Effects of halothane and enflurane on firing threshold of frog myelinated axons.

1. Firing thresholds and conduction latencies of single myelinated axons in frog sciatic nerves were monitored during impulse activity in vitro. Resting threshold and the activity dependence of threshold were studied as a function of the concentration of two inhalational anaesthetic agents, halothane and enflurane. 2. At concentrations comparable to those obtained during general anaesthesia both agents produced biphasic effects on the resting threshold. A step increase in the partial pressure of anaesthetic was followed first by a transient lowering of threshold, then by a slow rise to a steady-state level above the original baseline. Step decreases in anaesthetic were followed by transient rises before threshold dropped. Transients lasted 20-30 min. During these threshold transients, the average latency of impulse conduction changed monotonically. The prolongation of latency following an increase in anaesthetic was progressive, reaching steady state concurrently with threshold (20 min to greater than 1 h). 3. The anaesthetics reduced the long-lasting increased threshold ('depression') which normally follows repetitive impulse activity in axon membrane. 4. These actions of halothane at concentrations of 0.25-2.7% (0.14-1.54 mM) and enflurane at concentrations of 0.62-3.08% (0.35-1.73 mM) on resting threshold and on the activity-dependent increase in threshold increased monotonically with anaesthetic concentration. 5. The effects on excitability at steady state are consistent with block of voltage-dependent Na+ and K+ channels by these inhalational agents. Reduced depression may occur because the anaesthetics reduce the net ion transfer per impulse, slowing the substrate-driven Na+-K+-ATPase and thereby reducing electrogenic hyper-polarization. 6. The finding that general anaesthetics inhibit depression at clinically relevant concentrations supports the possibility that general anaesthesia is produced by inhibition of processes that modulate excitability of nerve membrane. We suggest that general anaesthetics produce unconsciousness and amnesia because they disrupt activity-dependent processes, which may thus remove temporal 'context' essential for interpreting nerve impulse patterns.