Halothane depresses action potential conduction in hippocampal axons

Mikulec, Anthony A.; Pittson, Sky; Amagasu, Shanti; Monroe, Frances A.; MacIver, M Bruce

doi:10.1016/s0006-8993(98)00348-5

Cited by 43 publications

(27 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Net inhibitory effects on nerve terminal excitability result from integration of these actions on multiple inward and outward currents, with I Na being most sensitive to isoflurane. These findings add to a growing body of evidence implicating depression of presynaptic action potential and transmitter release in the actions of volatile anesthetics (MacIver et al, 1996, Mikulec et al, 1998Perouansky and Hemmings, 2003).…”

Section: Isoflurane Depresses Nerve Terminal Action Potentials 805supporting

confidence: 56%

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

Ouyang

Hemmings

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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 Ϫ62.3 Ϯ 4.1 and 69.2 Ϯ 2.9 mV, respectively, in NHP terminals. Two components of outward K ϩ 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 2ϩ -activated K ϩ current (BK). Isoflurane reversibly inhibited AP amplitude and increased AP half-width in normal extracellular Ca 2ϩ (2.2 mM). In high extracellular Ca 2ϩ (10 mM), isoflurane also reduced the afterhypolarization peak amplitude. A transient tetrodotoxin-sensitive Na ϩ current (I Na ) was the principal current mediating the depolarizing phase of the AP. A slowly inactivating Cd 2ϩ -sensitive current (probably a voltagegated Ca 2ϩ 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 Ϯ 0.04 mM) inhibited AP waveform-evoked I Ca by 37.5 Ϯ 0.16% (p Ͻ 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 ϩ Ͼ K ϩ Ͼ Ca 2ϩ ) 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.

show abstract

Section: Isoflurane Depresses Nerve Terminal Action Potentials 805supporting

confidence: 56%

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

Ouyang

Hemmings

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…For young rats, the MAC value is slightly increased, and around 1.9% in juvenile rats [42]. This corresponds to a halothane concentration of about 0.7 mM in ACSF at 22°C [30]. Therefore, the halothane concentration used in most of our experiments (nominal 0.1%, which relates to 1.2 mM in the recording chamber) is about 1.8 times higher and, thus, not necessarily in the clinical range.…”

Section: Concentration Of Halothane In the Recording Chambermentioning

confidence: 73%

Reciprocal modulation of I h and I TASK in thalamocortical relay neurons by halothane

Budde

Coulon

Pawlowski

et al. 2008

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

By combining electrophysiological, immunohistochemical, and computer modeling techniques, we examined the effects of halothane on the standing outward current (I (SO)) and the hyperpolarization-activated current (I (h)) in rat thalamocortical relay (TC) neurons of the dorsal lateral geniculate nucleus (dLGN). Hyperpolarizing voltage steps elicited an instantaneous current component (I (i)) followed by a slower time-dependent current that represented I (h). Halothane reduced I (h) by shifting the voltage dependency of activation toward more negative potentials and by reducing the maximal conductance. Moreover, halothane augmented I (i) and I (SO). During the blockade of I (h) through Cs+, the current-voltage relationship of the halothane-sensitive current closely resembled the properties of a current through members of the TWIK-related acid-sensitive K+ (TASK) channel family (I (TASK)). Computer simulations in a single-compartment TC neuron model demonstrated that the modulation of I (h) and I (TASK) is sufficient to explain the halothane-induced hyperpolarization of the membrane potential observed in current clamp recordings. Immunohistochemical staining revealed protein expression of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel proteins HCN1, HCN2, and HCN4. Together with the dual effect of halothane on I (h) properties, these results suggest that I (h) in TC neurons critically depends on HCN1/HCN2 heterodimers. It is concluded that the reciprocal modulation of I (h) and I (TASK) is an important mechanism of halothane action in the thalamus.

show abstract

“…The available data cannot distinguish between anesthetic blockade of axonal Na ϩ channels that support axonal action potential conduction (Mikulec et al, 1998) from blockade of Na ϩ channels in the presynaptic bouton that are required for sufficient nerve terminal depolarization to activate the voltage-gated Ca 2ϩ channels coupled to exocytosis (Nicholls, 1993). Evidence from isolated nerve terminals (Schlame and Hemmings, 1995;Ouyang et al, 2003) and the calyx of Held (Wu et al, 2004) suggest that inhibition of Na ϩ channels in the presynaptic bouton is sufficient to inhibit transmitter release, although a contribution from depression of axonal action potential conduction may also be involved (Mikulec et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence from isolated nerve terminals (Schlame and Hemmings, 1995;Ouyang et al, 2003) and the calyx of Held (Wu et al, 2004) suggest that inhibition of Na ϩ channels in the presynaptic bouton is sufficient to inhibit transmitter release, although a contribution from depression of axonal action potential conduction may also be involved (Mikulec et al, 1998). The specific neuronal Na ϩ channel isoform(s) affected by isoflurane in cultured hippocampal neurons is not known.…”

Section: Discussionmentioning

confidence: 99%

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Hemmings¹,

Yan²,

Westphalen³

et al. 2005

Mol Pharmacol

View full text Add to dashboard Cite

General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potentialevoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na ϩ channel blocker tetrodotoxin, was relatively insensitive to isoflurane.Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA A receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca 2ϩ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca 2ϩ entry and exocytosis, possibly as a result of Na ϩ channel blockade and/or K ϩ channel activation, with the possibility of lesser contributions from Ca 2ϩ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.

show abstract

Halothane depresses action potential conduction in hippocampal axons

Cited by 43 publications

References 32 publications

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

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

Reciprocal modulation of I h and I TASK in thalamocortical relay neurons by halothane

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Contact Info

Product

Resources

About