title: Therapeutic effects of the putative P2X3/P2X2/3 antagonist A-317491 on cyclophosphamide-induced cystitis in rats.
abstract: It is suggested that ATP and purinergic P2X receptors are involved in overactive bladder. In this study, we investigated the effect of the recently developed P2X3 and P2X2/3 receptor antagonist A-317491 on cyclophosphamide (CYP)-induced cystitis to determine whether a P2X receptor antagonist could be beneficial for the treatment of bladder overactivity induced by CYP. Female Sprague-Dawley (SD) rats were given 150 mg/kg CYP (i.p.). When the micturition activity was observed for 24 h in a conscious and unrestrained condition, CYP-treated rats exhibited increased urinary frequency. Two days after CYP injection, cystometry was performed in conscious rats, in which the bladder was continuously infused with saline (5 ml/h). In CYP-treated rats, non-voiding contractions were interposed between micturitions, suggestive of hyper-reflexia. Intravenous administration of A-317491 (20 or 50 mg/kg) or pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium (PPADS; a nonselective purinergic receptor antagonist, 10 mg/kg) prolonged the interval of voiding contraction and reduced the non-voiding contractions. On the other hand, oxybutynin (1 mg/kg), a muscarinic receptor antagonist, did not affect the frequency of non-voiding or voiding contractions in CYP-treated rats. A-317491 at the higher dose decreased the amplitude of voiding contractions, but increased the micturition volume. The residual urine in the bladder increased after treatment with CYP; A-317491 and PPADS reduced this, whereas oxybutynin had no effect. These data suggest that A-317491 is effective at improving the signs of CYP-induced cystitis and that the P2X3 or P2X2/3 receptor pathway is involved in bladder overactivity observed during CYP-induced cystitis.
authors.affiliation: Department of Veterinary Pharmacology, Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan. itokt@cc.miyazaki-u.ac.jp
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Ito
authors.forename: Akihito
authors.initials: A
authors.lastname: Iwami
authors.forename: Hiromi
authors.initials: H
authors.lastname: Katsura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008333:Mandelic Acids / Q000494:pharmacology; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
chemical_list: C470346:A-317491; D008333:Mandelic Acids; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D003520:Cyclophosphamide; C005419:oxybutynin