ORIGIN OF TETANIC FADE IN ANESTHESIA

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DESCRIPTION: (Adapted from the applicant's abstract) Nondepolarizing blockers are used during surgical anesthesia in order to produce muscle relaxation. However, it is still uncertain whether they act on postsynaptic or presynaptic receptors to produce their characteristic tetanic fade after repetitive nerve stimulation. Fade could be caused by a use dependent failure of postsynaptic receptors or by a decrease in the release of acetylcholine from the presynaptic terminal. These studies are designed to find out the exact combinations of presynaptic and postsynaptic processes in the development of tetanic fade. Both d- tubocurarine and the alpha toxins from snake venom are competitive antagonists at the nicotinic acetylcholine receptor. It is well established that d-tubocurarine causes run down in the amplitude of endplate currents during repetitive nerve stimulation, but paradoxically there are many reports which indicate that the alpha toxins do not cause such fade. These findings have suggested to some that d-tubocurarine causes fade by blocking a presynaptic acetylcholine receptor which normally controls the release of acetylcholine. This theory is supported by the finding that alpha toxins do not cause fade and by autoradiographic studies which show that alpha bungarotoxin does not bind to the presynaptic terminal. However, other studies have indicated that alpha toxins cause dramatic fade just like d-tubocurarine. The applicants' explanation of the contradictory results for the effects of alpha toxins is that low concentrations of toxin cause fade but high concentrations do not cause fade. Because some investigators have consistently used high concentrations of toxin in their experiments, they have wrongly assumed that alpha toxins do not cause fade. High concentrations of toxin could have an additional effect which may suppress the appearance of fade. The applicants propose to test this hypothesis and to exactly determine the degree of fade produced by different concentrations of known alpha toxins in comparison to d-tubocurarine.