Synergistic effects of loxoprofen and glycine on the micturition reflex in consciousrats

Abstract

We examined the inhibitory effects of loxoprofen, a cyclooxygenase inhibitor, and glycine, a major inhibitory neurotransmitter, on the micturition reflex in conscious rats and hypothesized that these drugs would interact synergistically to inhibit micturition. Voiding behaviors were assessed using a metabolic cage. Oral loxoprofen decreased the urinary frequency, and only a high dose (10 mg/kg) significantly reduced the voided volume. With cystometry, intravenous loxoprofen (0.1-3 mg/kg) and glycine (30 and 100 mg/kg) prolonged the intercontraction intervals (ICI) in a dose-dependent manner, but did not change the maximum voiding pressure (MVP) in conscious rats. The combination of loxoprofen (3 mg/kg) and glycine (100 mg/kg) strongly prolonged the ICI more than with either drug alone. The lowest dose of loxoprofen (0.1 mg/kg) and glycine (30 mg/kg) did not affect either the ICI or the MVP, but their combination resulted in a significant increase in the ICI. These results suggest that the combined administration of loxoprofen and glycine produced a synergistic inhibitory effect on the micturition reflex.Bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH) induces various bladder dysfunctions. Nocturia in patients with BPH is one of the most bothersome symptoms of the disease. The presence of nocturia disrupts sleep, leading to daytime somnolence, depressive symptoms, cognitive dysfunction, and reduction in quality of life (10). Although nocturia in patients with BPH is commonly treated with α 1 -blockers and/or 5α-reductase inhibitors, using these drugs to reduce nocturia is not effective in many cases. Clinical reports have been published indicating that loxoprofen, a non-steroidal anti-inflammatory drug (NSAID), reduces not only pain and inflammation but also nocturia in patients with BPH (6,22).Other NSAIDs such as indomethacin also reduce the frequency of voiding and decrease the urine volume in patients with enuresis (1). NSAIDs including loxoprofen prevent prostaglandin (PG) synthesis by inhibiting the cyclooxygenase pathway. PGs, in particular PGE 2 , play an important role in regulating bladder function, and intravesical infusion of PGE 2 stimulates the micturition reflex by activating capsaicin-sensitive afferent nerves, leading to bladder overactivity in rats and humans (13,14,24). In addition, the urinary PGE 2 level has been reported to increase in patients with lower urinary tract obstruction (4). Previous studies have shown that NSAIDs decrease urinary frequency and increase bladder capacity in both normal and cystitis rats under urethane anesthesia (26,27). We also reported that loxoprofen inhibits enhancement of the micturition reflex after acetic acid-induced inflammation in conscious rats (24). However, the inhibitory effect of loxoprofen on the micturition reflex in normal, conscious states has not been fully examined. In addition, long-term use of NSAIDs is not recommended