AbstractInterstitial cystitis/ bladder pain syndrome (IC/BPS) is a progressive bladder
condition that presents with symptoms like bladder urgency, frequency, and pain. The aetiology of this condition remains uncertain, which hinders current treatment options. Amitriptyline (AMT) is a tricyclic antidepressant that can also be recommended as a second-line oral treatment for patients with IC/BPS to reduce the sensation of pain. Oral AMT in the management of IC/BPS has only been studied in a limited number of controlled and non-controlled trials. The direct actions of AMT on normal bladder function remain unexplored and although limited, clinical studies show that higher efficacy rates are associated with higher sustained doses of oral AMT; but common adverse events such as drowsiness and nausea affect the quality of patients’ life.
Along with oral treatment, patients can receive therapeutic agents luminally
through intravesical instillation. The therapeutic potential in administrating AMT
through the luminal route has not been explored. This approach limits the
systemic absorption of AMT and therefore, should result in no adverse effects.
The effects of direct incubation of AMT as well as luminal pre-treatment of AMT
were investigated on normal bladder function. Isolated strips of detrusor smooth
muscle, mucosa strips as well as intact bladder strips were exposed to several
pharmacological agents to investigate and compare the responses of control and
treated tissue strips.
Normal bladder function was affected in different ways by luminal and direct AMT administration. Luminal pre-treatment enhanced the amplitude of spontaneous contractions, enhanced contractile responses to muscarinic stimulation and altered relaxation. These changes may be due to alteration in the urothelialderived inhibitory factor UDIF regulation in the urothelium.
Direct incubation with a supra-clinical dose of AMT reduced the contractile effect by over 40%. This effect may be via inhibition of the intracellular calcium
signalling pathway that was also observed with treatment at clinical concentration but to a lesser extent. This is important for IC/BPS patients, as inhibiting involuntary bladder contractions would alleviate symptoms. Interestingly, the UDIF effect was completely abolished following treatment with AMT at supraclinical concentration but was not significantly altered following treatment at clinical concentration. AMT at supra-clinical concentration also significantly reduced the contractile responses to both α,β-mATP and KCl, which suggests that the action of AMT on the detrusor muscle may involve the neuronal P2X receptors as well as a depression of the intrinsic myogenic detrusor contraction.
Relaxation responses were significantly enhanced following treatment with AMT
at supraclinical concentration. More importantly, relaxation responses were also
significantly enhanced following treatment with a clinical concentration of AMT.
These results indicate that intravesical treatment with AMT may potentially be of
therapeutic benefit in patients with IC/BPS.
|Date of Award||20 Oct 2020|
|Supervisor||Russ Chess-Williams (Supervisor) & Catherine McDermott (Supervisor)|