Mechanism of neuromuscular blockade induced by phenthonium, a quaternary derivative of (-)-hyoscyamine, in skeletal muscles

Mechanism of neuromuscular blockade induced by phenthonium, a quaternary derivative of (-)-hyoscyamine, in skeletal muscles

Author Souccar, Caden Autor UNIFESP Google Scholar
Lima-Landman, MTR Google Scholar
Ballejo, G. Google Scholar
Lapa, Antonio José Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Abstract 1 the mechanisms underlying the postjunctional blockade induced by phenthonium [N-(4-phenyl) phenacyl 1-hyoscyamine] were investigated in mammalian and amphibian muscles. This muscarinic antagonist was previously shown to enhance specifically the spontaneous acetylcholine (ACh) release at concentrations that blocked neuromuscular transmission.2 in both rat diaphragm and frog sartorius muscles, phenthonium (Phen, 1-100 mu M) depressed the muscle twitches elicited by nerve stimulation (IC50: 23 mu M and 5 mu M, respectively), and blocked the nerve-evoked muscle action potential. the neuromuscular blockade was not reversed after incubation with neostigmine.3 Equal concentrations of Phen decreased the rate of rise and prolonged the falling phase of the directly elicited action potential in frog sartorius muscle fibres, indicating that the drug also affects the sodium and potassium conductance.4 Phen (50 and 100 mu M) protected the ACh receptor against alpha-bungarotoxin (BUTX) blockade in the mouse diaphragm allowing recording of endplate potentials and action potentials after 5 h wash with physiological salt solution.5 Phen (10-100 mu M) produced a concentration- and voltage-dependent decrease of the endplate current (e.p.c.), and induced nonlinearity of the current-voltage relationship. At high concentrations Phen also shortened the decay time constant of e.p.c (tau(e.p.c.)) and reduced its voltage sensitivity.6 At the same range of concentrations, Phen also reduced the initial rate of [I-125]-BUTX binding to junctional ACh receptors of the rat diaphragm (apparent dissociation constant = 24 mu M), the relationship between the degree of inhibition and antagonist concentration being that expected for a competitive mechanism.7 It is concluded that Phen affects the electrical excitability of the muscle fibre membrane, and blocks neuromuscular transmission through a mechanism that affects the agonist binding to its recognition site and ionic channel conductance of the nicotinic ACh receptor.
Keywords nicotinic receptor
noncompetitive blocker
ionic channel
endplate current
muscarinic antagonist
Language English
Date 1998-07-01
Published in British Journal of Pharmacology. Basingstoke: Stockton Press, v. 124, n. 6, p. 1270-1276, 1998.
ISSN 0007-1188 (Sherpa/Romeo, impact factor)
Publisher Stockton Press
Extent 1270-1276
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000074965000034

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