Protease-activated receptor-2-mediated contraction of urinary bladder is enhanced in cyclophosphamide-treated rats.
Protease-activated receptor-2 (PAR-2) is activated by serine proteases, such as trypsin and mast cell tryptase. Recently, we have shown that activators of PAR-2 contract the rat urinary bladder mainly by stimulating release of prostaglandins (PGs) from the mucosal layer. In the present study, we investigated how the PAR-2-mediated responses are altered in rats with cyclophosphamide (CYP)-induced cystitis. The contractile responses to trypsin and PAR-2 activating peptide (PAR-2 AP; SLIGRL-NH2) in the urinary bladders were augmented by treatment of rats with CYP. The contractile effects of these PAR-2 activators on the smooth muscles of the urinary bladder were also potentiated after induction of cystitis by CYP. On the other hand, CYP-induced cystitis significantly attenuated contractions produced by PGE2 in the smooth muscles of the urinary bladder. The PAR-2-mediated contractions were significantly prevented by indomethacin or NS-398, an inhibitor of cyclooxygenase-2. Both trypsin and PAR-2 AP increased the release of PGE2 from the urinary bladder mucosa and smooth muscle. CYP-induced cystitis enhanced the PAR-2 activators-induced PGE2 releases from the urinary mucosa without affecting those from the smooth muscle of the urinary bladder. The PGE2 releases were prevented by indomethacin or NS-398. The mRNAs for PAR-2 in the urinary bladder mucosa and smooth muscle preparations were not altered in CYP-induced cystitis. These results suggest that PAR-2-mediated responses were enhanced in bladders from CYP-treated rats. The enhancement of PAR-2-mediated contraction might be ascribed to the increased production of PGs and the altered sensitivity of smooth muscle to PAR-2 activators.
Nakahara
Tsutomu
T
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, 108-8641 Minato-ku, Tokyo, Japan. nakaharat@pharm.kitasato-u.ac.jp
Kubota
Yuko
Y
Saito
Maki
M
Sakamoto
Kenji
K
Ishii
Kunio
K
D000818:Animals; D051546:Cyclooxygenase 2; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000503:physiopathology*; D015232:Dinoprostone / Q000096:biosynthesis; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009092:Mucous Membrane / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology*
D007527:Isoenzymes; D009578:Nitrobenzenes; D044464:Receptor, PAR-2; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003520:Cyclophosphamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D014357:Trypsin; D015232:Dinoprostone; D007213:Indomethacin