Cyclooxygenase-2 contributes to functional changes seen on experimental hemorrhagic cystitis induced by ifosfamide in rat urinary bladder.
OBJECTIVE
Ifosfamide (IFS) is often involved in the occurrence of hemorrhagic cystitis due to direct contact of its metabolite acrolein with uroepithelium. It has been shown that COX-2 is involved in this pathogenesis. Thus, we aimed to study the functional changes on the urinary bladder in the putative modifications induced by IFS, as well as the COX-2 role in this process.


METHODS
IFS-treated rats were evaluated by cystometrography in absence or presence of COX inhibitors indomethacin or etoricoxib or in the presence of mesna. Experiments with isolated strips of urinary bladder obtained from animals with IFS-induced cystitis, either treated or not treated with COX inhibitors or mesna, were performed. Histological analyses, immunohistochemistry for COX-2, and measurement of plasma PGE(2) were also performed.


RESULTS
IFS treatment caused severe inflammation of the bladder tissue. Cystometrography recordings of IFS-treated rats revealed bladder with increased micturition frequency and enhanced filling intravesical pressure. Contractility of the isolated smooth muscle from the rat's bladder with IFS-induced cystitis showed decreased force development in response to KCl and CCh. Almost all effects induced by IFS were ameliorated by the use of COX inhibitors or mesna. Enzyme expression in the urinary bladder tissue was positive, and plasma concentration of PGE(2) was increased in IFS-treated animals and decreased significantly in etoricoxib-treated animals.


CONCLUSIONS
IFS causes important changes in the micturition physiology in rats, and the inhibition of the isoenzyme COX-2 could be an important event that could prevent the detrimental effects elicited by IFS-induced hemorrhagic cystitis.
Macedo
Francisco Y B
FY
Departamento de Fisiologia e Farmacologia Faculdade de Medicina, Universidade Federal do Ceará, Rua Cel Nunes de Melo 1127, Rodolfo Teofilo, 60430-270 Fortaleza, CE, Brazil.
Mourão
Lívia T C
LT
Palheta
Raimundo C
RC
Jucá
Davi M
DM
Lima
Roberto C P
RC
Neto
José de Sá C
Jde S
Magalhães
Pedro J C
PJ
Santos
Armênio A
AA
Souza
Marcellus H L P
MH
Brito
Gerly A C
GA
Ribeiro
Ronaldo A
RA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003556:Cystitis / Q000139:chemically induced* / Q000503:physiopathology; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced* / Q000503:physiopathology; D007069:Ifosfamide / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced; D008297:Male; D015080:Mesna / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D014554:Urination / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D015080:Mesna; D007069:Ifosfamide