Sexually dimorphic urethral activity in response to pharmacological activation of 5-HT_1A receptors in the rat

Abstract

In this study, we examined the possibility that 5-HT 1A receptors may underlie sexually dimorphic mechanisms affecting the regulation of urethral functions in anesthetized rats. Simultaneous recordings of intravesical pressure under isovolumetric conditions, external urethral sphincter-electromyography, and urethral perfusion pressure were used to examine the effects of a 5-HT1A receptor agonist [8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)] and antagonist (WAY-100635) on bladder and urethral functions. This research also evaluated the effects of 8-OH-DPAT and ␣-bungarotoxin (a neuromuscular blockade agent) on urethral continence using leak point pressure testing, and the distribution of 5-HT 1A receptors in the lower urinary tract was assessed by immunohistochemistry. The serotonergic mechanism that controls the urinary bladder and external urethral sphincter-electromyography activity showed no significant sexual differences, but urethral activity in urethral perfusion pressure and leak point pressure values exhibited some sexual differences. 8-OH-DPAT enhanced urethral pressure during continence in rats of both sexes, but the drug elevated the pressure during voiding in male rats and reduced it in female rats. The distribution of 5-HT 1A receptors in the spinal cord also showed some sexual differences. The present study contributes to our understanding of the role of 5-HT1A receptors in physiological and immunohistochemical properties of urethral smooth muscle in rats of different sexes. These findings may be a basis for the future development of pharmacotherapies for stress urinary incontinence in men. intravesical pressure; external urethral sphincter-electromyography; urethral perfusion pressure; 8-hydroxy-2-(di-n-propylamino)tetralin; WAY-100635; serotonin SEROTONERGIC AGENTS, such as duloxetine, are clinically used to treat stress urinary incontinence (SUI) in women (14). Despite satisfactory results in most female patients, there are few reports regarding the effect of duloxetine on SUI in men. Because the incidence of SUI in men is dramatically lower than in women, SUI is generally considered to be a female issue (27,42). However, epidemiological studies have suggested that men are sometimes severely afflicted with SUI (27) and suffer greater emotional impacts than women (44). Currently, duloxetine has not been approved for treating SUI in men, but the drug has been used off label in some pilot studies; the studies (17,40,48) showed that the drug may produce a marked improvement in men with urinary incontinence.The rat model has now gained great popularity as the main species for developing pharmacologically based treatments of SUI. Effects of a 5-HT receptor agonist on regulatory bladder functions have been extensively investigated in female animals (5,6,15,19,23,28,43). To the best of our knowledge, few studies have explored the role of 5-HT 1A receptors in regulating urethral functions in male rats. In addition, many cases of sexually anatomic and functional dimorphism in the lower urinary trac...

Does pharmacological activation of 5-HT1A receptors improve urine flow rate in female rats?

“…Although the urethra is more complex because it is not a rigid pipe and has the property of elasticity, the urethral cross-sectional diameter or area remains a critical factor determining the UFR. A study indicated that 8-OH-DPAT significantly reduced the urethral pressure during the micturition reflex in female rats treated with an NMB agent (14); this finding implies that 8-OH-DPAT may facilitate the urethral smooth muscle relaxation and increase the urethral cross-sectional diameter, thereby raising the UFR. This hypothesis was supported by our finding that the maximal UFR markedly increased at the initial segment of the entire flow duration (ϳ30% of the flow duration).…”

“…A study indicated that 8-OH-DPAT exerts a significant excitatory effect on pudendal-to-pudendal reflexes; this triggers the EUS burst center in the spinal cord, generating a prolonged EUS burst activity during voiding (4,14). However, the prolonged zero level of oscillatory waves did not continue after the 8-OH-DPAT treatment in rats with a paralyzed EUS (compare Fig.…”

“…To assess the role of 5-HT 1A receptors in the voiding function, 8-OH-DPAT (0.3 mg/kg iv) and WAY-100635 (0.1 mg/kg iv) were administered to 16 rats at intervals greater than 1 h; 8-OH-DPAT was administered before the WAY-100635 treatment in all experiments. These drugs were administered at previously described doses (7,14,21). The first posttreatment urodynamic examinations were completed within 20 -45 min following drug administration because of the short half-life of 8-OH-DPAT (11,21).…”

“…Our recent study indicated that the 5-HT 1A agonist 8-OH-DPAT significantly reduced the UFR during voiding in male rats (13). Furthermore, recent studies have demonstrated that 8-OH-DPAT increases urethral pressure (resistance) during the voiding reflex in male rats; however, it significantly reduces the pressure in female rats (14). The decrease in the UFR in male rats during voiding may be because of an increase in urethral pressure by 8-OH-DPAT.…”

“…However, contradictory results have led to various interpretations of these receptor subtype functions in different animal species. Because the rat model has recently been widely used as the main species model for investigating LUT functions, the effects of a 5-HT 1A receptor agonist on LUT functions have been extensively investigated in rats (4,7,11,14,17,19,31).…”