The lower urinary tract stores and periodically eliminates urine, and these functions are complexly regulated by both the peripheral nervous system and the central nervous system (CNS). In the CNS, thromboxane A2 (TxA2), an arachidonic acid metabolite known as a platelet aggregation factor, functions as a neuromodulator to modulate excitation of the glutamatergic nervous system [1], essential for voiding function in the CNS [2]. However, roles of brain TxA2 in regulating the micturition reflex are unclear. To clarify these roles, we investigated (1) effects of centrally administered TxA2 analog on the micturition reflex, and (2) effects of centrally pretreated each antagonist of TxA2 receptors (TP receptors) and glutamate receptors on the analog-induced responses in rats.

In urethane-anesthetized (0.8 g/kg, ip) male Wistar rats, a catheter was inserted into the bladder from the bladder dome to instill saline (12 ml/h) and to measure intravesical pressure. Two hours after the surgery, the instillation was started to evaluate intercontraction interval (ICI) and maximal voiding pressure (MVP). One hour after the start, U-46619 (a TxA2 analog, 1 or 10 nmol/rat) or vehicle was intracerebroventricularly (icv) administered. Evaluations of ICI and MVP were continued 2 h after the administration. Effects of central pretreatment with S-18886 (an antagonist of TP receptors, 300 nmol/rat, icv) or DNQX [an antagonist of AMPA type glutamate receptors (AMPA receptors), 0.3 or 3 nmol/rat, icv] on the U-46619 (10 nmol/rat, icv)-induced responses were also investigated. In addition, single cystometry (saline instillation at 12 ml/h) was also performed. After 4-5 times of single cystometry, U-46619 (10 nmol/rat) was icv administered, then single cystometry was performed during 40-80 min after the administration.

U-46619 (10 nmoll/rat, icv) significantly shortened ICI and reduced single-voided volume (Vv) and bladder capacity (BC) without affecting MVP, post-voided residual volume (Rv) or voiding efficacy (VE) (Fig. 1 and Table 1). The U-46619-induced ICI shortening was attenuated by S-18886 or DNQX (Fig. 2). Central administration of each antagonist alone showed no significant prolongation of ICI (data not shown).

Our data suggest that U-46619 centrally promotes the micturition reflex by enhancing bladder sensitivity to stored urine as shown by the U-46619-induced ICI shortening and reduction in Vv and BC without affecting MVP, Rv or VE. Central pretreatment with S-18886 suppressed the U-46619-induced ICI shortening, indicating that the shortening is mediated by brain TP receptors. However, centrally administered S-18886 alone did not induce ICI prolongation. Therefore, physiological levels of brain TxA2 might have minor impact on the micturition reflex in normal condition. In response to cerebral ischemia, brain TxA2 levels were increased and SQ29548 (a TP receptor antagonist) alleviated the ischemic injury in mice [3], therefore, the increased TxA2-induced enhancement of bladder sensitivity might be involved in the cerebral ischemia-induced bladder hyperactivity. Central pretreatment with DNQX suppressed the U-46619-induced ICI shortening, but we preliminary found that centrally pretreated MK-801 [an antagonist of NMDA type glutamate receptors (NMDA receptors)] showed no effect on the U-46619-induced responses. These results suggest that stimulation of brain TP receptors-induced facilitation of the micturition reflex may be mediated by brain AMPA, but not NMDA, receptors.

Stimulation of brain TP receptors facilitated the micturition reflex through brain AMPA receptors in rats. Therefore, brain TP receptors could be novel therapeutic targets for patients with lower urinary tract dysfunctions attributed to neurogenic bladder overactivity.

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