title: Inhibition of nitric oxide synthase prevents muscarinic and purinergic functional changes and development of cyclophosphamide-induced cystitis in the rat.
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.
authors: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 431, 40530 Gothenburg, Sweden.
authors: Patrik
authors: 0000-0001-9970-817X
authors: P
authors: Aronsson
authors: 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.
authors: Renata
authors: R
authors: Vesela
authors: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 431, 40530 Gothenburg, Sweden.
authors: Martin
authors: 0000-0003-3896-1862
authors: M
authors: Johnsson
authors: Department of Physiology and Pharmacology, Faculty of Medicine, Al-Quds University, P.O. Box 51000, Jerusalem, West Bank, Palestine.
authors: Yasin
authors: 0000-0002-4431-4138
authors: Y
authors: Tayem
authors: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
authors: Vladimir
authors: 0000-0003-3745-7648
authors: V
authors: Wsol
authors: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 431, 40530 Gothenburg, Sweden.
authors: Michael
authors: 0000-0003-2527-4713
authors: M
authors: Winder
authors: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 431, 40530 Gothenburg, Sweden.
authors: Gunnar
authors: G
authors: Tobin
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D016210:Methacholine Chloride; D000255:Adenosine Triphosphate; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D000241:Adenosine