Interaction among Agents that Block End-plate Depolarization Competitively

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Abstract
The influence of gallamine, metocurine, pancuronium and tubocurarine on depolarization of a mammalian muscle end-plate region was examined to determine whether the antagonists given in combination exerted a degree of block consistent with the simple classical competitive model. Depolarization was produced by carbachol in isolated guinea pig lumbrical muscles and recorded by the moving fluid electrode technique. The dose-response values obtained were fitted to a regression embedded in a split plot factorial experimental design such as to control and measure effects of variation among preparations, order of administration, time and level of block. Of the 6 possible pairings of the 4 drugs, 4 showed the simple additivity expected from a competitive mechanism, while 2 (pancuronium plus metocurine and metocurine plus gallamine) showed potentiation beyond additivity. In these latter 2 pairs the combination shifted the carbachol dose-response curve, respectively, 41 and 21% further than predicted from the classical model. The significance of this deviation in the light of alternative receptor models is discussed, and a model consistent with the observed results is outlined.