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NEUROPHARMACOLOGY

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

Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York

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 (I_K) were identified in voltage-clamp recordings: a transient I_K and a sustained I_K with minimal inactivation. Some terminals displayed a slowly activating I_K, 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 (I_Na) was the principal current mediating the depolarizing phase of the AP. A slowly inactivating Cd²⁺-sensitive current (probably a voltagegated Ca²⁺ current; I_Ca) followed the initial I_Na. Isoflurane reversibly inhibited both I_Na and I_Ca elicited by a voltage-stimulus based on an averaged AP waveform. The isoflurane IC₅₀ for AP waveform-evoked I_Na was 0.36 mM. Isoflurane (0.84 ± 0.04 mM) inhibited AP waveform-evoked I_Ca by 37.5 ± 0.16% (p < 0.05). The isoflurane IC₅₀ for peak I_K was 0.83 mM and for sustained I_K 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.

Address correspondence to: Dr. Hugh C. Hemmings, Jr., Department of Anesthesiology, Weill Medical College of Cornell University, Box 50, LC-203, 525 E. 68th St., New York, NY 10021. E-mail: hchemmi{at}med.cornell.edu

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