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.
- MeSH
- adenosin farmakologie MeSH
- adenosintrifosfát farmakologie MeSH
- cyklofosfamid MeSH
- cystitida farmakoterapie patologie patofyziologie MeSH
- imunohistochemie MeSH
- inhibitory enzymů farmakologie terapeutické užití MeSH
- mastocyty účinky léků patologie MeSH
- methacholinchlorid farmakologie MeSH
- močový měchýř účinky léků patologie patofyziologie MeSH
- potkani Sprague-Dawley MeSH
- purinergní receptory metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- svalová kontrakce účinky léků MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory metabolismus MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The aim of the present study was to investigate the relaxatory function of adenosine receptor subtypes in rat urinary bladder, and if it is altered in the state of inflammation. The in vitro responses to the P1 receptor agonist adenosine were investigated in the presence of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 1*10(-4)M). Experiments were performed on preparations from normal (healthy) rats and rats with cyclophosphamide (CYP; 100mg kg(-1) i. p.)-induced cystitis. The specific P1A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 1*10(-5)M) decreased the adenosine relaxatory response in normal bladders (-60%), but not in preparations from CYP pre-treated rats. Immunohistochemical findings support the hypothesis that the expression of P1A(1) receptors in the rat urinary bladder is decreased during cystitis. The adenosine-evoked relaxation was not affected by the specific P1A(2A) antagonist SCH 58261 (3*10(-7)M), neither in normal nor in CYP pre-treated rats. The relaxation to adenosine was, however, significantly increased by the specific P1A(3) antagonist MRS 1523 (1*10(-5)M) in preparations from both normal and CYP pre-treated rats, suggesting P1A(3) to be mediating bladder contraction. Thus, in the rat urinary bladder the relaxation to adenosine is mainly due to the P1A(1) receptor, while the P1A(3) receptor seems to be responsible for contractile responses. The DPCPX-resistant part of the relaxation is possibly due to the P1A(2B) receptor, the fourth subtype of the adenosine receptor family.
- MeSH
- adenosin farmakologie fyziologie MeSH
- agonisté purinergního receptoru P1 farmakologie MeSH
- antagonisté purinergního receptoru P1 farmakologie MeSH
- cystitida metabolismus patofyziologie MeSH
- hladké svalstvo účinky léků metabolismus patofyziologie MeSH
- krysa rodu rattus MeSH
- léková rezistence účinky léků fyziologie MeSH
- mediátory zánětu fyziologie MeSH
- močový měchýř účinky léků metabolismus fyziologie MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- purinergní receptory P2 - antagonisté farmakologie MeSH
- receptor adenosinový A1 fyziologie MeSH
- svalová kontrakce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
