LUT consequences, rather than downregulate normal function.

Soluble Guanylate Cyclase Activators to Treat Benign Prostatic Hyperplasia and associated LUTS.

This review summarises the presentations during a workshop session entitled "The Use of Soluble Guanylate Cyclase Activators to Treat Benign Prostatic Hyperplasia, Obstruction and Fibrosis - Mechanistic Concepts and Clinical Implications" at the International Continence Society (ICS) 2021 Melbourne Virtual meeting. Benign prostatic hyperplasia (BPH) is a highly prevalent condition that can result in bladder outflow obstruction (BOO) and development of lower urinary tract symptoms (LUTS), and by 80 years of age is present in about 75% of men. Current pharmacological therapies include α-adrenoceptor antagonists, 5α-reductase inhibitors, and the phosphodiesterase type 5 (PDE5) inhibitor, tadalafil. The efficacy of tadalafil suggests a role for nitric oxide (NO•) through activation of soluble guanylate cyclase (sGC) and production of cyclic guanosine 3'5'-monophosphate (cGMP), a cyclic nucleotide that relaxes smooth muscle, reduces neurotransmitter release and also acts as an antifibrotic agent. Patient refractoriness to tadalafil may be, for example, due to sGC inactivation due to oxidative stress. The workshop discussed the superiority of cinaciguat, an sGC activator that functions even when the enzyme is oxidised, over PDE5 inhibitors, and potentially its use in combination with agents that reduce formation of reactive oxygen species.

Calcineurin-dependent regulation of gap junction conductance and connexin phosphorylation in guinea pig left atrium.

Atrial fibrillation (AF) occurs from disordered atrial action potential conduction and is associated with reduced gap junction electrical conductance (Gj). The Ca2+ and calmodulin-dependent phosphatase, calcineurin, reduces Gj in ventricular myocardium via a protein phosphatase-1 (PP1)-dependent pathway culminating in phosphorylation of serine368 on connexin43 (pSer368-Cx43). However, characterisation of corresponding pathways in left atrial myocardium, which have a more complex connexin subtype profile, is undefined and was the aim of this study. Gj was measured in guinea-pig left atrium from the frequency-dependent variation of intracellular impedance; intracellular [Ca2+], ([Ca2+]i) in low-Na solution was measured by Fura-2 fluorescence. Phosphorylation of guinea-pig Ser368-Cx43 residues was measured by Western blot; Cx40 was immunoprecipitated and probed for serine/threonine residue phosphorylation. Low-Na solution reversibly reduced Gj, in turn attenuated or prevented by calcineurin inhibitors cyclosporin-A or CAIP, respectively. Moreover, Ser368-Cx43 phosphorylation in low-Na solution was also prevented by CAIP. Changes were partially prevented by fostreicin (FST), a protein phosphatase-2A (PP2A) inhibitor; but not by tautomycin, a PP1 inhibitor. Serine/threonine residues on Cx40 were also phosphorylated in low-Na solution; prevented by CAIP and attenuated by FST. Reduced Gj with raised [Ca2+]i is paralleled by a changed Cx43/Cx40 phosphorylation status; changes mediated by calcineurin and PP2A-dependent pathways, but not PP1. The pharmacological profile underlying changes to guinea-pig atrial gap junction electrical conductance with raised intracellular [Ca2+]i is fundamentally different from that in ventricular myocardium. This provides a targeted drug model whereby atrial and ventricular myocardium can be selectively targeted to correct conduction defects.

Functional, histological and molecular characteristics of human exstrophy detrusor.

INTRODUCTION: Bladder exstrophy is a congenital anomaly involving foetal exposure and protrusion of the open bladder through an incomplete lower abdominal wall. Techniques to surgically correct exstrophy after birth have greatly improved, but it still presents a major challenge to achieve continence and a good quality of life for patients and their families as the pathophysiology of bladder dysfunction is unknown. OBJECTIVES: A multimodal approach was used to characterise the histological and biomechanical properties of exstrophy detrusor. These were correlated with myocyte responses to agonists and an evaluation of developmental signalling pathways to evaluate the cause of bladder dysfunction in exstrophy. STUDY DESIGN: Detrusor muscle specimens were obtained during corrective surgery from four exstrophy groups: neonatal (1-3 days, n = 8), younger children (7 months-5 years, n = 13) and older children (8-14 years, n = 11) undergoing secondary procedures and cloacal exstrophy (16 days-9 years, n = 9); control specimens were obtained from children (3 months-9 years, n = 14) undergoing surgery for other pathologies but with normal bladder function. Five lines of experiments were undertaken: measurement of connective tissue to detrusor muscle ratio, contractile responses to electrical and agonist stimulation; in vitro biomechanical stiffness, intracellular Ca2+ responses to contractile agonists and immunohistochemistry for proteins (MMP-7, cyclinD1, ß-catenin and c-myc) involved in fibrosis generation. Exstrophy data were compared with those from the control group. RESULTS: Exstrophy tissue demonstrated reduced smooth muscle compared with connective tissue, reduced contractile responses and greater mechanical stiffness. However, intracellular Ca2+ responses to agonists were maintained. These changes were greatest in neonatal and cloacal exstrophy samples and least in those from older paediatric bladders. Immunolabelled MMP-7, ß-catenin and c-myc were reduced in exstrophy samples. DISCUSSION: These results highlight the reality that newborns with exstrophy have significantly reduced compliance and bladder underactivity, which may persist or return to normal values with surgery and age. The primary cause of underactivity is increased connective tissue in relation to detrusor muscle; however, detrusor myocyte function remains normal. Finally, the increase of the smooth muscle content in the paediatric bladder group indicates a remodelling response of the bladder to surgical correction and time. Excess gestational fibrosis is associated with changed expression of key proteins in the Wnt-signalling pathway, a potential aetiological factor and therapeutic target. CONCLUSION: Results point to connective tissue deposition as the primary pathological process that determines bladder function with normal myocyte function. Future research that reduces connective tissue deposition may lead to improvement in outcomes for these children.

Diagnosing Paroxysmal Atrial Fibrillation: Are Biomarkers the Solution to This Elusive Arrhythmia?

Atrial fibrillation (AF) is the commonest sustained arrhythmia globally and results in significantly increased morbidity and mortality including a fivefold risk of stroke. Paroxysmal atrial fibrillation (PAF) constitutes approximately half of all AF cases and is thought to represent an early stage of the disease. This intermittent form of atrial arrhythmia can be a challenge to identify and as a result many affected individuals are not prescribed appropriate antithrombotic therapy and hence are at risk of stroke and thromboembolism. Despite these adverse outcomes there have been relatively few diagnostic advances in the field since the introduction of the Holter monitor in 1949. This review aims to establish the available evidence for electrophysiological, molecular, and morphological biomarkers to improve the detection of PAF with reference to the underlying mechanisms for the condition.

Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations.

BACKGROUND AND PURPOSE: The aim of this study was to quantify and characterize the mechanism of non-neuronal ACh release from bladder urothelial cells and to determine if urothelial cells could be a site of action of anti-muscarinic drugs. EXPERIMENTAL APPROACH: A novel technique was developed whereby ACh could be measured from freshly isolated guinea pig urothelial cells in suspension following mechanical stimulation. Various agents were used to manipulate possible ACh release pathways in turn and to study the effects of muscarinic receptor activation and inhibition on urothelial ATP release. KEY RESULTS: Minimal mechanical stimulus achieved full ACh release, indicating a small dynamic range and possible all-or-none signal. ACh release involved a mechanism dependent on the anion channel CFTR and intracellular calcium concentration, but was independent of extracellular calcium, vesicular trafficking, connexins or pannexins, organic cation transporters and was not affected by botulinum-A toxin. Stimulating ACh receptors increased ATP production and antagonizing them reduced ATP release, suggesting a link between ACh and ATP release. CONCLUSIONS AND IMPLICATIONS: These results suggest that release of non-neuronal ACh from the urothelium is large enough and well located to act as a modulator of ATP release. It is hypothesized that this pathway may contribute to the actions of anti-muscarinic drugs in reducing the symptoms of lower urinary tract syndromes. Additionally the involvement of CFTR in ACh release suggests an exciting new direction for the treatment of these conditions.

T-type Ca2+ channels and the urinary and male genital tracts.

T-type Ca(2+) channels are widely expressed throughout the urinary and male genital tracts, generally alongside L-type Ca(2+) channels. The use of pharmacological blockers of these channels has suggested functional roles in all regions, with the possible exception of the ureter. Their functional expression is apparent not just in smooth muscle cells but also in interstitial cells that lie in close proximity to muscle, nerve and epithelial components of these tissues. Thus, T-type Ca(2+) channels can contribute directly to modulation of muscle function and indirectly to changes of epithelial and nerve function. T-type Ca(2+) channel activity modulates phasic contractile activity, especially in conjunction with Ca(2+)-activated K(+) channels, and also to agonist-dependent responses in different tissues. Upregulation of channel density occurs in pathological conditions associated with enhanced contractile responses, e.g. overactive bladder, but it is unclear if this is causal or a response to the pathological state. Moreover, T-type Ca(2+) channels may have a role in the development of prostate tumours regulating the secretion of mitogens from neuroendocrine cells. Although a number of selective channel blockers exist, their relative selectivity over L-type Ca(2+) channels is often low and makes evaluation of T-type Ca(2+) channel function in the whole organism difficult.

Randomized clinical trial on enhanced recovery versus standard care following open liver resection.

BACKGROUND: Enhanced recovery programmes (ERPs) have been shown to reduce length of hospital stay (LOS) and complications in colorectal surgery. Whether ERPs have the same benefits in open liver resection surgery is unclear, and randomized clinical trials are lacking. METHODS: Consecutive patients scheduled for open liver resection were randomized to an ERP group or standard care. Primary endpoints were time until medically fit for discharge (MFD) and LOS. Secondary endpoints were postoperative morbidity, pain scores, readmission rate, mortality, quality of life (QoL) and patient satisfaction. ERP elements included greater preoperative education, preoperative oral carbohydrate loading, postoperative goal-directed fluid therapy, early mobilization and physiotherapy. Both groups received standardized anaesthesia with epidural analgesia. RESULTS: The analysis included 46 patients in the ERP group and 45 in the standard care group. Median MFD time was reduced in the ERP group (3 days versus 6 days with standard care; P < 0·001), as was LOS (4 days versus 7 days; P < 0·001). The ERP significantly reduced the rate of medical complications (7 versus 27 per cent; P = 0·020), but not surgical complications (15 versus 11 per cent; P = 0·612), readmissions (4 versus 0 per cent; P = 0·153) or mortality (both 2 per cent; P = 0·987). QoL over 28 days was significantly better in the ERP group (P = 0·002). There was no difference in patient satisfaction. CONCLUSION: ERPs for open liver resection surgery are safe and effective. Patients treated in the ERP recovered faster, were discharged sooner, and had fewer medical-related complications and improved QoL. REGISTRATION NUMBER: ISRCTN03274575 (http://www.controlled-trials.com).

Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists.

Spinal cord transection (SCT) leads to an increase in spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase in interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders, and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP, and UTP. We have investigated the hypothesis that these agents underlie the increase in spontaneous activity. Rats underwent lower thoracic spinal cord transection, and their bladder sheets or strips, with intact mucosa except where specified, were used for experiments. Isometric tension was recorded and propagating Ca(2+) and membrane potential (E(m)) waves were recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9 ± 0.4/min); ADP, UTP, and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y(6)-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca(2+)/E(m) waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca(2+)/E(m) waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space.

How does the urothelium affect bladder function in health and disease? ICI-RS 2011.

