Login to Access Video or Poster Abstract: MP82-09
Sources of Funding: NIH R01DK107450_x000D_

Introduction

The spinal serotonin (5HT) system is well known to be involved in the control of lower urinary tract function, and we previously reported that 5HT receptors such as 5HT_1A or 5HT_2C, have respectively inhibit or enhance the urethral continence reflex during sneezing in rats. However, because there are multiple 5HT receptor subtypes, it is often difficult to determine the subtype-specific mechanism. Thus, we examined the role of 5HT₇ receptors in the urethral continence mechanism using a rat model of stress urinary incontinence (SUI), in which endogenous 5HT was depleted by p-chlorophenylalanine (PCPA).

Methods

Female Sprague-Dawley rats were used. PCPA (200 mg/kg/day) was administered intraperitoneally for two days. Thereafter, using a microtransducer-tipped catheter inserted to the mid-urethra, we assessed urethral baseline pressure (UBP), amplitudes of urethral responses during sneezing (AURS) and abdominal pressure during sneezing (Pabd) under urethane anesthesia before and after administration of following drugs. First, we investigated the effects of a 5HT₇ and partial 5HT_1A agonist (LP 44 = LP, 0.3mg/kg, iv) in PCPA-administered rats. To suppress the partial 5HT_1A effect of LP, a 5HT_1A antagonist (WAY 100635 = WAY, 0.1 mg/kg, iv) was administered before LP treatment. Secondly, we investigated whether the effects of LP in the presence of WAY were inhibited by a 5HT₇ antagonist (SB 269970 = SB, 0.1 mg/kg, iv), which was administered with WAY prior to LP administration. All data are shown in cmH₂O.

Results

After LP administration (n = 6), UBP and AURS were significantly increased compared to the PCPA + WAY (n = 4) or PCPA only group (n = 7) (UBP: 15.2 vs 16.8 vs 26.6, AURS: 30.0 vs 32.2 vs 50.5 [PCPA only vs PCPA + WAY vs PCPA + WAY + LP], respectively) (Figure). However, in the presence of the SB, UBP and AURS were not significantly increased after LP administration (n = 6) compared to the PCPA + WAY (n = 6) or PCPA only group (n = 6). Pabd had no statistical difference among groups.

Conclusions

The 5HT₇ receptor exerts the facilitatory effects on the urethral baseline activity and the urethral continence reflex during stress conditions such as sneezing, which are reportedly attributable to contractions of smooth and striated urethral sphincter muscles, respectively. Thus, 5HT₇ agonists could be effective for the treatment of SUI.

Funding

NIH R01DK107450_x000D_