EFFECT OF DRUGS ON VOLTAGE-DEPENDENT IONIC CONDUCTANCE IN MEMBRANES

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The purpose of this project is to better understand how drugs affect the mechanisms of the ionic conductance in membranes which are voltage-dependent and excitable. Emphasis has recently focused on the effect of the reactive derivatives of molecular oxygen on the lobster neuromuscular junction. Oxygen and these derivatives have been implicated as causative agents in a wide number of physiological and pathological processes, such as the bactericidal action of granulocytes, aging, and ischemic reperfusion injury. We have found that 1 micromolar hydrogen peroxide inhibits reversibly the evoked excitatory junction potential (ejp). This effect is not on the glutamate post-synaptic receptor, since this peroxide inhibition is abolished when glutamate is exogeneously applied to the preparation. At concentrations above 0.1 millimolar hydrogen peroxide, the peroxide inhibition is only partially abolished in the presence of glutamate. Thus, at high concentrations, the post-synaptic receptor is inhibited. Pretreatment with thiourea, a free radical scavenger, provides some protection against the peroxide inhibition. This is evidence suggesting that at least part of the peroxide inhibition is mediated by the hydroxyl free radical. Part of the peroxide inhibition might also be due to hydroperoxide production and membrane lipid peroxidation. The effect of elevated partial pressures of oxygen on the squid giant synapse is also being investigated.