Dual, but not selective, COX-1 and COX-2 inhibitors, attenuate acetic acid-evoked bladder irritation in the anaesthetised female cat.
Non-selective cyclooxygenase (COX) inhibitors exert effects on lower urinary tract function in several species. The exact contributions of COX-1 and COX-2 isozymes have not been studied much. The present studies investigated the effects of non- and selective COX inhibitors on bladder irritation in the cat.Chloralose-anaesthetised female cats were catheterised through the bladder dome for cystometric evaluation of bladder responses to intravesical infusion of saline or acetic acid. Bladder capacity, voiding efficiency, threshold pressure, and reflex-evoked bladder contraction amplitude and duration were measured. The cat COX selectivity of the doses of inhibitors examined was determined using an in vitro whole-blood assay and analysis of plasma levels. Pretreatment with indomethacin or ketoprofen (non-selective COX inhibitors; 0.3 mg kg(-1) i.v.) inhibited acetic acid-evoked irritation (characterised by a decrease in bladder capacity in vehicle pretreated animals). FR-122047 (selective COX-1 inhibitor), NS-398 and nimesulide (selective COX-2 inhibitors; 1 and 3 mg kg(-1) i.v.) had no effects on bladder irritation. Analysis of plasma levels of the doses examined and determination of COX-1 and COX-2 inhibition in cat whole blood confirmed the reported selectivity of these compounds in this species. The present studies suggest that dual COX inhibition is required to attenuate acetic acid-evoked bladder irritation in the cat.
Urogenital Biology, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406-0939, USA.
Alexandra
A
Wibberley
Gerald P
GP
McCafferty
Christopher
C
Evans
Richard M
RM
Edwards
J Paul
JP
Hieble
D019342:Acetic Acid / Q000008:administration & dosage / Q000633:toxicity; D000758:Anesthesia; D000818:Animals; D002415:Cats; D051545:Cyclooxygenase 1 / Q000097:blood*; D051546:Cyclooxygenase 2 / Q000097:blood*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012021:Reflex, Abnormal / Q000187:drug effects; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D001745:Urinary Bladder Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C085131:1-((4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl)-4-methylpiperazine; D012965:Sodium Chloride; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019342:Acetic Acid; C012655:nimesulide; D007213:Indomethacin