Neuro-urologyChronic Administration of Anticholinergics in Rats Induces a Shift from Muscarinic to Purinergic Transmission in the Bladder Wall
Introduction
Anticholinergics such as oxybutynin (Oxyc) and fesoterodine (Fesoc) are currently the first-line pharmacotherapy for the treatment of patients with overactive bladder (OAB), about 90% of whom suffer from idiopathic OAB [1], [2]. By blocking the muscarinic receptors on the detrusor muscle, the neuromuscular junction is inhibited. A potential action at the urothelial and suburothelial level has also been suggested [2], with a possible effect on C-fiber activity [3]. However, the compliance rate of patients taking anticholinergics is notoriously low. Indeed, Yeaw et al. found a 6-mo compliance rate of only 28%, significantly lower than other chronic therapeutic areas [4]. The reason for discontinuing this medication class has not been clearly determined, but it may be due to a combination of side effects, financial costs, and loss of drug efficiency [5]. Oxyc and Fesoc are more frequently discontinued than other anticholinergic agents [6]. Understanding the molecular mechanism of the failure of anticholinergics will help physicians treat patients more efficiently.
Bladder physiology is mediated by multiple signaling molecules [7]. Excitation of parasympathetic efferents causes release of acetylcholine, which is generally seen as the main neurotransmitter in the voiding cycle, and of adenosine triphosphate (ATP) at the nerve endings [8] These transmitters act respectively on muscarinic acetylcholine receptors (mainly mAChR2 and mAChR3) and purinergic receptors (mainly purinergic receptor P2X, ligand-gated ion channel, 1 [P2X1]) to cause detrusor smooth-muscle contraction [9], [10]. The relative importance of both signaling molecules is highly dependent on the species [11]. In rats, ATP plays a substantial role in the initiation of the voiding contraction, whereas its role seems to be much less important in humans [11], [12].
The chronic, systemic administration of anticholinergics in animal models induces urodynamic changes after long-term administration of a low dose of Oxyc [13]. In this study, we evaluated the effects of such administration on molecular and in vivo characteristics of the bladder physiology. Long-term Oxyc administration exerts a bimodal action on muscarinic and purinergic receptors. The functional expression of mAChR is decreased, while the relative importance of purinergic system is enhanced. These results may help explain the loss of efficiency of anticholinergic-based treatment on patients with OAB.
Section snippets
Material and methods
The timeline of experiments is shown in Figure 1.
Decreased efficiency of oxybutynin
To rule out any renal dysfunction that may affect bladder function, we tested the influence of chronic administration of Oxyc on the diuresis (Fig. 2a) and the drinking behavior (Fig. 2b) of rats. Before implantation, the average fluid intake volume during 24 h was 15.8 ± 1.6 ml (n = 6), and the average voided volume was 11.1 ± 1.9 ml (n = 6). These volumes did not change significantly at days 7, 14, 21, and 28 after implantation of an Oxyc-administering pump.
The rats were placed in a metabolic
Discussion
Our results offer more insight into the effects of chronic administration of anticholinergic agents on bladder physiology. These effects could partially explain the high discontinuation rate of anticholinergics used for the treatment of OAB. Indeed, after the implantation of an Oxyc-administering osmotic pump in healthy rats, we noted that the efficacy of Oxyc in lowering the number of voiding events decreased. Also, the acute effect of Oxyc was abolished after chronic Oxyc treatment. These two
Conclusions
Our data indicated that chronic administration of anticholinergics leads to reduced functional expression and a shift of the bladder contraction mechanisms from muscarinic to purinergic systems. This mechanism may contribute to the reduced effectiveness and concomitant low compliance of anticholinergic treatment in human patients.
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Shared first authorship.