Bishara, S.; (2010) Muscarinic and purinergic signalling within the bladder. Doctoral thesis , UCL (University College London).

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Abstract

The aim of this thesis is to improve our understanding of muscarinic and purinergic neurotransmission within the urinary bladder both within the detrusor muscle and the urothelium as both sites are therapeutic targets. The M2 receptor is the most populous muscarinic receptor in the detrusor muscle however its role is unclear, as detrusor contractility has been demonstrated to be mediated principally by the M3 receptor. The role of the M2 muscarinic receptor in guinea pig and human detrusor contractility was examined through organ bath experiments. Significant M2 modulation of contractility in patients with neuropathic overactivity and overactive bladder symptoms was demonstrated through inhibition of agonist dose response curves and electrical field stimulation with the selective M2 inhibitor methoctramine. Furthermore cAMP elevation through the adenylate cyclase activator forskolin produced an identical and non-additive inhibition to that achieved through methoctramine suggesting that cAMP inhibition is an important mechanism of M2 activation in the detrusor. Detrusor contractility was further assessed through an isolated cell technique and this demonstrated further evidence of M2 mediated contraction of the detrusor indicating that the site of action of M2 agonism is directly within the detrusor cells. Ussing chamber experiments to examine the effect of the exogenous addition of neurotransmitters on the electrical properties of the urothelium were carried out. These demonstrated that cholinergic agonists had no effect but ATP resulted in an increased negativity of the basolateral surface of the urothelium only when added to the luminal but not the basolateral surface. As ATP release from the urothelium has been found to be associated with inflammation and the sensory nerves are adjacent to the basolateral surface, we believe this represents a sensory mechanism whereby a luminal inflammatory signal is transduced electrically across the urothelium to activate the sensory nerves.

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