title: Adenosine receptor antagonism suppresses functional and histological inflammatory changes in the rat urinary bladder.
abstract: Cyclophosphamide (CYP) induces an interstitial cystitis-like inflammation. The resulting bladder dysfunction has been associated with increased release of adenosine-5'-triphosphate (ATP), structural bladder wall changes and contractile impairment. Due to the inflammatory modulatory effects of purines it was presently wondered if pre-treatment with P1 and P2 purinoceptor antagonists affect the CYP-induced alterations. Rats were pre-treated with saline or antagonists for five days, and 60 h before the in vitro functional examination the rats were administered either saline or CYP. Histological examination revealed CYP-induced bladder wall thickening largely depending on submucosal enlargement, mast cell invasion of the detrusor muscle, increase in muscarinic M5 receptor expression and macrophage migration inhibitory factor (MIF) occurrence in large parts of the urothelium. Functionally, methacholine- and ATP-evoked contractions were smaller in urinary bladders from CYP-treated rats. Pre-treatment with the P2 purinoceptor antagonist suramin and the P1A2B antagonist PSB1115 did not to any great extent affect the CYP-induced changes. The P1A1 antagonist DPCPX, however, abolished the difference of methacholine-evoked contractions between saline- and CYP-treated rats. ATP-evoked contractions were reduced in control after the DPCPX pre-treatment, but not in cystitis. The functional observations for DPCPX were supported by its suppression of CYP-induced submucosal thickening, muscarinic M5 receptor expression and, possibly, detrusor mast cell infiltration and the spread of urothelial MIF occurrence. Thus, P1A1 is an important pro-inflammatory receptor in the acute CYP-induced cystitis and a P1A1 blockade during the initial phase may suppress CYP-induced cystitis. P1A1 purinoceptors seem to regulate contractility in healthy and in inflamed rat urinary bladders.
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 431, SE-40530 Gothenburg, Sweden. patrik.aronsson@pharm.gu.se
authors.forename: Patrik
authors.initials: P
authors.lastname: Aronsson
authors.forename: Martin
authors.initials: M
authors.lastname: Johnsson
authors.forename: Renata
authors.initials: R
authors.lastname: Vesela
authors.forename: Michael
authors.initials: M
authors.lastname: Winder
authors.forename: Gunnar
authors.initials: G
authors.lastname: Tobin
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007166:Immunosuppressive Agents / Q000633:toxicity; D066298:In Vitro Techniques; D007211:Indoles; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D009093:Mucus / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043642:Receptor, Muscarinic M5 / Q000378:metabolism; D013194:Staining and Labeling; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D014970:Xanthines / Q000008:administration & dosage*
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; D007166:Immunosuppressive Agents; D007211:Indoles; D058915:Purinergic P1 Receptor Antagonists; D043642:Receptor, Muscarinic M5; D014970:Xanthines; C007293:DAPI; D000255:Adenosine Triphosphate; D003520:Cyclophosphamide; C051360:1,3-dipropyl-8-cyclopentylxanthine