Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Systemic administration of local anesthetics has beneficial perioperative properties and an anesthetic-sparing and antiarrhythmic effect, although the detailed mechanisms of these actions remain unclear. In the present study, we investigated the effects of a local anesthetic, lidocaine, on hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that contribute to the pacemaker currents in rhythmically oscillating cells of the heart and brain. Voltage-clamp recordings were used to examine the properties of cloned HCN subunit currents expressed in Xenopus laevis oocytes and human embryonic kidney (HEK) 293 cells under control condition and lidocaine administration. Lidocaine inhibited HCN1, HCN2, HCN1-HCN2, and HCN4 channel currents at 100 μM in both oocytes and/or HEK 293 cells; it caused a decrease in both tonic and maximal current (∼30-50% inhibition) and slowed current activation kinetics for all subunits. In addition, lidocaine evoked a hyperpolarizing shift in half-activation voltage (ΔV(1/2) of ∼-10 to -14 mV), but only for HCN1 and HCN1-HCN2 channels. By fitting concentration-response data to logistic functions, we estimated half-maximal (EC(50)) concentrations of lidocaine of ∼30 to 40 μM for the shift in V(1/2) observed with HCN1 and HCN1-HCN2; for inhibition of current amplitude, calculated EC(50) values were ∼50 to 70 μM for HCN1, HCN2, and HCN1-HCN2 channels. A lidocaine metabolite, monoethylglycinexylidide (100 μM), had similar inhibitory actions on HCN channels. These results indicate that lidocaine potently inhibits HCN channel subunits in dose-dependent manner over a concentration range relevant for systemic application. The ability of local anesthetics to modulate I(h) in central neurons may contribute to central nervous system depression, whereas effects on I(f) in cardiac pacemaker cells may contribute to the antiarrhythmic and/or cardiovascular toxic action.
Biel,
Hyperpolarization-activated cation channels: a multi-gene family.
1999, Pubmed
Biel,
Hyperpolarization-activated cation channels: a multi-gene family.
1999,
Pubmed
Biel,
Hyperpolarization-activated cation channels: from genes to function.
2009,
Pubmed
Brown,
Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes.
1995,
Pubmed
Cerbai,
Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart.
1997,
Pubmed
Chaplan,
Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.
2003,
Pubmed
Chen,
HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents.
2005,
Pubmed
Chen,
HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine.
2009,
Pubmed
Chen,
Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.
2005,
Pubmed
,
Xenbase
DiFazio,
The anesthetic potency of lidocaine in the rat.
1976,
Pubmed
DiFrancesco,
A study of the ionic nature of the pace-maker current in calf Purkinje fibres.
1981,
Pubmed
Edvardsson,
Clinical value of plasma concentrations of antiarrhythmic drugs.
1987,
Pubmed
Estes,
Therapeutic serum lidocaine and metabolite concentrations in patients undergoing electrophysiologic study after discontinuation of intravenous lidocaine infusion.
1989,
Pubmed
Gaughen,
The effect of too much intravenous lidocaine on bispectral index.
2006,
Pubmed
Halkin,
Influence of congestive heart failure on blood vessels of lidocaine and its active monodeethylated metabolite.
1975,
Pubmed
Heavner,
Cardiac toxicity of local anesthetics in the intact isolated heart model: a review.
2002,
Pubmed
Himes,
Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane.
1977,
Pubmed
Hoppe,
Characterization of the hyperpolarization-activated inward current in isolated human atrial myocytes.
1998,
Pubmed
Hoppe,
Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts.
,
Pubmed
Irisawa,
Cardiac pacemaking in the sinoatrial node.
1993,
Pubmed
Kingery,
A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes.
1997,
Pubmed
Koppert,
Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery.
2004,
Pubmed
Ludwig,
Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.
2003,
Pubmed
Macri,
Structural elements of instantaneous and slow gating in hyperpolarization-activated cyclic nucleotide-gated channels.
2004,
Pubmed
Marcil,
Antinociceptive effects of tetrodotoxin (TTX) in rodents.
2006,
Pubmed
McCormick,
Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones.
1990,
Pubmed
Moosmang,
Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues.
2001,
Pubmed
Narahashi,
Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes.
1972,
Pubmed
Pinter,
Intravenous antiarrhythmic agents.
2001,
Pubmed
Proenza,
Pacemaker channels produce an instantaneous current.
2002,
Pubmed
Ragsdale,
Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
1994,
Pubmed
,
Xenbase
Santoro,
Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS.
2000,
Pubmed
,
Xenbase
Satoh,
Effect of lidocaine on membrane currents in rabbit sino-atrial node cells.
1984,
Pubmed
Senturk,
Effects of intramuscular administration of lidocaine or bupivacaine on induction and maintenance doses of propofol evaluated by bispectral index.
2002,
Pubmed
Smith,
Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study.
2004,
Pubmed
Spain,
Post-inhibitory excitation and inhibition in layer V pyramidal neurones from cat sensorimotor cortex.
1991,
Pubmed
Tamura,
Effects of antiarrhythmic drugs on the hyperpolarization-activated cyclic nucleotide-gated channel current.
2009,
Pubmed
Trujillo,
Antiarrhythmic agents: drug interactions of clinical significance.
2000,
Pubmed
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wang,
Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans.
2000,
Pubmed
