Local anaesthetics block hyperpolarization-activated inward current in rat small dorsal root ganglion neurones.
(1) Hyperpolarizing voltage steps evoke slowly activating inward currents in a variety of neurones and in cardiac cells. This hyperpolarization-activated inward current (I(h)) is thought to play a significant role in cell excitability, firing frequency, or in setting of the resting membrane potential in these cells. We studied the effects of lidocaine, mepivacaine, QX-314 and bupivacaine as well as its enantiomers on I(h) in the membrane of dorsal root ganglion neurones (DRG). (2) The patch-clamp technique was applied to small dorsal root ganglion neurones identified in 200 micro M thin slices of young rat DRGs. Under voltage-clamp conditions, the whole-cell I(h) current was recorded in the presence of different concentrations of the local anaesthetics. In current-clamp mode the resting membrane potential and the voltage response of DRG neurones to injected current pulses were investigated. (3) I(h) was reversibly blocked by bupivacaine, lidocaine and mepivacaine applied externally in clinically relevant concentrations. Concentration-response curves gave half-maximum inhibiting concentrations of 55, 99 and 190 micro M, respectively. Bupivacaine block of the I(h) current was not stereoselective. No significant effect was observed when QX-314 was applied to the external surface of the membrane. (4) In current-clamp experiments 60 micro M bupivacaine slightly hyperpolarized the membrane. The membrane stimulation by low-amplitude current pulses in the presence of bupivacaine showed an increase of the hyperpolarizing responses. (5) Our findings suggest an important role of the I(h)-block by local anaesthetics in the complex mechanism of drug action during epidural and spinal anaesthesia.
Bischoff
Ulrike
U
Department of Physiology, Justus-Liebig-University, 35392 Giessen, Germany.
Bräu
Michael E
ME
Vogel
Werner
W
Hempelmann
Gunter
G
Olschewski
Andrea
A
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000502:physiology; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008619:Mepivacaine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D015221:Potassium Channels; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D019789:Tetraethylammonium; D013997:Time Factors
D000779:Anesthetics, Local; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788; C012647:QX-314; D019789:Tetraethylammonium; D008012:Lidocaine; D008619:Mepivacaine; D002045:Bupivacaine