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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

UROGENITAL SYSTEM

In the normal human bladder, atropine will block at least 95% of
parasympathetic nerve-mediated contraction, indicating that its
innervation is predominantly cholinergic; purinergic signalling is
responsible for the atropine-resistant component of contraction (40).
There are a number of examples of the purinergic component of
cotransmission increasing in pathological conditions. One is that
purinergic nerve-mediated contraction of the human bladder is
increased to 40% in pathophysiological conditions such as interstitial
cystitis, outflow obstruction, idiopathic detrusor instability and
probably also neurogenic bladder. ATP release from bladder
epithelial cells from patients with interstitial cystitis is significantly
greater than from healthy cells and there is increase of expression of
P2X2 and P2X3 receptors in urothelial cells. P2X1 receptor subtype
expression markedly increased in obstructed bladder and in the
absence of P2X3 receptors in mouse knockouts, the bladder is
hyperactive.

Purinergic signalling also plays a role in afferent sensation from
the bladder. ATP is released from urothelial cells when the bladder is
distended. Sensory-nerve recording has indicated that P2X3 receptors
are involved in mediating the nerve responses to bladder distension,
providing mechanosensory feedback involving both the micturition
reflex and pain (32). This, too, might be a potential target for
pharmacological manipulation in the treatment of detrusor instability.

In ageing rats there is an increased sensitivity of the bladder
to ATP, but no change in response to acetylcholine or potassium
chloride. Comparable results have been found showing increased
purinergic, but not cholinergic neurotransmission, to ageing human
bladder smooth muscle. Activation of P2 receptors in the brain stem
(both periaqueductal grey matter and Barrington’s nucleus/locus
ceruleus) generate patterns of activity in the parasympathetic
innervation of the bladder. In patients with idiopathic detrusor
instability, there is abnormal purinergic transmission in the bladder;
this may account for some of the symptoms and provide a novel
therapeutic target for treatment of overactive bladder (41). Voiding
dysfunction involves P2X3 receptors in awake chronic spinal cord
injured rats, which raises the possibility that P2X3 antagonists might

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