Presentation Authors: Pradeep Tyagi*, Naoki Yoshimura, Pittsburgh, PA
Introduction: UAB is the manifestation of detrusor underactivity (DU), which is defined as a contraction of reduced strength and/or duration resulting in prolonged bladder emptying. Bethanechol is a synthetic cholinomimetic drug, but it is ineffective in UAB presumably for its non-selective agonist action on prejunctional and post-junctional muscarinic receptors. A recent pilot study found that Acotiamide reduces the post-void residual urine volume (PVR) of DU patients, but a direct effect of Acotiamide on bladder is unknown.
Methods: Longitudinal, urothelium intact bladder strips were removed from euthanized Sprague-Dawley rats (10-12 weeks old) and suspended isometrically under a tension of 10 mN in 37Â°C organ bath constantly gassed with 95% oxygen-5% carbon dioxide. After an equilibration period of 90 min, nerve-mediated contractions (tetrodotoxin-sensitive) were generated by electrical field stimulation of strips (EFS: 5 ms pulses, 1-64Hz, 5s train at 20V) in presence or absence of Acotiamide 1-2ÂµM. EFS evoked contraction amplitude with single stimulation at each frequency was normalized with the response to 120mM KCl. Similar studies were performed on a single bladder obtained from organ donors.
Results: Published studies on recombinant receptors reports that the IC50 of Acotiamide for muscarinic receptors is 1-10ÂµM. TTX sensitive EFS contractions evoked at 8-32Hz in rat bladder strips were significantly enhanced by Acotiamide 1ÂµM (Two -way ANOVA followed Sidakâ€™s multiple comparison; *p < 0.01). In comparison, EFS evoked contractions of human bladder strips were significantly enhanced at 32Hz by Acotiamide 2ÂµM. Meanwhile, Acotiamide 1- 2ÂµM has no effect on rat and human bladder contractility in absence of EFS and the enhancement of EFS contractions was abolished by 1 Î¼M tetrodotoxinindicating a prejunctional effect for Acotiamide.
Conclusions: These findings support that prejunctional muscarinic receptor M4 subtype expressed in bladder of several species participate in a negative feedback mechanism for regulating acetylcholine (ACh) secretion from postganglionic cholinergic nerve terminals. The treatment of UAB may be improved by antimuscarinic agents which selectively block prejunctional M4 receptors and not post-junctional M3 receptors.
Source of Funding: University Pittsburgh Physicians Foundation