PT  - JOURNAL ARTICLE
AU  - Gary W. Lawrence
AU  - K. Roger Aoki
AU  - J. Oliver Dolly
TI  - Excitatory Cholinergic and Purinergic Signaling in Bladder Are Equally Susceptible to Botulinum Neurotoxin A Consistent with Co-Release of Transmitters from Efferent Fibers
AID  - 10.1124/jpet.110.169342
DP  - 2010 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1080--1086
VI  - 334
IP  - 3
4099  - http://jpet.aspetjournals.org/content/334/3/1080.short
4100  - http://jpet.aspetjournals.org/content/334/3/1080.full
SO  - J Pharmacol Exp Ther2010 Sep 01; 334
AB  - Mediators of neuromuscular transmission in rat bladder strips were dissected pharmacologically to examine their susceptibilities to inhibition by botulinum neurotoxins (BoNTs) and elucidate a basis for the clinical effectiveness of BoNT/A in alleviating smooth muscle spasms associated with overactive bladder. BoNT/A, BoNT/C1, or BoNT/E reduced peak and average force of muscle contractions induced by electric field stimulation (EFS) in dose-dependent manners by acting only on neurogenic, tetrodotoxin-sensitive responses. BoNTs that cleaved vesicle-associated membrane protein proved to be much less effective. Acetylcholine (ACh) and ATP were found to provide virtually all excitatory input, because EFS-evoked contractions were abolished by the muscarinic receptor antagonist, atropine, combined with either a desensitizing agonist of P2X1 and P2X3 or a nonselective ATP receptor antagonist. Both transmitters were released in the innervated muscle layer and, thus, persisted after removal of urothelium. Atropine or a desensitizer of the P2X1 or P2X3 receptors did not alter the rate at which muscle contractions were weakened by BoNT/A. Moreover, although cholinergic and purinergic signaling could be partially delineated by using high-frequency EFS (which intensified a transient, largely atropine-resistant spike in muscle contractions that was reduced after P2X receptor desensitization), they proved equally susceptible to BoNT/A. Thus, equi-potent blockade of ATP co-released with ACh from muscle efferents probably contributes to the effectiveness of BoNT/A in treating bladder overactivity, including nonresponders to anticholinergic drugs. Because purinergic receptors are known mediators of sensory afferent excitation, inhibition of efferent ATP release by BoNT/A could also help to ameliorate acute pain and urgency sensation reported by some recipients.