Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Authors:
  • HHHugh C. Hemmings
    Hugh C. Hemmings
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Abstract
We characterized the effects of the volatile anesthetic isoflurane on the ion currents that contribute to the action potential (AP) in isolated rat neurohypophysial (NHP) nerve terminals using patch-clamp electrophysiology. Mean resting membrane potential and AP amplitude were -62.3 ± 4.1 and 69.2 ± 2.9 mV, respectively, in NHP terminals. Two components of outward K+ current (IK) were identified in voltage-clamp recordings: a transient IK and a sustained IK with minimal inactivation. Some terminals displayed a slowly activating IK, probably the big Ca2+-activated K+ current (BK). Isoflurane reversibly inhibited AP amplitude and increased AP half-width in normal extracellular Ca2+ (2.2 mM). In high extracellular Ca2+ (10 mM), isoflurane also reduced the afterhypolarization peak amplitude. A transient tetrodotoxin-sensitive Na+ current (INa) was the principal current mediating the depolarizing phase of the AP. A slowly inactivating Cd2+-sensitive current (probably a voltagegated Ca2+ current; ICa) followed the initial INa. Isoflurane reversibly inhibited both INa and ICa elicited by a voltage-stimulus based on an averaged AP waveform. The isoflurane IC50 for AP waveform-evoked INa was 0.36 mM. Isoflurane (0.84 ± 0.04 mM) inhibited AP waveform-evoked ICa by 37.5 ± 0.16% (p < 0.05). The isoflurane IC50 for peak IK was 0.83 mM and for sustained IK was 0.73 mM, with no effect on the voltage dependence of activation. The results indicate that multiple voltage-gated ion channels (Na+ > K+ > Ca2+) in NHP terminals, although not typical central nervous system terminals, are inhibited by the volatile general anesthetic isoflurane. The net inhibitory effects of volatile anesthetics on nerve terminal action potentials and excitability result from integrated actions on multiple voltage-gated currents.

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