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.