The role of the inflammatory mediators in modulating bladder contractile activity.

  • Zane Stromberga

Student thesis: Doctoral Thesis

Abstract

Urinary bladder inflammation has been observed in various lower urinary tract disorders, including overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS). However, the mechanisms underlying these conditions are not fully understood. It is apparent that acetylcholine release is involved, yet other mediators and regulator chemicals may also influence bladder function and sensation. There is a particular interest in identifying which receptors other than muscarinic are functional within the bladder wall and capable of mediating overall contractility. Furthermore, there are reports of an increased presence of inflammatory mediators within the bladder and urine of patients suffering from OAB and IC/BPS. Therefore, the involvement of immune cells and the various inflammatory mediators released at sites of inflammation is an important avenue to explore. Understanding the actions of these mediators and the associated receptor systems may reveal future therapeutic targets for lower urinary tract dysfunction. This thesis aimed to determine the effect of histamine and the five primary prostaglandins on tonic contractions and phasic activity of the urinary bladder. This led to an additional aim to investigate the age-associated contractile responses observed to histamine and prostaglandin E2. Isolated tissue baths containing adjacent strips of urothelium with lamina propria or detrusor were used to examine the key receptor systems involved in the contractions observed in response to stimulation with histamine or prostaglandin. In response to histamine, tonic contractions and spontaneous phasic activity were significantly enhanced. The receptor subtype involved in mediating this response was determined to be the H1 receptor with no involvement of the H3 and H4 receptors. The treatment with the H2 receptor antagonist enhanced urothelium with lamina propria (U&LP) tonic contractions to histamine, whereas stimulation with the receptor agonist-induced relaxation. In detrusor, the H1 receptor was also involved in mediating the responses to histamine. However, no involvement of the H2, H3 or H4 receptors was determined. Further studies assessing an older animal model revealed that ageing impacts the responses to histamine in detrusor, although it does not influence U&LP tissue. Additional differences between the two age groups included the involvement of the H2 receptor in U&LP responses. In juvenile animals, the H2 receptor stimulation relaxed the U&LP preparations, whereas this receptor had no influence on contraction in adult animals. The inhibition observed from H1 receptor antagonists as consistent in reducing tonic contractions and phasic activity in both juvenile and adult animal models. All five prostaglandins stimulated contractions in both U&LP and detrusor with an identified potency of PGE2 > PGF2α > TXA2 > PGD2 > PGI2. Only 34% of isolated detrusor preparations developed an initial phasic activity in the absence of any stimulation. However, the application of all prostaglandin agonists induced this phasic activity in the majority of the remaining preparations. Further investigation of the PGE2 receptor subtypes revealed that increases in contractions to PGE2 were not mediated by any of the EP receptor subtypes. Other receptor systems, such as the purinergic and cholinergic, were also shown to be not involved in this response. The presence of an FP receptor antagonist significantly inhibited increases to tonic contractions in U&LP and detrusor in response to both PGE2 and PGF2α. Therefore, the contractile response to PGE2 appears to be mediated, at least partially, via the FP receptor in both U&LP and detrusor, suggesting some conversion of PGE2 to PGF2α upon contact with tissue. The findings in this thesis demonstrate that both histamine and prostaglandin receptor systems are capable of modulating tonic and phasic contractions of detrusor smooth muscle, and urothelium with lamina propria. Across all mediators considered, histamine, prostaglandin E2 and F2α exhibited the most pronounced effects on tonic contractions and phasic activities in both layers of the urinary bladder. Therefore, it is feasible that these receptor systems within the bladder wall could act as novel future therapeutic targets in the treatment of lower urinary tract disorders.
Date of Award4 Feb 2021
Original languageEnglish
SupervisorChristian Moro (Supervisor) & Russ Chess-Williams (Supervisor)

Cite this

'