title: Lidocaine blocks the hyperpolarization-activated mixed cation current, I(h), in rat thalamocortical neurons.
abstract: BACKGROUND
  The mechanisms that underlie the supraspinal central nervous system effects of systemic lidocaine are poorly understood and not solely explained by Na(+) channel blockade. Among other potential targets is the hyperpolarization-activated cation current, I(h), which is blocked by lidocaine in peripheral neurons. I(h) is highly expressed in the thalamus, a brain area previously implicated in lidocaine's systemic effects. The authors tested the hypothesis that lidocaine blocks I(h) in rat thalamocortical neurons.
  
  
  METHODS
  The authors conducted whole cell voltage- and current-clamp recordings in ventrobasal thalamocortical neurons in rat brain slices in vitro. Drugs were bath-applied. Data were analyzed with Student t tests and ANOVA as appropriate; α = 0.05.
  
  
  RESULTS
  Lidocaine voltage-independently blocked I(h), with high efficacy and a half-maximal inhibitory concentration (IC(50)) of 72 μM. Lidocaine did not affect I(h) activation kinetics but delayed deactivation. The I(h) inhibition was accompanied by an increase in input resistance and membrane hyperpolarization (maximum, 8 mV). Lidocaine increased the latency of rebound low-threshold Ca(2+) spike bursts and reduced the number of action potentials in bursts. At depolarized potentials associated with the relay firing mode (>-60 mV), lidocaine at 600 μM concurrently inhibited a K(+) conductance, resulting in depolarization (7-10 mV) and an increase in excitability mediated by Na(+)-independent, high-threshold spikes.
  
  
  CONCLUSIONS
  Lidocaine concentration-dependently inhibited I(h) in thalamocortical neurons in vitro, with high efficacy and a potency similar to Na(+) channel blockade. This effect would reduce the neurons' ability to produce intrinsic burst firing and δ rhythms and thereby contribute to the alterations in oscillatory cerebral activity produced by systemic lidocaine in vivo.
authors.affiliation: Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Putrenko
authors.forename: Stephan K W
authors.initials: SK
authors.lastname: Schwarz
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002317:Cardiovascular Agents; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D002586:Cesium / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors*; D003627:Data Interpretation, Statistical; D055724:Electrophysiological Phenomena; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007395:Interneurons / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000166:cytology* / Q000187:drug effects
chemical_list: D000779:Anesthetics, Local; D002317:Cardiovascular Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788; D002586:Cesium; D008012:Lidocaine