MECHANISM OF NEUROMUSCULAR BLOCKADE INDUCED BY PHENTHONIUM, A QUATERNARY DERIVATIVE OF (-)-HYOSCYAMINE, IN SKELETAL-MUSCLES

1 The mechanisms underlying the postjunctional blockade induced by phe nthonium [N-(4-phenyl) phenacyl 1-hyoscyamine] were investigated in ma mmalian and amphibian muscles. This muscarinic antagonist was previous ly shown to enhance specifically the spontaneous acetylcholine (ACh) r elease at concentrations that blocked neuromuscular transmission. 2 In both rat diaphragm and frog sartorius muscles, phenthonium (Phen, 1-1 00 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 a fter incubation with neostigmine. 3 Equal concentrations of Phen decre ased 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 Phe n (50 and 100 mu M) protected the ACh receptor against alpha-bungaroto xin (BUTX) blockade in the mouse diaphragm allowing recording of endpl ate potentials and action potentials after 5 h wash with physiological salt solution. 5 Phen (10-100 mu M) produced a concentration- and vol tage-dependent decrease of the endplate current (e.p.c.), and induced nonlinearity of the current-voltage relationship. At high concentratio ns 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 concentrat ions, Phen also reduced the initial rate of [I-125]-BUTX binding to ju nctional ACh receptors of the rat diaphragm (apparent dissociation con stant = 24 mu M), the relationship between the degree of inhibition an d antagonist concentration being that expected for a competitive mecha nism. 7 It is concluded that Phen affects the electrical excitability of the muscle fibre membrane, and blocks neuromuscular transmission th rough a mechanism that affects the agonist binding to its recognition site and ionic channel conductance of the nicotinic ACh receptor.