La supresión de los canales TASK reduce la sensibilidad a los anestésicos locales para inducir convulsiones
TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures.
Du G, Chen X, Todorovic MS, Shu S, Kapur J, Bayliss DA.
Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Anesthesiology. 2011 Nov;115(5):1003-11. doi: 10.1097/ALN.0b013e3182343660.
Abstract
BACKGROUND: Local anesthetics (LAs) are typically used for regional anesthesia but can be given systemically to mitigate postoperative pain, supplement general anesthesia, or prevent cardiac arrhythmias. However, systemic application or inadvertent intravenous injection can be associated with substantial toxicity, including seizure induction. The molecular basis for this toxic action remains unclear. METHODS: We characterized inhibition by different LAs of homomeric and heteromeric K channels containing TASK-1 (K2P3.1, KCNK3) and TASK-3 (K2P9.1, KCNK9) subunits in a mammalian expression system. In addition, we used TASK-1/TASK-3 knockout mice to test the possibility that TASK channels contribute to LA-evoked seizures. CONCLUSIONS: These data suggest that increased neuronal excitability associated with TASK channel inhibition by LAs contributes to seizure induction. Because all LAs were capable of evoking seizures in TASK channel deleted mice, albeit at higher doses, the results imply that other molecular targets must also be involved in this toxic action.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211141/pdf/nihms-328350.pdf
Los canales de sodio como Diana de los anestésicos locales
The sodium channel as a target for local anesthetic drugs.
Fozzard HA, Sheets MF, Hanck DA.
Cardiac Electrophysiology Laboratory, Department of Medicine, The University of Chicago Chicago, IL, USA.
Front Pharmacol. 2011;2:68. doi: 10.3389/fphar.2011.00068. Epub 2011 Nov 1.
Abstract
Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA), which have been used for local and regional anesthesia and for excitatory problems such as epilepsy and cardiac arrhythmia. These drugs are prototypes for new analgesic drugs. The drug-binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated) position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205381/pdf/fphar-02-00068.pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
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