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Mechanisms of action of botulinum neurotoxins, β 3 ‐adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI‐RS 2011
Author(s) -
Kanai Anthony,
Zabbarova Irina,
Oefelein Michael,
Radziszewski Piotr,
Ikeda Youko,
Andersson KarlErik
Publication year - 2012
Publication title -
neurourology and urodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 90
eISSN - 1520-6777
pISSN - 0733-2467
DOI - 10.1002/nau.21246
Subject(s) - overactive bladder , medicine , mirabegron , cystometry , detrusor muscle , receptor , urinary bladder , resiniferatoxin , agonist , neuroscience , dorsal root ganglion , adrenergic receptor , pharmacology , endocrinology , spinal cord , trpv1 , transient receptor potential channel , biology , pathology , alternative medicine , psychiatry
Background Botulinum neurotoxins type A (BoNT/A), β 3 ‐adrenergic receptor agonists, and phosphodiesterase type 5 (PDE5) inhibitors are promising agents that mitigate lower urinary tract symptoms by attenuating the sensory system. However, whether they act directly on afferent nerves or indirectly through the other cell types is unclear. Methods Spinal cord transected female mice were used as a model for neurogenic bladder overactivity. In vivo methods utilized decerebrate mouse cystometry. In vitro approaches included optical mapping of Ca 2+ transient, single unit afferent nerve recordings and tension measurements from bladder sheets and wall cross‐sections. Immunohistochemistry was used to measure the expression of β 3 ‐adrenergic receptors on dorsal root ganglion (DRG) neurons. Results Our unique approaches revealed the direct effects of BoNT/A in inhibiting neuropeptide release and firing rates in afferents following bladder injections. β 3 ‐adrenergic receptor agonists are demonstrated to directly inhibit afferent nerve firing independent of the relaxing effects on bladder smooth muscle. Moreover, data suggest the expression of these receptors on DRG neurons that send projections to the bladder. The mechanism of action of PDE5 inhibitors on bladder overactivity is discussed. Discussion The questions raised during the plenary session of the 2011 International Consultation on Incontinence‐Research Society meeting regarding the benefits of BoNT/A, β 3 ‐adrenergic receptor agonist and PDE5 inhibitor treatments of overactive bladder are addressed. Conclusion Our findings suggest that the abovementioned agents, in low enough concentrations, can directly inhibit afferent excitability without decreasing detrusor contractility. Accordingly, they have considerable potential for treating the sensory component of lower urinary tract dysfunctions. Neurourol. Urodynam. 31:300–308, 2012. © 2012 Wiley Periodicals, Inc.