The urothelium is a multifunctional tissue that not only acts as a barrier between the vesical contents of the lower urinary tract and the underlying tissues but also acts as a sensory organ by transducing physical and chemical stresses to the attendant afferent nervous system and underlying smooth muscle. This review will consider the nature of the stresses that the urothelium can transduce; the transmitters that mediate the transduction process; and how lower urinary pathologies, including overactive bladder syndrome, painful bladder syndrome and bacterial infections, are associated with alterations to this sensory system. In particular, the role of muscarinic receptors and the TRPV channels system will be discussed in this context. The urothelium also influences the contractile state of detrusor smooth muscle, both through modifying its contractility and the extent of spontaneous activity; potential pathways are discussed. The potential role that the urothelium may play in bladder underactivity is introduced, as well as potential biomarkers for the condition that may cross the urothelium to the urine. Finally, consideration is given to vesical administration of therapeutic agents that influence urinary tract function and how the properties of the urothelium may determine the effectiveness of this mode of delivery.

Modeling the urinary tract-computational, physical, and biological methods.

Models of the lower urinary tract are used to understand better the physiological and pathological functions of the tract and to gain insight into the relative importance of different components. The key requirement of a model is described, namely: to involve a continuous iteration with experiment; whereby experiments provide parameters and validation for components of the model, which is then used to generate hypotheses, which are tested experimentally. Different types of models are described: computational models that describe mathematically the whole urinary tract or components; physical models useful especially in testing medical devices; and tissue-engineered models. The purpose of modeling is first described in terms of the ability of models to predict the properties of the system of interest, using components that have a physiological interpretation, and to gain insight into the relative importance of different components. Examples are used to illustrate the use of modeling the urinary tract with reference to the different categories listed above.

Bladder compliance what does it represent: can we measure it, and is it clinically relevant?

AIMS: To report the conclusion of the Think Thank 8 on Compliance Discussions during the second ICI-RS meeting in 2010. METHODS: During a 3-day meeting a group of specialists discussed bladder compliance, what it represents, how it can be measured and if it is clinically relevant. RESULTS: Bladder compliance is the result of a mathematical calculation of the volume required for a unit rise of pressure measured during a cystometric filling. It gives an indication on how the different mechanisms in the bladder wall react on stretching. There is a need of standardization of measurement and suggestions for this are given in the text. Pitfalls are described and how to avoid them. There is a wide range of compliance values in healthy volunteers and groups of patients. Poor compliance needs to be defined better as it can have significant clinical consequences. Prevention and treatment are discussed. CONCLUSION: If compliance is correctly measured and interpreted, it has importance in urodynamic testing and gives information relevant for clinical management.

Intracellular Ca(2+) regulation and electrophysiolgical properties of bladder urothelium subjected to stretch and exogenous agonists.

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.

Animal models and their use in understanding lower urinary tract dysfunction.

This review will highlight appropriate animal models for the study of a number of disorders involving changes to lower urinary tract function. A major hurdle to the development of animal models for human lower urinary tract disorders is that the clinical pathophysiology of the latter mostly remain idiopathic. Acute injury/inflammation of otherwise healthy animals has often been used to study effects on a target tissue/organ. However, these "acute" models may not adequately address the characteristics of "chronic" visceral disorders. In addition, the relevance of observed changes following acute injury/inflammation, in terms of possible therapeutic targets, may not reflect that which occurs in the human condition. We have therefore emphasized the situations when animal models are required to investigate lower urinary tract disorders and what they should set out to achieve. In particular we have discussed the merits and disadvantages of a number of paradigms that set out to investigate specific lower urinary tract disorders or situations associated with these conditions. These include animal models of overactive bladder, stress urinary incontinence, ageing and congenital defects of the urinary tract and bladder pain syndrome.

Is the urothelium intelligent?

