ION EXCHANGE PROCESSES AT THE NEUROMUSCULAR JUNCTION OF VOLUNTARY MUSCLE

¹ Department of Pharmacology and Brain Research Institute, UCLA School of Medicine, Los Angeles, California

Evidence is presented that quaternary ammonium neuromuscular blocking agents interact with the receptors at the neuromuscular junction by ion exchange. This implies that these blocking agents unite with or leave their receptors by stoichiometric exchange with an ion or ions of the same charge and that the electrovalencies and concentrations of both exchanging ions must enter into any quantitative treatment of the processes involved. In these respects the ion exchange method differs from classical receptor theory. The agreement between the ion exchange equations and the experimental data was tested in a number of ways. Extrapolation to zero concentration of competing quaternary ammonium ion indicated that quaternary ions bound to the receptors were only free to leave it when ions of similar charge were present for exchange. The data obtained with both d-tubocurarine and gallamine gave linear plots with the appropriate equations and provided usable equilibrium (selectivity) constants; 1.913 for the d-tubocurarine-C10 exchange and 0.084 for the gallamine-ClO exchange. An estimate of the ratio of the electrovalency of do to that of d-tubocurarine gave a value of 0.91 and of C10 to that of gallamine, a value of 0.67. Finally, the selectivity constants were used to estimate receptor occupancy in a series of depolarization experiments, and it was shown that the receptor occupancy required to produce a given antagonism was the same for d-tubocurarine and gallamine over a wide range of block in spite of the differences in potency and electrovalency of these agents. The ion exchange equations and the experimental results are consistent with the idea that the receptors for C10 uptake and depolarization and for d-tubocurarine and gallamine are the same. Moreover, the receptor has carrier-like properties.