Excitatory cholinergic and purinergic signaling in bladder are equally susceptible to botulinum neurotoxin a consistent with co-release of transmitters from efferent fibers.
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 P2X(1) and P2X(3) 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 P2X(1) or P2X(3) 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.
Lawrence
Gary W
GW
International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.
Aoki
K Roger
KR
Dolly
J Oliver
JO
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism*; D009476:Neurons, Efferent / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D051381:Rats; D011983:Receptors, Purinergic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D050825:Synaptosomal-Associated Protein 25 / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects*; D050987:Vesicle-Associated Membrane Protein 1 / Q000037:antagonists & inhibitors / Q000276:immunology
D018377:Neurotransmitter Agents; D011983:Receptors, Purinergic; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050987:Vesicle-Associated Membrane Protein 1; D013779:Tetrodotoxin; D000255:Adenosine Triphosphate; D019274:Botulinum Toxins, Type A