In vitro modulation of HERG channels by organochlorine solvent trichlormethane as potential explanation for proarrhythmic effects of chloroform.
Acute chloroform intoxication can cause depression of the central nervous system and may lead to death from lethal arrhythmias or respiratory arrest. Thus, the organic solvent is no longer in clinical use as an anaesthetic, but still plays a role in cases of suicide, homicide or inhalation for psychotropic effects. Several cases of lethal arrhythmia after intoxication with chloroform have been described. Pharmacological inhibition of cardiac "human ether-à-go-go-related gene" (HERG) potassium channels is linked to proarrhythmic effects of cardiac and noncardiac drugs. To further investigate the electrophysiological basis of the arrhythmogenic potential of chloroform, we analysed inhibitory effects of chloroform on cloned HERG potassium channels, heterologously expressed in Xenopus oocytes and in Human Embryonic Kidney (HEK 293) cells using the double-electrode voltage-clamp technique and the whole-cell patch-clamp technique, respectively. In HEK cells, chloroform blocked HERG tail currents with an IC(50) of 4.97mM. Biophysical properties were further investigated in the Xenopus oocyte expression system. Onset and wash-out of block was fast and inhibition was completely reversible. Chloroform did not alter channel activation, however, direct channel inactivation was accelerated significantly. Steady-state-inactivation of HERG was not affected. Chloroform dependent block of HERG channels was voltage dependent with a decrease of inhibition at more positive membrane potentials. No frequency-dependence of block could be observed. In summary, chloroform blocked HERG potassium channels probably in a toxicologically relevant concentration. These findings contribute to the pathophysiology of proarrhythmic effects in acute chloroform intoxication.
Scholz
Eberhard P
EP
3rd Department of Internal Medicine (Cardiology), Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Alter
Markus
M
Zitron
Edgar
E
Kiesecker
Claudia
C
Kathöfer
Sven
S
Thomas
Dierk
D
Kreye
Volker A W
VA
Kreuzer
Jörg
J
Becker
Rüdiger
R
Katus
Hugo A
HA
Greten
Johannes
J
Karle
Christoph A
CA
D000818:Animals; D002460:Cell Line; D002725:Chloroform / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000196:embryology; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D012997:Solvents / Q000633:toxicity*; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000378:metabolism; D014982:Xenopus laevis
D051638:Ether-A-Go-Go Potassium Channels; D012997:Solvents; D002725:Chloroform