Alteration of muscarinic and purinergic receptors in urinary bladder of rats with cyclophosphamide-induced interstitial cystitis.
We characterized muscarnic and purinergic receptors and urodynamic parameters in the bladder of cyclophosphamide (CYP)-treated rats to clarify the mechanisms involved in the pathophysiology of interstitial cystitis (IC). In the cystometry of CYP-treated rats compared with control rats, the micturition interval and micturition volume were significantly (55% and 77%, respectively) decreased and the frequency of micturition and basal pressure were significantly (3 and 2.3 times, respectively) increased. These changes in urodynamic parameters may characterize the detrusor overactivity occurring in CYP-treated rats. The maximal number of binding sites (B(max)) for specific binding of [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) and alphabeta-methylene ATP [2,8-(3)H]tetrasodium salt ([(3)H]alphabeta-MeATP) was significantly (43% and 31%, respectively) decreased in the bladder of CYP-treated rats compared with control rats. On the other hand, the apparent dissociation constant (K(d)) for neither radioligand was significantly altered by the CYP treatment. K(i) value for the inhibition of bladder [(3)H]NMS binding by antimuscarinic agents (oxybutynin, tolterodine, darifenacin, and AF-DX 116) did not differ significantly between control and CYP-treated rats. The inhibition constant (K(i)) for the inhibition of bladder [(3)H]alphabeta-MeATP binding by purinergic antagonists (A-317491, PPADS) was significantly higher in CYP-treated rats than control rats. In conclusion, CYP treatment has been shown to cause down-regulation of pharmacologically relevant (muscarinic and purinergic) receptors in the bladder of rats. Thus, the present study offers further pharmacological evidence that both muscarinic and purinergic mechanisms contribute significantly to the urinary dysfunction due to IC.
Kageyama
Aiko
A
Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Fujino
Tomomi
T
Taki
Yuko
Y
Kato
Yoshihisa
Y
Nozawa
Yoshihisa
Y
Ito
Yoshihiko
Y
Yamada
Shizuo
S
D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity; D018856:Cystitis, Interstitial / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D007166:Immunosuppressive Agents / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology*; D014563:Urodynamics
D007166:Immunosuppressive Agents; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D003520:Cyclophosphamide