Potentiation of MPTP by 4-phenylpyridine on the neuromuscular blockade in mouse phrenic nerve-diaphragm.
Potentiation by 4-phenylpyridine (a MAO-B inhibitor) on the neuromuscular blocking action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in mouse phrenic nerve-diaphragm. MPTP blocked nerve-evoked twitches in a concentration (1-200 microM)-dependent manner. 4-Phenylpyridine, but not pargyline or tranylcypromine potentiated this inhibitory effect of MPTP. Pretreatment with 50 microM 4-phenylpyridine, reduced IC50 (concentration for 50% inhibition of twitch amplitude) values of MPTP from 53 to 18 microM and d-tubocurarine from 0.7 to 0.3 microM, respectively. 4-Phenylpyridine also enhanced the inhibitory action of MPTP and d-tubocurarine on acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm. The twitch inhibition induced by alpha-bungarotoxin and the specific binding of [125I]alpha-bungarotoxin to the mouse diaphragm were potentiated by 4-phenylpyridine but the inhibitory action of MPTP and d-tubocurarine on [125I]alpha-bungarotoxin binding were not significantly changed by pretreatment with 4-phenylpyridine. Electrophysiological studies revealed that the inhibitory actions of MPTP and d-tubocurarine on the amplitudes of m.e.p.ps and e.p.ps were augmented by 4-phenylpyridine. These indicate that 4-phenylpyridine enhanced the neuromuscular blocking action of the MPTP and d-tubocurarine at the postsynaptic nicotinic acetylcholine receptors. The implication of this finding is that the possible application of 4-phenylpyridine in the MPTP-induced Parkinson's disease is limited by its potentiation on the neuromuscular blocking action of MPTP.
Hsu
K S
KS
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, R.O.C.
Lin-Shiau
S Y
SY
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D004357:Drug Synergism; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D008839:Microelectrodes; D009045:Motor Endplate / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects; D010791:Phrenic Nerve / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects; D012132:Respiratory Muscles / Q000187:drug effects / Q000294:innervation*; D014403:Tubocurarine / Q000494:pharmacology
D002038:Bungarotoxins; D015259:Dopamine Agents; D009466:Neuromuscular Blocking Agents; D011725:Pyridines; D011978:Receptors, Nicotinic; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C051448:4-phenylpyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000109:Acetylcholine; D014403:Tubocurarine