title: Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists.
abstract: 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.
authors.affiliation: The Institute of Biosciences and Medicine, University of Surrey, Guildford, UK. c.h.fry@surrey.ac.uk
authors.forename: C H
authors.initials: CH
authors.lastname: Fry
authors.forename: J S
authors.initials: JS
authors.lastname: Young
authors.forename: R I
authors.initials: RI
authors.lastname: Jabr
authors.forename: C
authors.initials: C
authors.lastname: McCarthy
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: A J
authors.initials: AJ
authors.lastname: Kanai
mesh_terms: D000465:Algorithms; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D005455:Fluorescent Antibody Technique; D018613:Microscopy, Confocal; D009092:Mucous Membrane / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D058912:Purinergic P2Y Receptor Agonists / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology; D014530:Uridine Diphosphate / Q000627:therapeutic use; D014544:Uridine Triphosphate / Q000627:therapeutic use; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000503:physiopathology; D019459:Urothelium / Q000502:physiology
chemical_list: D058912:Purinergic P2Y Receptor Agonists; D014530:Uridine Diphosphate; D014544:Uridine Triphosphate