Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes.
OBJECTIVE
The chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes.


RESULTS
Single atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (I(Ks), I(Kr), in guinea pig, I(to), I(Kur), I(K1) in humans) were recorded at 36 degrees C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of I(Ks) with a half maximal concentration (EC(50)) of 6.8 nmol/l. 10 micromol/l HMR 1556 almost completely inhibited I(Ks) (97.2+/-3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. I(Kr) currents were not affected up to concentrations of 10 micromol/l. HMR 1556 did not inhibit other potassium currents in human atrium: I(to), I(Kur) and the classical inward rectifier potassium current I(K1) were not significantly affected up to concentrations that completely blocked I(Ks) (10 micromol/l).


CONCLUSIONS
HMR 1556 is a highly-potent blocker of I(Ks) channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of I(Ks) vs. I(Kr) blockade, the drug's new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.
Bosch
Ralph F
RF
Abteilung III, Medizinische Klinik, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. ralph.bosch@uni-tuebingen.de
Schneck
Alexander C
AC
Csillag
Saskia
S
Eigenberger
Bernd
B
Gerlach
Uwe
U
Brendel
Joachim
J
Lang
Hans J
HJ
Mewis
Christian
C
Gögelein
Heinz
H
Seipel
Ludger
L
Kühlkamp
Volker
V
D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology*
D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides