Cholinergic nitric oxide release from the urinary bladder mucosa in cyclophosphamide‐induced cystitis of the anaesthetized rat

• Published in: British journal of pharmacology Vol. 153; no. 7; pp. 1438 - 1444
• Main Authors: Andersson, M C, Tobin, G, Giglio, D
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Bacterial diseases; Bacterial diseases of the urinary system; Biological and medical sciences; Cyclophosphamide; cystitis; Cystitis - physiopathology; Disease Models, Animal; Dose-Response Relationship, Drug; Farmakologi och toxikologi; Human bacterial diseases; Infectious diseases; Male; Medical sciences; Methacholine Chloride - pharmacology; Mucous Membrane - metabolism; Mucous Membrane - physiopathology; Muscarinic Agonists - administration & dosage; Muscarinic Agonists - pharmacology; Muscarinic Antagonists - administration & dosage; Muscarinic Antagonists - pharmacology; muscarinic receptor; Nephrology. Urinary tract diseases; nitric oxide; Nitric Oxide - metabolism; Pharmacology and Toxicology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3 - metabolism; Receptor, Muscarinic M5 - metabolism; Research Papers; urinary bladder; Urinary Bladder - metabolism; Urinary Bladder - physiopathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; urothelium; Urothelium - metabolism; Urothelium - physiopathology; Antineoplastic agent; Urinary system disease; Rat; Mucosa; Rodentia; Urinary tract disease; urothelium; Alkylating agent; Oxazaphosphinane derivatives; Cholinergic receptor; Vertebrata; Cyclophosphamide; Mammalia; Urinary system; Urinary bladder; Nitrogen mustard; Animal; Nitric oxide; Bladder disease; Muscarinic receptor; Cystitis; Release
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.6

Background and purpose: 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. Experimental approach: 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. Key results: The muscarinic receptor agonist methacholine (MeCh; 0.5–5 μg 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 μg 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 Nω‐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 and implications: 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. British Journal of Pharmacology (2008) 153, 1438–1444; doi:10.1038/bjp.2008.6; published online 4 February 2008