title: Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats.
abstract: Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors may suppress detrusor overactivity symptoms and possess anti-inflammatory properties. The aim of the present study was to investigate whether inhibition of ROCK reduces cystometric and histopathological changes associated with CYP-induced cystitis. The rats received GSK 269962, a ROCK inhibitor, at a dose of 30 mg/kg daily, or vehicle for 7 days. Then, acute chemical cystitis leading to bladder overactivity was induced by CYP injection (200 mg/kg i.p.). Following CYP injection, cystometric studies with physiological saline were performed. Moreover, bladder edema (by the Evans Blue dye leakage technique) and urothelium thickness were measured. CYP injection resulted in a significant increase in cystometric parameters: basal pressure, threshold pressure, bladder contraction duration, relaxation time, detrusor overactivity index, non-voiding contractions amplitude, and non-voiding contractions frequency as well as increased Evans Blue extravasation into bladder tissue, whereas micturition voiding pressure, voided volume, post-void residual, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit non-voiding contractions as well as urothelium thickness were significantly decreased in CYP-injected rats. Administration of GSK 269962 normalized the abovementioned CYP injection-induced changes. Inhibition of ROCK was found to ameliorate CYP-induced detrusor overactivity and bladder inflammation. Our data indicate uroprotective effects following ROCK inhibition, which further suggests that this strategy may become an interesting pharmacological tool to prevent urinary adverse effects in patients treated with chemotherapy using CYP.
authors.affiliation: Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland. wrobelandrzej@yahoo.com.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wróbel
authors.affiliation: Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, Akademicka 19, 20-033, Lublin, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Doboszewska
authors.affiliation: Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Rechberger
authors.affiliation: Department of Applied Pharmacy, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Rojek
authors.affiliation: Department of Applied Pharmacy, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Serefko
authors.affiliation: Department of Applied Pharmacy, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Poleszak
authors.affiliation: Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Chodźki 1, 20-093, Lublin, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Skalicka-Woźniak
authors.affiliation: Department of Toxicology, Medical University of Lublin, Jaczewskiego 8b, 20-093, Lublin, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Dudka
authors.affiliation: Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, Akademicka 19, 20-033, Lublin, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000188:drug therapy; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; C516969:N-(3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo(4,5-c)pyridin-6-yl)oxy)phenyl)-4-((2-(4-morpholinyl)ethyl)oxy)benzamide; D010069:Oxadiazoles; D003520:Cyclophosphamide; D054460:rho-Associated Kinases
keywords: Bladder inflammation; Cyclophosphamide-induced cystitis; Cystometry; Overactive bladder; Rho kinase inhibitor