DU Is Induced by Low Levels of Urinary ATP in a Rat Model of Partial Bladder Outlet Obstruction: The Incidence of Both Events Decreases after Deobstruction

Objectives. To investigate, in initial phases of bladder outlet obstruction (BOO), the urinary ATP levels, the incidence of detrusor underactivity (DU), and if they change after deobstruction. Methods. Adult female Wistar rats submitted to partial BOO (pBOO) and sham-obstruction were used. Cystometry was performed 3 or 15 days after pBOO and fluid was collected from the urethra for ATP determination. Bladders were harvested for morphological evaluation of the urothelium. DU was defined as the average of voiding contractions (VC) of sham-operated animals, with 3 SD at 15 days after the sham surgery. In another group of animals in which pBOO was relieved at 15 days and bladders were let to recover for 15 days, the incidence of DU and ATP levels were also accessed. The Kruskal–Wallis test was followed by Dunn’s multiple comparisons test, and Spearman’s correlation test was used. Results. DU was present in 13% and 67% of the bladders at 3 and 15 days after pBOO, respectively, and in 20% of the bladders at 15 days after deobstruction. ATP levels were significantly lower in DU/pBOO versus sham and non-DU/pBOO rats. A strong positive correlation between ATP levels and VC/min was obtained (r = 0.63). DU bladders had extensive areas in which umbrella cells appeared stretched, the width exceeding that presented by sham animals. Conclusions. Low urothelial ATP parallels with a high incidence of DU early after pBOO.

1. Introduction
Detrusor underactivity (DU) associated with prolonged partial bladder outlet obstruction (pBOO) is mostly attributed to the impairment of the detrusor muscle and the efferent pathway [1, 2]. However, effective detrusor contractions cannot be generated in the absence of sensory input arising from the bladder [3]. During bladder distension, the stretch of urothelial cells causes the release of signalling molecules among which ATP plays a key role after binding to P2X3 purinergic receptors expressed in the rich suburothelial sensory fibre network [4–6]. The disruption of this urothelial sensory fibre crosstalk decreases the frequency of expulsive bladder voiding contractions (VC) and increases the postvoid residual urine [5].

At the beginning of the obstructive process, bladders develop compensatory mechanisms to increase the strength of detrusor contraction, among which detrusor hypertrophy is the most evident [7, 8]. However, after variable periods, decompensation may supervene, resulting in weak contractions unable to initiate and maintain normal micturition [7, 8]. In the switch from compensated into decompensated stages, a decrease in blood perfusion is a constant finding in men, pigs, and rodents suffering from prolonged pBOO [4, 9]. Although ischemia may injure parasympathetic and sensory nerves, the urothelium, which has the highest metabolic rate in the whole bladder, is particularly vulnerable [2, 10].

A recent clinical study showed that 79% of men with DU and BOO submitted to prostatectomy recovered spontaneous voiding [11]. This observation seems to indicate that reversible events rather than an irreversible replacement of smooth muscle cells by collagen [7, 9] or bladder denervation [1] participate in the early development of DU. The rapid urothelial turnover makes the reactivation of the ATP-mediated urothelial sensory fibre crosstalk as one foreseeable event. With these in mind, this study tested the hypothesis that DU observed in initial phases of pBOO courses with low levels of urinary ATP and that correction of pBOO increases the proportion of animals with normal bladders and normal levels of urinary ATP.