Loss of Purinergic P2X₃and P2X₅Receptor Innervation in Human Detrusor from Adults with Urge Incontinence

Abstract

Activation of purinergic P2X receptors associated with the parasympathetic nerves that supply the human bladder smooth muscle (detrusor) is implicated in control of detrusor contractility. The relative abundance of all seven subtypes colocalized with synaptic vesicles on parasympathetic nerves was examined in specimens from normal adult bladder, infants, and in adults with overactive detrusor contractility and a diagnosis of idiopathic detrusor instability (IDI) to determine whether receptor distribution varied with age or in patients with incontinence. Alteration in control of detrusor innervation was examined with P2X subtype-specific antibodies and an antibody against synaptic vesicles, using immunofluorescence and confocal microscopy. Detrusor samples were taken from: controls, at cystectomy for cancer or cystoscopic biopsy for hematuria (n = 22; age 33-88), child bladder, at surgical correction of vesico-ureteric reflux (n = 21; age 4 months to 2 years), and adults with detrusor instability at cystoscopy-cystodistension (n = 18; age 30-81). Adult specimens contained muscle with large varicosities (1.2 microm) along parasympathetic nerves with colocalized patches of all P2X(1-7) subtypes. Infant bladder revealed little evidence of P2X at age <9 months but approached adult levels at 2 years. Detrusor from IDI patients revealed selective absence of P2X(3) and P2X(5) beneath all the varicosities. This specific lack of P2X(3) and P2X(5) may impair control of detrusor contractility and contribute to the pathophysiology of urge incontinence.

Identification of Atropine- and P2X1Receptor Antagonist-Resistant, Neurogenic Contractions of the Urinary Bladder

“…Furthermore, although the P2X 1 is the main P2X subunit present in human detrusor smooth muscle, its expression is unchanged in dysfunctional bladder (Moore et al, 2001;O'Reilly et al, 2002). It is notable that the P2X 4 subunit is also expressed, and its colocalization with nerve varicosities more than doubles in tissue from adults with IDI (Moore et al, 2001;O'Reilly et al, 2002). Interestingly, pregnancy in rats is also associated with an increase in P2X 4 subunit junctional clustering (Yunaev et al, 2000), and the PPADS-sensitive component of neurogenic contractions is smaller in pregnant rats (Knight and Burnstock, 2004).…”

“…These contractions are abolished by prolonged exposure to ␣,␤-meATP and so assumed to be mediated by ATP and P2X 1 receptors, but this has not been confirmed using P2X 1 receptor antagonists. Furthermore, although the P2X 1 is the main P2X subunit present in human detrusor smooth muscle, its expression is unchanged in dysfunctional bladder (Moore et al, 2001;O'Reilly et al, 2002). It is notable that the P2X 4 subunit is also expressed, and its colocalization with nerve varicosities more than doubles in tissue from adults with IDI (Moore et al, 2001;O'Reilly et al, 2002).…”

Purinergic signalling in the urinary tract in health and disease

“…A further possible explanation for the increased potency of ATP in generating contractions in detrusor from unstable bladders may be reduced extracellular ATP hydrolysis [281]. Reduction of P2X3 and P2X5 receptors in human detrusor from adults with urge incontinence has been claimed [495]. The possibility that the increase in purinergic transmission is due to increased neural release of ATP, reduction in ectoATPase activity or to changes in gap junctions between muscle cells has been raised [50,249].…”

Expression of purinergic P2X2-receptors in neurogenic bladder dysfunction due to spinal cord injury: a preliminary immunohistochemical study

“…In patients with idiopathic overactive bladder (OAB), an increased expression of the P 2 X 2 subtype protein 8 and a loss of P 2 X 3 and P 2 X 5 proteins have been described. 9 Thus, it seems that an abnormal expression of P 2 X receptors may lead to a disturbance of the purinergic inhibitory control of the parasympathetic release of acetylcholine. 9 As, however, ATPase activity is also altered in the tissue of overactive detrusor, P 2 X receptor expression and abnormalities in ATPase activity may both influence purinergic signalling in detrusor overactivity.…”

“…9 Thus, it seems that an abnormal expression of P 2 X receptors may lead to a disturbance of the purinergic inhibitory control of the parasympathetic release of acetylcholine. 9 As, however, ATPase activity is also altered in the tissue of overactive detrusor, P 2 X receptor expression and abnormalities in ATPase activity may both influence purinergic signalling in detrusor overactivity. 10 Studies evaluating the expression of P 2 X receptors in neurogenic detrusor overactivity are rare.…”