Inhibition of nitric oxide synthase prevents muscarinic and purinergic functional changes and development of cyclophosphamide-induced cystitis in the rat.

Patrik Aronsson,Vladimir Wsol,Michael Winder,Gunnar Tobin,Renata Vesela,Martin Johnsson,Yasin Tayem

doi:10.1155/2014/359179

Patrik Aronsson, Vladimir Wsol + Show 5 more

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https://doi.org/10.1155/2014/359179

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Abstract

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.

Highlights

In rodents, as well as in humans, cyclophosphamide (CYP) treatment induces cystitis, which includes alterations both at functional and histological levels [1, 2]
Rats were pretreated with saline, the muscarinic receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) (1 mg/kg ip), or the nitric oxide synthase (NOS) inhibitor L-NAME (30 mg/kg ip) for five days. 60 h before the experiments the rats were treated with saline or CYP
We have recently demonstrated that pretreatment with the P1A1 antagonist DPCPX alleviate the symptoms to CYPinduced cystitis [31], and the aims of the current study were to examine if muscarinic receptors and Nitric oxide (NO) are involved in the inflammation in experimental CYPinduced cystitis, as well as to investigate if there exists a link between the two

Summary

Introduction

As well as in humans, cyclophosphamide (CYP) treatment induces cystitis, which includes alterations both at functional and histological levels [1, 2]. Functional changes occur via hampered efferent and afferent effects [3,4,5,6] In conscious rats, this results in frequent micturitions of smaller volumes [7,8,9]. The reduction of the parasympathetic contractile response in CYP-treated rats depends partly on an increased production of nitric oxide (NO) due to sensitization of urothelial muscarinic receptor stimulated NO effects [6, 14, 15]. CYP-induced morphological changes include bladder wall thickening [18], mast cell appearance in the smooth muscle [19], and upregulation of the expression of urothelial muscarinic M5 receptors [6, 20]

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