Inhibition of Nitric Oxide Synthase Prevents Muscarinic and Purinergic Functional Changes and Development of Cyclophosphamide-Induced Cystitis in the Rat

Abstract EN

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.