Pharmacological evaluation of the role of cyclooxygenase isoenzymes on the micturition reflex following experimental cystitis in rats

Abstract

Prostanoids, generated from cyclooxygenase (COX) isoenzymes, play a role in the physiological function of the lower urinary tract and are important mediators of inflammatory hyperalgesia. The present work evaluates the effects of the COX-1/COX-2 inhibitor dexketoprofen as well as of a selective COX-2 inhibitor, NS-398, on urodynamic function following endotoxin (LPS) or cyclophosphamide (CYP)-induced inflammation of the urinary bladder. The application of arachidonic acid (330 microgram rat(-1)) onto the serosal surface of the urinary bladder in control rats elicited bladder contractions which could be blocked in a dose-dependent manner by dexketoprofen (0.1 - 3 mg kg(-1), i.v.) but not by NS-398 (0.2 - 6 mg kg(-1), i.v. ). Dexketoprofen (3 mg kg(-1), i.v.) decreased the micturition frequency and increased the pressure threshold for triggering the micturition either when administered within 15 min or 3 h following surgery in control animals. NS-398 (6 mg kg(-1), i.v.) decreased the micturition frequency and increased the pressure threshold when administered 3 h but not 15 min following surgery. Administration of LPS (2 mg kg(-1), i.v., 90 - 120 min) increased both the micturition frequency and the pressure threshold for triggering the micturition reflex. Changes in urodynamic parameters induced by LPS were prevented by doses of either dexketoprofen (1 mg kg(-1), i.v.) or NS-398 (2 mg kg(-1), i.v.) which were ineffective in control animals. Pretreatment with CYP (150 mg kg(-1), i.p., 48 h) increased the micturition frequency, pressure threshold, and the minimal intravesical pressure but decreased the mean amplitude of micturition contractions. In CYP-treated rats, dexketoprofen (1 mg kg(-1), i.v.) or NS-398 (2 mg kg(-1), i.v.) blocked the CYP-induced urodynamic changes with exception of the micturition contraction amplitude. These results indicate that COX-1 may be involved in modulating the threshold for activating the micturition reflex in the normal rats and also demonstrates that inhibition of COX-2 prevents or reverses the urodynamic changes associated with bladder inflammation induced either by surgery, LPS or CYP treatments.

Figure 1

Traces showing the effect of dexketoprofen (1 mg kg⁻¹, i.v.), LPS (2 mg kg⁻¹, i.v.) or CYP (150 mg kg⁻¹, i.p. 48 h before) in cystometries. The administration of dexketoprofen or LPS is indicated by the arrow. In X axis is represented the time (h:mins:s) after having started cystometries, in Y axis the intravesical pressure (mmHg). (A) Represents the effect of dexketoprofen in control rats. (B) The effect of LPS in control rats. (C) The effect of LPS in dexketoprofen-pretreated rats. (D) The effect of dexketoprofen in CYP-pretreated rats.

Figure 2

Effect of dexketoprofen (3 mg kg⁻¹, i.v.) or NS-398 (6 mg kg⁻¹, i.v.) on cystometries performed in control rats 15 min after bladder catheter insertion. (A) Represents the effect on the micturition frequency. (B) The effect on the pressure threshold for triggering micturition contractions. Fisher's LSD test: ^*P<0.05 vs time-matched vehicle-treated group; NS-398⁺P<0.05 vs time-matched dexketoprofen-treated group. Each point and bar represents mean±s.e.mean of 10 experiments.

Figure 3

Effect of dexketoprofen (3 mg kg⁻¹, i.v.) or NS-398 (6 mg kg⁻¹, i.v.) on cystometries performed in control rats 3 h after bladder catheter insertion and 2 h after having started cystometries. (A) Represents the effect on the micturition frequency. (B) The effect on the pressure threshold for triggering micturition contractions. Fischer's LSD test: dexketoprofen and NS-398 ^*P<0.05 vs time-matched vehicle-treated group and vs their own basal values (time 0). Each point and bar represents mean±s.e.mean of eight experiments.

Figure 4

Effect of dexketoprofen (1 mg kg⁻¹, i.v.) or NS-398 (2 mg kg⁻¹, i.v.) on cystometries performed in control rats 3 h after bladder catheter insertion and 2 h after having started cystometries. (A) Represents the effect on the micturition frequency. (B) The effect on the pressure threshold for triggering micturition contractions. Fisher's LSD test: dexketoprofen ^*P<0.05 vs time-matched vehicle-treated group and vs their own basal values (time 0). Each point and bar represents mean±s.e.mean of 12 experiments.

Figure 5

Effect of LPS (2 mg kg⁻¹, i.v.) on cystometries performed 3 h after bladder catheter insertion and 2 h after having started cystometries in vehicle- dexketoprofen (1 mg kg⁻¹, i.v.)- or NS-398 (2 mg kg⁻¹, i.v.)-pretreated rats. The arrow indicates LPS administration. (A) Represents the effect on the micturition frequency. (B) The effect on the pressure threshold for triggering micturition contractions. Fisher's LSD test: ⁺P<0.05 vs time 0, ^*P<0.05 vs time-matched vehicle-treated group. Each point and bar represents mean±s.e.mean of 12 experiments.

Figure 6

Effect of dexketoprofen (1 mg kg⁻¹, i.v.) or NS-398 (2 mg kg⁻¹, i.v.) on cystometries performed in CYP (150 mg kg⁻¹, i.p., 48 h before)-treated rats 3 h after bladder catheter insertion and 2 h after having started cystometries. (A) Represents the effect on the micturition frequency. (B) The effect on the pressure threshold for triggering micturition contractions. (C) The effect on the minimal pressure. (D) The effect on the mean amplitude of micturition contractions. Fisher's LSD test: dexketoprofen ^*P<0.05 vs time-matched vehicle-treated group and vs their own basal values (time 0). Each point and bar represents mean±s.e.mean of 12 experiments.