AbstractInterstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by pelvic pain, urinary frequency, urgency and nocturia with no evidence of bacteria or pathology. Treatment is multimodal consisting of conservative, oral, intravesical or surgical treatments for symptom control. The American Urological Association approves the intravesical use of dimethyl sulphoxide (DMSO) while it is not recommended by the European Urological Association due to insufficient evidence. Other intravesical therapies such as resiniferatoxin (RTX) and capsaicin have been trialled clinically and are not yet approved due to inconsistent results and pungency, although they could provide long-term pain relief. Therefore, this thesis aims to investigate intravesical DMSO, RTX and capsaicin and their vehicles on bladder function to address the lack of evidence surrounding DMSO and to provide possible explanations for the inconsistency and pungency associated with RTX and capsaicin.
Luminally applied DMSO, RTX and capsaicin including the respective vehicles for RTX and capsaicin (10% and 30% ethanol) were examined in pig bladders, while intravesical RTX and its vehicle (10% ethanol) were examined in mouse bladders. In pig bladders, mediator release was assessed in the urothelium/lamina propria (U/LP) during and immediately after treatment. Histological and functional studies were assessed in U/LP, detrusor and intact sections immediately after treatment. In mouse bladders, voiding behaviour was assessed before and after treatment in vivo while mediator release and bladder function were examined 24-hours after treatment ex vivo. For both models, pharmacological, mechanical and electrical stimuli were used to compare control and treated tissues.
In pig bladders, DMSO, capsaicin, 10% or 30% ethanol alterered mediator release from the U/LP while DMSO and 30% ethanol produced significant sloughing of the urothelium. DMSO enhanced U/LP muscarinic responses and detrusor nerve-mediated responses. RTX altered purinergic signalling in intact tissues and capsaicin depressed detrusor responses to muscarinic stimulation. 10% ethanol enhanced U/LP spontaneous activity while 30% ethanol depressed U/LP responses to purinergic stimulation but enhanced the responses to KCl. 30% ethanol also enhanced U/LP and detrusor responses to muscarinic stimulation and enhanced detrusor responses to nerve-mediated stimulation. In mouse bladders, RTX increased voiding frequency in vivo. Ex vivo, RTX reduced serosal acetylcholine, enhanced contractile responses to purinergic stimulation and KCl while a more substantial cholinergic component occurred during nerve-mediated stimulation. 10% ethanol altered luminal mediator release, enhanced spontaneous activity, the contractile responses to purinergic, muscarinic and nerve-mediated stimulation.
In IC/BPS patients, the integrity of the urothelium can be significantly affected ranging from normal and intact to thin and denuded. The loss of urothelium is correlated with pain. DMSO and 30% ethanol produce many side effects in the full thickness pig urothelium in contrast to 10% ethanol, although, it produces considerable side effects in the thinner urothelium found in mouse bladders. The impact of RTX and capsaicin is minor compared to their ethanol vehicles, and alternate vehicles may reduce the side effects. DMSO appears to have no target in the bladder while RTX and capsaicin must reach nerves in the sub-urothelium to be effective. Therefore, the state of the urothelium may determine efficacy of treatment.
|Date of Award||15 Jun 2019|
|Supervisor||Russ Chess-Williams (Supervisor) & Catherine McDermott (Supervisor)|