Nitric oxide (NO) has pivotal roles in cyclophosphamide- (CYP-) induced cystitis during which mucosal nitric oxide synthase (NOS) and muscarinic M5 receptor expressions are upregulated. In cystitis, urothelial muscarinic NO-linked effects hamper contractility. Therefore we wondered if a blockade of this axis also affects the induction of cystitis in the rat. Rats were pretreated with saline, the muscarinic receptor antagonist 4-DAMP (1 mg/kg ip), or the NOS inhibitor L-NAME (30 mg/kg ip) for five days. 60 h before the experiments the rats were treated with saline or CYP. Methacholine-, ATP-, and adenosine-evoked responses were smaller in preparations from CYP-treated rats than from saline-treated ones. Pretreatment with 4-DAMP did not change this relation, while pretreatment with L-NAME normalized the responses in the CYP-treated animals. The functional results were strengthened by the morphological observations; 4-DAMP pretreatment did not affect the parameters studied, namely, expression of muscarinic M5 receptors, P1A1 purinoceptors, mast cell distribution, or bladder wall enlargement. However, pretreatment with L-NAME attenuated the differences. Thus, the current study provides new insights into the complex mechanisms behind CYP-induced cystitis. The NO effects coupled to urothelial muscarinic receptors have a minor role in the development of cystitis. Inhibition of NOS may prevent the progression of cystitis.

Department of Biochemical Sciences Faculty of Pharmacy Charles University Heyrovskeho 1203 50005 Hradec Kralove Czech Republic

Department of Pharmacology Institute of Neuroscience and Physiology Sahlgrenska Academy University of Gothenburg P O Box 431 40530 Gothenburg Sweden

Department of Pharmacology Institute of Neuroscience and Physiology Sahlgrenska Academy University of Gothenburg P O Box 431 40530 Gothenburg Sweden ; Department of Biochemical Sciences Faculty of Pharmacy Charles University Heyrovskeho 1203 50005 Hradec Kralove Czech Republic

Department of Physiology and Pharmacology Faculty of Medicine Al Quds University P O Box 51000 Jerusalem West Bank Palestine

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