ABSTRACT
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.
Subject(s)
Computer Simulation , Models, Biological , Tissue Engineering , Ureter/physiology , Urinary Bladder/physiology , Afferent Pathways/physiology , Animals , Cells, Cultured , Humans , Mechanotransduction, Cellular , Systems Integration , Tissue Culture Techniques , Ureter/innervation , Urinary Bladder/innervation , Urination , Urodynamics , Urologic Diseases/physiopathologyABSTRACT
BACKGROUND AND PURPOSE: ATP, released from urothelial cells, modulates afferent nerve firing from the urinary bladder. Here, we have characterized ATP release from the rat bladder mucosa in response to acid, capsaicin, electrical field stimulation (EFS) and stretch, using agonists and antagonists at transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs). EXPERIMENTAL APPROACH: Rat mucosal strips (containing urothelium and lamina propria) in Perspex microbaths were superfused with Krebs solution. ATP was measured after exposure of matched strips to acid (pH 6.6-5.0), capsaicin (0.1-10 microM), EFS or stretch (150% of original length). KEY RESULTS: Median basal ATP release was 3.46 nmol g(-1). The mucosal strips responded to stimuli with potency order (median, IQR): acid (pH 5.6-6.0) 286 (103-555) > 10 microM capsaicin 188 (117-431) > 10 Hz EFS 63.0 (13.3-96.4) > stretch 24.4 (6.73-55.1) nmol ATP g(-1). ATP release in response to acid was pH dependent (P < 0.05). Responses to capsaicin did not desensitize nor were they concentration dependent. TRPV1 antagonist, capsazepine (10 microM) abolished capsaicin-evoked ATP release, and reduced acid-evoked (pH 6.5) release to 30% (P < 0.001). The ASIC channel antagonists gadolinium (0.1 mM) and amiloride (0.3 microM) reduced (P < 0.05) the acid-evoked (pH 6.5) release to 40 and 6.5% respectively. ASIC (ASIC1, ASIC2a, ASIC2b, ASIC3) and two TRPV1 gene products were detected in mucosal and detrusor extracts. CONCLUSIONS AND IMPLICATIONS: Capsaicin (at TRPV1) and acid (at both TRPV1 and ASIC) induce ATP release from the rat bladder mucosa. This ATP appears to be principally of urothelial origin. This study highlights the importance of ATP and acid as signalling molecules in modulating bladder function.
Subject(s)
Adenosine Triphosphate/metabolism , Nerve Tissue Proteins/metabolism , Sodium Channels/metabolism , TRPV Cation Channels/metabolism , Urinary Bladder/metabolism , Acid Sensing Ion Channels , Animals , Capsaicin/administration & dosage , Capsaicin/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , Hydrochloric Acid/pharmacology , Hydrogen-Ion Concentration , Male , Mucous Membrane/drug effects , Mucous Membrane/metabolism , Nerve Tissue Proteins/drug effects , Rats , Rats, Sprague-Dawley , Sodium Channels/drug effects , TRPV Cation Channels/agonists , TRPV Cation Channels/antagonists & inhibitors , Urinary Bladder/drug effectsABSTRACT
BACKGROUND AND PURPOSE: The bladder urothelium is now known to have active properties. Our aim was to investigate the contractile properties of the urinary mucosa in response to the tachykinin neurokinin A (NKA) and carbachol. EXPERIMENTAL APPROACH: Discrete concentration-response curves for carbachol and NKA were obtained in matched strips of porcine detrusor, mucosa and intact bladder, suspended in organ baths. The effects of inhibitors and tachykinin receptor antagonists were studied on NKA-mediated contractions in mucosal strips. Intact sections of bladder and experimental strips were processed for histology and immunohistochemistry. KEY RESULTS: All types of strips contracted to both carbachol and NKA. Mucosal responses to NKA (pD2 7.2) were higher than those in intact strips and were inhibited by the NK2 receptor antagonist SR48968 (pKB 9.85) but not the NK1 receptor antagonist SR140333, tetrodotoxin or indomethacin. Immunostaining for smooth muscle actin and vimentin occurred under the urothelium and on blood vessels. Desmin immunostaining and histological studies showed only sparse smooth muscle to be present in the mucosal strips. Removal of smooth muscle remnants from mucosal strips did not alter the responses to NKA. CONCLUSIONS AND IMPLICATIONS: This study has shown both functional and histological evidence for contractile properties of the mucosa, distinct from the detrusor. Mucosal contractions to NKA appear to be directly mediated via NK2 receptors. The main cell type mediating mucosal contractions is suggested to be suburothelial myofibroblasts. Mucosal contractions may be important in vivo for matching the luminal surface area to bladder volume.
