Control of bladder function by peripheral nerves: avenues for novel drug targets

The micturition reflex involves afferent nerve activation when the bladder is sufficiently full and subsequent controlled firing of parasympathetic efferent nerves to contract the detrusor muscle as part of the voiding mechanism. Alteration of the sensitivity of afferent activation or loss of control over transmitter release could lead to sensory- or motor-activated incontinence, respectively. The control mechanisms that regulate these 2 activities remain poorly understood. Current opinion is that the sensation of bladder fullness is relayed by afferent nerves in the mucosal layer, which are activated by the release of chemical mediators, such as adenosine triphosphate (ATP), from the urothelium when it is stretched as the bladder fills. This hypothesis supports the concept that other chemical signals that affect bladder sensation (eg, changes in urine composition and agents such as capsaicin) can modulate the sensitivity of the basic system. It has also been proposed that a layer of myofibroblasts immediately below the basal lamina of the urothelium acts as a variable gain regulator of the sensory process between ATP release and afferent excitation. These myofibroblasts are functionally connected to form an electrical syncytium, make close contact with nerves, and respond by generating electrical responses and transient increases in intracellular Ca2+ when exposed to ATP. On the efferent side, using a guinea pig detrusor model, possible modulators of transmitter release have been investigated, including adenosine (the breakdown product of the neurotransmitter ATP). Adenosine reduces the force of nerve-mediated contractions by acting predominantly at presynaptic sites at the nerve-muscle junction via a subtype of an adenosine receptor-the A1 receptor. An additional effect, possibly via A2 receptors, is also present on the detrusor muscle itself. These actions of adenosine are less evident in human detrusor muscle but remain a potential modulatory target. In summary, the cellular and molecular regulation of bladder fullness sensation and efferent transmitter release are becoming better understood and represent potential drug targets for the management of detrusor overactivity.