title: Modulation of bladder function by luminal adenosine turnover and A1 receptor activation.
abstract: The bladder uroepithelium transmits information to the underlying nervous and musculature systems, is under constant cyclical strain, expresses all four adenosine receptors (A(1), A(2A), A(2B), and A(3)), and is a site of adenosine production. Although adenosine has a well-described protective effect in several organs, there is a lack of information about adenosine turnover in the uroepithelium or whether altering luminal adenosine concentrations impacts bladder function or overactivity. We observed that the concentration of extracellular adenosine at the mucosal surface of the uroepithelium was regulated by ecto-adenosine deaminase and by equilibrative nucleoside transporters, whereas adenosine kinase and equilibrative nucleoside transporters modulated serosal levels. We further observed that enriching endogenous adenosine by blocking its routes of metabolism or direct activation of mucosal A(1) receptors with 2-chloro-N(6)-cyclopentyladenosine (CCPA), a selective agonist, stimulated bladder activity by lowering the threshold pressure for voiding. Finally, CCPA did not quell bladder hyperactivity in animals with acute cyclophosphamide-induced cystitis but instead exacerbated their irritated bladder phenotype. In conclusion, we find that adenosine levels at both surfaces of the uroepithelium are modulated by turnover, that blocking these pathways or stimulating A(1) receptors directly at the luminal surface promotes bladder contractions, and that adenosine further stimulates voiding in animals with cyclophosphamide-induced cystitis.
authors.affiliation: Department of Medicine, Renal Electrolyte Division,University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261, USA.
authors.forename: H Sandeep
authors.initials: HS
authors.lastname: Prakasam
authors.forename: Heather
authors.initials: H
authors.lastname: Herrington
authors.forename: James R
authors.initials: JR
authors.lastname: Roppolo
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Gerard
authors.initials: G
authors.lastname: Apodaca
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003520:Cyclophosphamide / Q000009:adverse effects; D003556:Cystitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000473:pathology / Q000502:physiology; D005260:Female; D023421:Models, Animal; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D001743:Urinary Bladder / Q000473:pathology / Q000502:physiology*
chemical_list: D043682:Receptor, Adenosine A1; C058394:2-chloro-N(6)cyclopentyladenosine; D003520:Cyclophosphamide; D000241:Adenosine