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 neuromuscu lar blocking action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (M PTP) was studied in mouse phrenic nerve-diaphragm. MPTP blocked nerve- evoked twitches in a concentration (1-200 muM)-dependent manner. 4-Phe nylpyridine, but not pargyline or tranylcypromine potentiated this inh ibitory effect of MPTP. Pretreatment with 50 muM 4-phenylpyridine, red uced IC50 (concentration for 50% inhibition of twitch amplitude) value s of MPTP from 53 to 18 muM and d-tubocurarine from 0.7 to 0.3 muM, re spectively. 4-Phenylpyridine also enhanced the inhibitory action of MP TP and d-tubocurarine on acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm. The twitch inhibition induced by alph a-bungarotoxin and the specific binding of [I-125]alpha-bungarotoxin t o the mouse diaphragm were potentiated by 4-phenylpyridine but the inh ibitory action of MPTP and d-tubocurarine on [I-125]alpha-bungarotoxin binding were not significantly changed by pretreatment with 4-phenylp yridine. Electrophysiological studies revealed that the inhibitory act ions 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-phenylpyr idine enhanced the neuromuscular blocking action of the MPTP and d-tub ocurarine at the postsynaptic nicotinic acetylcholine receptors. The i mplication of this finding is that the possible application of 4-pheny lpyridine in the MPTP-induced Parkinson's disease is limited by its po tentiation on the neuromuscular blocking action of MPTP.