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Physiological Laboratory, Cambridge.

1. The effects of 'clinical' concentrations of some general anaesthetics on the minimum stimulus required to produce an action potential in the squid giant axon have been examined as a function of time from exposure to the anaesthetic. The resting potential in these experiments was also monitored. 2. The minimum stimulus varied with time in different ways for different anaesthetics. For chloroform, diethyl ether, n-pentanol, halothane and cyclopropane the stimulus initially declined, reached a minimum after about 3 min and then recovered to near-normal values at 10-15 min. For n-pentane, cyclopentane and, to a lesser extent methoxyflurane, the stimulus often declined to such low values that the axon exhibited spontaneous action potentials which persisted until the anaesthetic was removed. For one substance, the experimental local anaesthetic diheptanoyl phosphatidylcholine, the stimulus increased considerably over the 10-15 min required to reach the steady state. In all instances the axons reverted to normal behaviour after removal of the anaesthetic although the time course by which they did so was more variable than for the initial exposure. 3. For all anaesthetics the resting potential changed in the positive direction monotonically by ca. 1-5 mV and reached a steady state in approximately 3 min. On removal of the anaesthetic the resting potential returned to normal, also monotonically. 4. The voltage-gated Na+ and K+ currents were significantly affected even at the low anaesthetic concentrations used. Estimates of the changes in the Hodgkin-Huxley parameters were obtained partly by direct experiment and partly from results previously obtained for higher anaesthetic concentrations. 5. The time dependencies of the minimum stimuli have been accounted for semi-quantitatively in terms of the resting potential changes and the voltage shifts in the Na+ current steady-state activation, and the time dependencies respectively of these two parameters. 6. Quantitative calculations of the resting potential changes for comparison with experiment have been made based on the changes in K+ conductance determined in the preceding paper (Haydon, Requena & Simon, 1988) and changes in the Hodgkin-Huxley parameters of the Na+ and delayed-rectifier K+ currents. 7. Calculations of the minimum stimulus in the steady state have been made from the experimental resting potential changes and from the anaesthetic-affected Hodgkin-Huxley parameters. Good agreement with the experimental stimuli was found, especially in the prediction of high and low values.

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