Selective reduction of neurotransmitter release by cAMP-dependent pathways in mouse detrusor

Parasympathetic nerve-mediated contractions of detrusor smooth muscle are generated by ATP and acetylcholine (ACh) release from efferent nerve terminals. In humans, ACh is responsible for detrusor contractions in normal human bladders, whereas ATP has an additional role in overactive bladder pathologies. The ATP metabolite, adenosine, relaxes nerve-mediated contractions, with a potential action via presynaptic adenosine A1 receptor activation and subsequent suppression of neuronal ATP release. We investigated the effect of A1 receptor activation and downstream cAMP-dependent pathways on nerve-mediated ATP and ACh release, and detrusor contraction in mouse detrusor. Bladders from male C57BL/6 mice (12 wk) were used for in vitro experiments. Upon electrical field stimulation of intact preparations (detrusor and mucosal layers), ATP or ACh release was measured simultaneously with tension recordings. Activation of A1 receptors by adenosine or exogenous agonists reduced the lower frequency component of nerve-mediated contractions and neuronal ATP release. The A1 receptor antagonist abolished these effects. A1 receptor activation inhibits adenylyl cyclase (AC) activity and cAMP generation. The effect of A1 receptor activation was mimicked by a PKA antagonist but not by modulators of exchange proteins activated by cAMP, demonstrating that modulation of nerve-mediated ATP release is via PKA. Adenosine had no effect on ACh release or the higher frequency component of nerve-mediated contractions. Differential regulation of neurotransmitter release is possible at the detrusor nerve-muscle junction, as demonstrated by A1 receptor activation, and downstream inhibition of AC, cAMP generation, and PKA. The ability to specifically attenuate ATP release offers a potential to target purinergic motor pathways enhanced in overactive bladder pathologies

An Exploration of the Control of Micturition Using a Novel in Situ Arterially Perfused Rat Preparation

Our goal was to develop and refine a decerebrate arterially perfused rat (DAPR) preparation that allows the complete bladder filling and voiding cycle to be investigated without some of the restrictions inherent with in vivo experimentation [e.g., ease and speed of set up (30 min), control over the extracellular milieu and free of anesthetic agents]. Both spontaneous (naturalistic bladder filling from ureters) and evoked (in response to intravesical infusion) voids were routinely and reproducibly observed which had similar pressure characteristics. The DAPR allows the simultaneous measurement of bladder intra-luminal pressure, external urinary sphincter–electromyogram (EUS–EMG), pelvic afferent nerve activity, pudendal motor activity, and permits excellent visualization of the entire lower urinary tract, during typical rat filling and voiding responses. The voiding responses were modulated or eliminated by interventions at a number of levels including at the afferent terminal fields (intravesical capsaicin sensitization–desensitization), autonomic (ganglion blockade with hexamethonium), and somatic motor (vecuronium block of the EUS) outflow and required intact brainstem/hindbrain-spinal coordination (as demonstrated by sequential hindbrain transections). Both innocuous (e.g., perineal stimulation) and nociceptive (tail/paw pinch) somatic stimuli elicited an increase in EUS–EMG indicating intact sensory feedback loops. Spontaneous non-micturition contractions were observed between fluid infusions at a frequency and amplitude of 1.4 ± 0.9 per minute and 1.4 ± 0.3 mmHg, respectively and their amplitude increased when autonomic control was compromised. In conclusion, the DAPR is a tractable and useful model for the study of neural bladder control showing intact afferent signaling, spinal and hindbrain co-ordination and efferent control over the lower urinary tract end organs and can be extended to study bladder pathologies and trial novel treatments

Understanding the Impact of Urinary Incontinence in Persons with Dementia:Development of an Interdisciplinary Service Model

Introduction. Prevalence of urinary symptoms such as incontinence (UI) in patients with dementia is estimated to exceed 50%. The resultant psychological and socio-economic burden can be substantial. Our aim was to develop a dedicated urology service within a cognitive impairment clinic in order to treat and better understand the bothersome urinary symptoms suffered by persons with dementia. Methods. Patients attending this clinic were invited to be assessed and interviewed by urologist, together with their family and/or carer. In addition, formal history, examination and relevant investigations, themes of importance such as quality of life, and select question items were drawn from validated questionnaires. Multidisciplinary team (MDT) meeting was carried out on the same day. Outcomes of the first 75 patients with UI and dementia have been reported. Results. Average age was 70 years (range 58–98). Majority of persons had a diagnosis of Alzheimer’s disease (n = 43, 57%). Average score for how much urine leakage interferes with everyday life was 7.7/10 (range 2–10). 58.7% (n = 44) revealed some degree of sleep disturbance due to UI. 83% (n = 62) stated daily activities were limited due to UI. Two-thirds of persons with dementia (n = 50) stated their bladder problem makes them feel anxious. 88% (n = 67) felt the topic was socially embarrassing. All carers stated that the person’s continence issues affect the care they provide. Less than one-third of carers (30.7%, n = 23) were aware of or had been in contact with any bladder and bowel community service. More than half of the carers (n = 46, 65%) were concerned incontinence may be a principal reason for future nursing home admission. Conclusion. UI can be distressing for persons with dementia. Care partners were concerned about loss of independence and early nursing home admission. Awareness of bladder and bowel services should be increased

The association between constipation and lower urinary tract symptoms in parous middle-aged women:a prospective cohort study

Objective: To examine the prospective association between constipation and risk of developing lower urinary tract symptoms (LUTS) in parous middle-aged women. Materials and Methods: The study uses data from 3,729 women from the Avon Longitudinal Study of Parents and Children who provided self-reports of medication intake for constipation at two time points (Baseline): 2001–2003 and 2003–2005. Women with LUTS at baseline were excluded. After 10 years of follow-up, women provided self-reports of LUTS using an adapted version of the International Consultation on Incontinence Questionnaire on Female LUTS. LUTS were categorized according to International Continence Society definitions as stress urinary incontinence (UI), urgency UI, mixed UI, nocturia, increased daytime frequency, urgency, hesitancy, and intermittency. LUTS were considered present if symptoms were reported to occur at least “sometimes” for all subtypes, except for increased daytime frequency (≥9 times) and nocturia (≥2 times nightly). Results: At follow-up, the prevalence of any LUTS was 40%. Women (mean age 43.3 years, standard deviation 0.5), who took medication for constipation at either time point had increased risks of urgency (adjusted relative risks [RRs] = 1.35; 95% confidence interval [CI] 1.04–1.95) and hesitancy (adjusted RR = 1.72; 95% CI 1.04–3.01) compared with women who reported not using medication for constipation at either time point. The risk of urgency (adjusted RR = 1.94; 95% CI 1.15–3.29) and hesitancy (adjusted RR = 1.78; 95% CI 1.03–4.19) was greater for women who reported taking medication for constipation at both time points. There was no evidence that constipation was associated with stress UI, urgency UI, mixed UI, nocturia, increased daytime frequency, and intermittency. Conclusion: Constipation is prospectively associated with an increased risk of urgency and hesitancy among parous middle-aged women. If further research finds evidence that this association is causal, this implies that women should seek treatment to alleviate constipation to reduce their consequent risk of developing these LUTS

Development and initial testing of valves opened by Valsalva (abdominal straining):Proof of principle for urinary catheters or male urethra

We hypothesised that raising the abdominal pressure could provide a non-manual approach to opening a urinary valve, with potential application for indwelling catheters or an intraurethral device. The ‘Vysera’ valve remains closed during short high amplitude spikes but opens when a pre-defined low-amplitude pressure is maintained for a pre-specified duration, allowing sustained abdominal straining to achieve voluntary opening. The valve was subjected to in vitro performance and microbiological tests. Parameters for valve specification were selected by review of a large urodynamic database with nominal opening pressure of 75 cmH2O +/-15 cmH2O (range 60-90 cmH2O) and valve pressure was refined using early clinical results. Valve housings were designed for the end of a Foley catheter, and for male post-prostatectomy intraurethral placement. Preliminary clinical evaluation was undertaken for both designs, incorporating qualitative feedback. In vitro testing of the catheter valve demonstrated only minimal encrustation. On clinical evaluation of the catheter-sited value, six of seven patients (86%) were able to open the valve intentionally by straining. When inactive, none of the patients experienced leakage (7/7=100%), while five (71%) leaked when they coughed. The intraurethral device was successfully placed with image intensifier guidance under general anaesthetic in five of nine patients. Three patients used the device; initial leakage resolved as patients mobilised. However, in contrast to the catheter-sited valve, the intraurethral device was difficult to tolerate for even a few hours. Removal was performed under local anaesthesia with a flexible cystoscope and stent grasper. We conclude that storage and bladder emptying using a strain-activated valve are feasible for a catheter valve and an intra-urethral device. The valve parameters need to be matched to individual patients. For the intraurethral device, additional development is needed to improve the stent housing and valve performance