Cholinergic nitric oxide release from the urinary bladder mucosa in cyclophosphamide-induced cystitis of the anaesthetized rat.
OBJECTIVE
Previous reports have suggested that nitric oxide (NO) may be released by cholinergic stimuli in the rat bladder in cyclophosphamide-induced cystitis, affecting bladder function. In the current study, we evaluated the effects of cyclophosphamide-induced cystitis on muscarinic whole bladder contractile responses in vivo, and further, if NO might be released from the mucosa by cholinergic stimuli.


METHODS
Male rats were pre-treated either with cyclophosphamide (100 mg kg(-1); to induce cystitis) or saline (serving as controls). 60 h later, rats were anaesthetized and bladder pressure monitored.


RESULTS
The muscarinic receptor agonist methacholine (MeCh; 0.5-5 microg kg(-1) i.v.) induced similar contractions (i.e. bladder pressure increases) in inflamed bladders as in controls, which were attenuated dose-dependently by the muscarinic M1/M3/M5 antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP; 0.1-1000 microg kg(-1) i.v.). In inflamed bladders, the cholinergic bladder contractions were enhanced after removing the mucosa, while cholinergic contractions were similar in intact and urothelium-denuded inflamed bladders in the presence of the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 30 mg kg(-1) i.v.). L-NAME attenuated the antagonistic effect of 4-DAMP on MeCh-induced contractions in intact inflamed bladders. However L-NAME did not affect the antagonism by 4-DAMP of MeCh-induced contractions of urothelium-denuded bladders, under control conditions or with cyclophosphamide-induced cystitis.


CONCLUSIONS
In cyclophosphamide-induced cystitis, the cholinergic function of the bladder is altered. In the inflamed bladder, NO seems to be released via cholinergic stimuli through mucosal muscarinic M3/M5 receptors, presumably on urothelial cells, affecting bladder function.
Andersson
M C
MC
Department of Pharmacology, the Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden.
Tobin
G
G
Giglio
D
D
D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009092:Mucous Membrane / Q000378:metabolism / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D043642:Receptor, Muscarinic M5 / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000503:physiopathology*; D019459:Urothelium / Q000378:metabolism / Q000503:physiopathology
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5; D016210:Methacholine Chloride; D009569:Nitric Oxide; D003520:Cyclophosphamide