Search

The external urethral sphincter (EUS), composed of skeletal muscle, along with a smooth muscle-lined internal urethral sphincter (IUS), have crucial roles in maintaining continence during bladder filling and facilitating urine flow during voiding. Disruption of this complex activity has profound consequences on normal lower urinary tract function during the micturition cycle. However, relatively little is known about the normal and pathological functions of these particular muscle types, how activity can be manipulated and regulated and why, for example, loss of EUS function and sarcopenia is associated with ageing. Here we discuss the unique physiological, biochemical and metabolic properties of striated and smooth muscle components of the urethral sphincter, which have distinct roles in maintaining continence during bladder filling. Relevant in vivo models for investigation of pathophysiological mechanisms, and for pre-clinical evaluation of therapeutic approaches are reviewed. Electromyography and Urethral Pressure Profile recordings are pivotal to understanding the function and dysfunction of the EUS and for clinical evaluation of e.g. urinary retention. Pre-clinical and clinical studies have revealed that age- or disease-related tissue remodelling that lead to filling/voiding disorders may be mitigated with emerging therapeutic approaches.

Purpose:: The main goal of this study was to determine the effects of arginine vasopressin (AVP) and desmopressin on bladder contractility and to examine whether the effects of these vasopressin receptor (VR) agonists differ in young versus aged animals. These aims were addressed using urinary bladders from young (3 months) and aged (24 month) female Fischer 344 rats that were isolated and dissected into strips for isometric tension recordings. Bladder strips were exposed to AVP and desmopressin through the perfusate, and tension changes recorded. Results:: In young rat bladders, AVP, an agonist at both vasopressin-1 receptors (V1Rs) and vasopressin-2 receptor (V2Rs), concentration-dependently caused contraction of bladder strips with a sensitivity that was greater in young versus aged bladder strips. Removal of the mucosa did not alter the sensitivity of young bladder strips to AVP yet enhanced the AVP sensitivity of aged bladder strips. The differential sensitivity to AVP between young denuded and aged denuded bladder strips was similar. In contrast to AVP, desmopressin (V2R selective agonist) relaxed bladder strips. This response was reduced by removal of the mucosa in young, but not aged, bladder strips. Conclusion:: These findings support a direct role for VRs in regulating detrusor tone with V1Rs causing contraction and V2Rs relaxation. In aged bladders, the contractile response to V1R activation is attenuated due to release of a mucosal factor that attenuates V1R-induced contractions. Also in aged bladders, the relaxation response to V2R activation is attenuated by lack of release of a mucosal factor that contributes to V2R-induced relaxation. Thus age-associated changes in the bladder mucosa impair the effects of VRs on bladder tone. Because the V2R signaling system is impaired in the older bladder, administering an exogenous V2R agonist (e.g., desmopressin) could counteract this defect. Thus, desmopressin could potentially increase nighttime bladder capacity through detrusor relaxation in concert with decreased urine production, reducing nocturnal voiding frequency.

Purpose or the research:: Nearly 300,000 people are affected by spinal cord injury (SCI) with approximately 18,000 new cases annually, according to the National SCI Statistics Center. SCI affects physical mobility and impairs the function of multiple internal organs to cause lower urinary tract (LUT) dysfunctions manifesting as detrusor sphincter dyssynergia (DSD) and neurogenic detrusor overactivity (NDO) with detrimental consequences to the quality of life and increased morbidity. Multiple lines of evidence now support time dependent evolution of the complex SCI pathology which requires a multipronged treatment approach of immediate, specialized care after spinal cord trauma bookended by physical rehabilitation to improve the clinical outcomes. Instead of one size fits all treatment approach, we propose adaptive drug treatment to counter the time dependent evolution of SCI pathology, with three small molecule drugs with distinctive sites of action for the recovery of multiple functions. Principal results:: Our findings demonstrate the improvement in the recovery of hindlimb mobility and bladder function of spinal cord contused mice following administration of small molecules targeting neurotrophin receptors, LM11A-31 and LM22B-10. While LM11A-31 reduced the cell death in the spinal cord, LM22B-10 promoted cell survival and axonal growth. Moreover, the soluble guanylate cyclase (sGC) activator, cinaciguat, enhanced the revascularization of the SCI injury site to promote vessel formation, dilation, and increased perfusion. Major conclusions:: Our adaptive three drug cocktail targets different stages of SCI and LUTD pathology: neuroprotective effect of LM11A-31 retards the cell death that occurs in the early stages of SCI; and LM22B-10 and cinaciguat promote neural remodeling and reperfusion at later stages to repair spinal cord scarring, DSD and NDO. LM11A-31 and cinaciguat have passed phase I and IIa clinical trials and possess significant potential for accelerated clinical testing in SCI/LUTD patients.