Effect of cyclooxygenase inhibitors on the micturition reflex in rats: correlation with inhibition of cyclooxygenase isozymes.
OBJECTIVE
To investigate the role of cyclooxygenase (COX) isozymes (COX-1 and -2) in the regulation of bladder volume capacity (BVC) in several rat urodynamic models, using a selection of nonsteroidal anti-inflammatory drugs (NSAIDs), some selective for COX-2, correlating the potency of the tested compounds in the urodynamic models and their in vitro potency as inhibitors of COX isozymes, to verify the relative importance of the different isozymes.


METHODS
The effects of an i.v. administration of several nonselective and selective COX-2 inhibitors (indomethacin, meloxicam, naproxen, aspirin, paracetamol, flurbiprofen, nimesulide, NS-398, celecoxib, rofecoxib and L 745337) on bladder filling and voiding were evaluated in conscious and anaesthetized rats by cystometry. The cystometry was done in conscious rats 1 day after catheter implantation, by filling the bladder with dilute acetic acid (0.2%) or saline, and again with saline 5 days after catheterization. Effects on isovolumic bladder contractions in anaesthetized rats were also evaluated.


RESULTS
All the NSAIDs tested dose-dependently increased BVC; their potency at increasing BVC during infusion of the bladder with acetic acid was similar to that evaluated with saline on cystometry 1 day after catheterization. When a nonselective (naproxen) and a selective (nimesulide) COX-2 inhibitor were tested in rats with bladders infused with saline 5 days after catheterization, their effects on BVC were significantly lower than those evaluated at 1 day. All tested compounds dose-dependently inhibited isovolumic bladder contractions in anaesthetized rats. There was a good correlation between the potency in inhibiting the isovolumic bladder contractions in anaesthetized rats and in increasing BVC during cystometry in conscious rats with the bladder infused with acetic acid. The potency of the compounds in the cystometry model with bladders infused with acetic and in the isovolumic bladder voiding contractions correlated well with COX-2 inhibition, but not COX-1.


CONCLUSIONS
Both nonselective and COX-2 selective inhibitors are more active in inhibiting the micturition reflex in rats with bladder overactivity caused by bladder irritation than in normal rats. The potency of the anti-inflammatory compounds in inhibiting bladder overactivity induced by chemical or surgical irritation, and their activity in a cystometrographic model practically independent of bladder irritation (isovolumic bladder contractions in anaesthetized rats), was related to the potency as inhibitors of COX-2 isozyme. This suggests that the involvement of prostaglandins in the micturition reflex in rats is mainly mediated by this isozyme.
Pharmaceutical R & D Division, Recordati SpA, Via M. Civitali 1, 20148 Milan, Italy. angelico.p@recordati.it
Patrizia
P
Angelico
Luciano
L
Guarneri
Cristina
C
Velasco
Rita
R
Cova
Amedeo
A
Leonardi
David E
DE
Clarke
Rodolfo
R
Testa
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D007527:Isoenzymes / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects*; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects*
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes