Antagonism of botulinum toxin-induced muscle weakness by 3,4-diaminopyridine in rat phrenic nerve-hemidiaphragm preparations.
The effects of the potassium channel inhibitor and putative botulinum toxin antagonist 3,4-diaminopyridine (3,4-DAP) were investigated in vitro on the contractile properties of rat diaphragm muscle. In the presence of 100 pM botulinum neurotoxin A (BoNT/A), twitches elicited by supramaximal nerve stimulation (0.1 Hz) were reduced to approximately 10% of control in 3 hr at 37 degrees C. Addition of 3,4-DAP led to a rapid reversal of the BoNT/A-induced depression of twitch tension. In the presence of 100 microM 3,4-DAP, antagonism of the BoNT/A-induced blockade began within 30-40 sec and reached 82% of control with a half-time of 6.7 min. The beneficial effect of 3,4-DAP was well maintained and underwent little or no decrement relative to control for at least 8 hr after addition. Application of 1 microM neostigmine 1 hr after 3,4-DAP led to a further potentiation of twitch tension, but this action lasted for < 20 min. Moreover, neostigmine caused tetanic fade during repetitive stimulation. In contrast to the efficacy of the parent compound, the quaternary derivative of 3,4-DAP, 3,4-diamino-1-methyl pyridinium produced little or no twitch potentiation up to a concentration of 1 mM. The potassium channel blocker, tetraethylammonium, generated a transient potentiation followed by a sustained depression of twitch tensions. It is concluded that 3,4-DAP is of benefit in antagonizing the muscle paralysis following exposure to BoNT/A. Co-application of neostigmine or tetraethylammonium with 3,4-DAP, however, appears to confer no additional benefit.
Adler
M
M
Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Scovill
J
J
Parker
G
G
Lebeda
F J
FJ
Piotrowski
J
J
Deshpande
S S
SS
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001905:Botulinum Toxins / Q000032:analysis* / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009388:Neostigmine / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012133:Respiratory Paralysis / Q000139:chemically induced* / Q000503:physiopathology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
C095862:3,4-diamino-1-methylpyridinium; D000631:Aminopyridines; D002121:Calcium Channel Blockers; D011726:Pyridinium Compounds; D013757:Tetraethylammonium Compounds; D009388:Neostigmine; C038615:2,3-diaminopyridine; D001905:Botulinum Toxins