Depression by isoflurane of the action potential and underlying voltage-gated ion currents in isolated rat neurohypophysial nerve terminals.
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 Ca(2+)-activated K(+) current (BK). Isoflurane reversibly inhibited AP amplitude and increased AP half-width in normal extracellular Ca(2+) (2.2 mM). In high extracellular Ca(2+) (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 Cd(2+)-sensitive current (probably a voltagegated Ca(2+) 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 IC(50) 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 IC(50) 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(+) > Ca(2+)) 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.
Ouyang
Wei
W
Department of Anesthesiology, Weill Medical College of Cornell University, Box 50, LC-203, 525 E. 68th St., New York, NY 10021, USA.
Hemmings
Hugh C
HC
D000200:Action Potentials / Q000187:drug effects*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003864:Depression, Chemical; D004594:Electrophysiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010904:Pituitary Gland, Posterior / Q000503:physiopathology*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D000779:Anesthetics, Local; D018377:Neurotransmitter Agents; D015221:Potassium Channels; D013779:Tetrodotoxin; D007530:Isoflurane; D002118:Calcium