Pathophysiology of urinary incontinence in murine models

Abstract

Urethral closure mechanisms under stress conditions consist of passive urethral closure involving connective tissues, fascia and/or ligaments in the pelvis and active urethral closure mediated by hypogastric, pelvic and pudendal nerves. Furthermore, we have previously reported that the active urethral closure mechanism might be divided into two categories: (i) the central nervous control passing onto Onuf's nucleus under sneezing or coughing; and (ii) the bladder-to-urethral spinal reflex under Valsalvalike stress conditions, such as laughing, exercise or lifting heavy objects. There are over 200 million people worldwide with urinary incontinence, a condition that is associated with a significant social impact and reduced quality of life. Therefore, basic research for urinary continence mechanisms in response to different stress conditions can play an essential role in developing treatments for stress urinary incontinence. It has been clinically shown that the etiology of stress urinary incontinence is divided into urethral hypermobility and intrinsic sphincter deficiency, which could respectively correspond to passive and active urethral closure dysfunction. In this review, we summarize the representative stress urinary incontinence animal models and the methods to measure leak point pressures under stress conditions, and then highlight stress-induced urinary continence mechanisms mediated by active urethral closure mechanisms, as well as future pharmacological treatments of stress urinary incontinence. In addition, we introduce our previous reports including sex differences in urethral closure mechanisms under stress conditions and urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.

Effect of a 5‐HT2c receptor agonist on urethral closure mechanisms in female rats

“…In a previous study, the sneeze‐induced LPP increased by 12.8 cmH 2 O after injection of a 5‐HT2b/2c agonist in VD rats . Our results demonstrated that descending bulbo‐spinal serotonergic pathways enhance the activity of spinal excitatory interneurons in Onuf's nucleus via the 5‐HT2c receptor to promote active urethral closure …”

“…7 Our results demonstrated that descending bulbo-spinal serotonergic pathways enhance the activity of spinal excitatory interneurons in Onuf's nucleus via the 5-HT2c receptor to promote active urethral closure. 4 We found that A-URE was significantly lower in VD rats than in normal rats, and the LPP in response to manual compression was also significantly lower in VD rats compared to normal rats. The urethral pressure is mediated by contraction of the external urethral sphincter and the pelvic floor muscles under control of the pudendal nerves and somatic nerves.…”

“…A recent review focusing on neurophysiological mechanisms in the control of urethral closure provided information suggesting there may be potential pharmacological approaches to treatment of SUI . Noradrenergic and serotonergic pathways are considered to play an important role in maintaining urethral closure . 5‐Hydroxytryptamine 2c (5‐HT2c) receptors are distributed in the central nervous system, and 5‐HT2c receptor agonists have been used for regulation of substance abuse and food intake .…”

“…3 Noradrenergic and serotonergic pathways are considered to play an important role in maintaining urethral closure. 4 5-Hydroxytryptamine 2c (5-HT2c) receptors are distributed in the central nervous system, and 5-HT2c receptor agonists have been used for regulation of substance abuse and food intake. 5,6 Interestingly, serotonergic pathways enhance the activity of excitatory spinal interneurons that form synapses with motoneurons in Onuf's nucleus, or directly activate motoneurons in Onuf's nucleus via 5-HT2c receptors to maintain active urethral closure (Figure 1).…”

Midurethral support is also necessary for reflex closure of the urethra

“…Both Kamo et al and Constantinou described several clinical findings supporting this mechanism: urethral pressure increase starts before cough transmission, is higher than the intravesical pressure increase, and is reduced by bilateral pudendal blockade . The active closure reflex consists of two parts …”