The urothelium separates the urinary tract lumen from underlying tissues of the tract wall. Previously considered as merely an effective barrier between these two compartments it is now recognized as a more active tissue that senses and transduces information about physical and chemical conditions within the urinary tract, such as luminal pressure, urine composition, etc. To understand this sensory function it is useful to consider the urothelium and suburothelium as a functional unit; containing uroepithelial cells, afferent and efferent nerve fibers and suburothelial interstitial cells. This structure responds to alterations in its external environment through the release of diffusible agents, such as ATP and acetylcholine, and eventually modulates the activity of afferent nerves and underlying smooth muscles. This review considers different stresses the urothelium/suburothelium responds to; the particular chemicals released; the cellular receptors that are consequently affected; and how nerve and muscle function is modulated. Brief consideration is also to regional differences in the urothelium/suburothelium along the urinary tract. The importance of different pathways in relaying sensory information in the normal urinary tract, or whether they are significant only in pathological conditions is also discussed. An operational definition of intelligence is used, whereby a system (urothelium/suburothelium) responds to external changes, to maximize the possibility of the urinary tract achieving its normal function. If so, the urothelium can be regarded as intelligent. The advantage of this approach is that input-output functions can be mathematically formulated, and the importance of different components contributing to abnormal urinary tract function can be calculated.

The physiological function of lower urinary tract smooth muscle.

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.

Aberrant Ca2+ oscillations in smooth muscle cells from overactive human bladders.

Overactive bladder (OAB) syndrome is highly prevalent and costly, but its pathogenesis remains unclear; in particular, the origin of involuntary detrusor muscle activity. To identify the functional substrate for detrusor muscle overactivity, we examined intracellular Ca(2+) oscillations in smooth muscle cells from pathologically overactive human bladders. Basal cytoplasmic Ca(2+) concentration was elevated in smooth muscle cells from overactive bladders. Unprovoked, spontaneous rises of Ca(2+) were also identified. These spontaneous Ca(2+) oscillations were Ca(2+)-dependent, sensitive to L-type Ca(2+) channel antagonist verapamil and also attenuated by blocking SR Ca(2+) reuptake. The fraction of spontaneously active cells was higher in cells from overactive bladders and the magnitude of spontaneous Ca(2+) oscillations also greater. Spontaneous action potentials or depolarising oscillations were also observed, associated with Ca(2+) rise; with a higher percentage of cells from idiopathic OAB, but not in neurogenic OAB. Low concentrations of NiCl(2) attenuated both spontaneous electrical and Ca(2+) activation. This study provides the first evidence that spontaneous, autonomous cellular activity-Ca(2+) and membrane potential oscillations, originates from detrusor smooth muscle in human bladders, mediated by extracellular Ca(2+) influx and intracellular release. Such cellular activity underlies spontaneous muscle contraction and defective Ca(2+) activation contributes to up-regulated contractile activity in overactive bladders.

The function of suburothelial myofibroblasts in the bladder.

The properties of suburothelial myofibroblasts are described, and their possible role in shaping sensory responses from the bladder wall are discussed. Suburothelial myofibroblasts consist of long spindle-shaped cells that form a distinctive layer below the urothelium and are connected to each other through connexin 43 gap junctions. Isolated cells from guinea pig or human bladders display spontaneous fluctuations of membrane potential and intracellular [Ca(2+)], and respond in a similar way to exogenous application of adenosine triphosphate (ATP) or lowering of extracellular pH. ATP generates an intracellular Ca(2+) transient via activation of a P2Y receptor, which in turn initiates a Ca(2+)-sensitive Cl(-) current inward at the normal membrane potential of -50 to -60 mV. Of the P2Y receptor subtypes identified by immunolabeling, the most prominent was the P2Y(6) receptor. Cell pairs, without the formation of gap junctions, elicit augmented responses to exogenous agonists. Mechanical stimulation of the suburothelial layer in intact cross-sections of the bladder elicited Ca(2+) waves that propagated across the suburothelial layer before invading the detrusor layer. This indicates that the suburothelial layer forms a discrete functional layer of cells capable of propagating signals over many cell lengths. A function for suburothelial myofibroblasts is proposed whereby they act as an amplification stage in the sensory response to bladder-wall stretch, as occurs during bladder filling.