BERKELEY, CA (UroToday.com) - It has been proposed that β3-adrenoceptor (β3-AR) agonists inhibit not only the efferent, but also the afferent pathways innervating the bladder via release of nitric oxide (NO) or an unidentified inhibitory factor from the urothelium,[1, 2, 3, 4] which actively participates in sensory functions, expressing various receptors for mediators released from the urothelium itself in response to various stimuli. Moreover, previous studies demonstrated that CL316,243, a β3-AR agonist, reduced bladder non-voiding contractions  of myogenic origin  in a rat model of a partial bladder outlet obstruction. These myogenic autonomous bladder activities may generate localized microcontractions. Such localized microcontractions can facilitate afferent activities even in normal bladder of the human, guinea pig, and rat,[8, 9, 10] and may possibly play a key role in development of urgency.
We have established the measurement of the Aδ- or C-fiber single-unit fiber afferent activities (SAAs) innervating the bladder mechano-sensitive primary afferent nerves and have investigated the effect of several drugs in this experimental set-up.[11, 12, 13] In the present study, we evaluated the effects of mirabegron, a novel β3-AR agonist, on primary bladder mechano-sensitive SAAs and bladder microcontractions and compared with those of oxybutynin in normal rat.
The results of the present first experiment, in response to bladder filling, demonstrated that mirabegron inhibited the afferent activities of both Aδ- and C-fibers in a dose-dependent manner, which was more remarkable for Aδ-fibers than C-fibers. Moreover, in this first experiment, the inhibition of afferent activities appeared to synchronize with a decrease in bladder microcontractions during filling. To further evaluate the possible relationship between microcontractions and afferent activities in response to mirabegron-administration, we made the second experiments under an isovolumetric condition, investigating direct effects of mirabegron on bladder microcontractions and mechano-sensitive afferent activities, and compared with those of oxybutynin. The results of this second experiment showed that mirabegron inhibited both the bladder microcontractions and Aδ-fiber activity at doses, which did not decrease the bladder pressure. This suggests that the microcontractions may link to the mechano-sensitive afferent activities of Aδ-fiber, and mirabegron inhibits the afferent activities through the suppression of the microcontractions. The microcontractions observed in the present study are of myogenic origin as no reflex arc through the L6 dorsal roots was preserved in the experimental set-up. At higher doses, which also decreased bladder pressure, mirabegron inhibited C-fiber activity, suggesting their linkage. On the other hand, oxybutynin did not alter either bladder microcontractions or mechano-sensitive afferent activities.
In conclusion, mirabegron can inhibit single unit mechano-sensitive bladder afferent activities, especially of Aδ-fibers rather than C-fibers, which is associated with the suppression of the bladder microcontractions in the rat.
Since we have demonstrated that another β3-AR agonist, CL316,243, can inhibit prostaglandin E2 (PGE2)-induced C-fiber hyperactivity, we are planning to determine whether mirabegron can inhibit the afferent hyperactivity induced by chemical inflammation such as PGE2 or acrolein, a metabolite of cyclophosphamide, or induced by bladder outlet obstruction. These further investigations will help to explore possible additional actions of the β3-AR agonist as a therapeutic agent for OAB or other bladder sensory disorders.
- Birder LA, Apodaca G, De Groat WC and Kanai AJ. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Physiol 1998;275:F226-9.
- Birder LA, Nealen ML, Kiss S, et al. Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 2002;22:8063-70.
- Murakami S, Chapple CR, Akino H, Sellers DJ and Chess-Williams R. The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int 2007;99:669-73.
- Otsuka A, Shinbo H, Matsumoto R, Kurita Y and Ozono S. Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 2008;377:473-81.
- de Groat WC. The urothelium in overactive bladder: passive bystander or active participant? Urology 2004;64:7-11.
- Woods M, Carson N, Norton NW, Sheldon JH and Argentieri TM. Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat. J Urol 2001;166:1142-7.
- Igawa Y, Mattiasson A and Andersson KE. Micturition and premicturition contractions in unanesthetized rats with bladder outlet obstruction. J Urol 1994;151:244-9.
- Drake MJ, Harvey IJ and Gillespie JI. Autonomous activity in the isolated guinea pig bladder. Exp Physiol 2003;88:19-30.
- Drake MJ, Harvey IJ, Gillespie JI and Van Duyl WA. Localized contractions in the normal human bladder and in urinary urgency. BJU Int 2005;95:1002-5.
- Drake MJ, Hedlund P, Harvey IJ, et al. Partial outlet obstruction enhances modular autonomous activity in the isolated rat bladder. J Urol 2003;170:276-9.
- Aizawa N, Homma Y and Igawa Y. Effects of Mirabegron, a Novel beta3-Adrenoceptor Agonist, on Primary Bladder Afferent Activity and Bladder Microcontractions in Rats Compared With the Effects of Oxybutynin. Eur Urol 2012;62:1165-73.
- Aizawa N, Igawa Y, Nishizawa O and Wyndaele JJ. Effects of nitric oxide on the primary bladder afferent activities of the rat with and without intravesical acrolein treatment. Eur Urol 2011;59:264-71.
- Aizawa N, Igawa Y, Nishizawa O and Wyndaele JJ. Effects of CL316,243, a beta 3-adrenoceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol Urodyn 2010;29:771-6.
Naoki Aizawa,a Yukio Homma,b and Yasuhiko Igawaa as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan