Effect of Dofetilide and d-Sotalol on the ATP-Sensitive Potassium Channel of Rabbit Ventricular Myocytes.
BACKGROUND: The ability of dofetilide and d-sotalol to maintain their class III action during ischemia is uncertain. We investigated the effect of these two drugs on the ATP-sensitive potassium channel (I(KATP)), which plays a major role in ischemia-induced action potential duration shortening. METHODS AND RESULTS: The activity of I(KATP) channels was studied in excised membrane patches of single ventricular myocytes, obtained by standard enzymatic dissociation techniques from New Zealand white rabbits. Dofetilide demonstrated a dose-dependent block of I(KATP) with an EC(50) of 51 +/- 1 µM in inside-out patches, Its ability to block the channel was substantially less when applied to the external membrane surface. d-Sotalol significantly blocked I(KATP) (42% reduction) at a concentration of 10 µM but not at 1 µM. As with dofetilide, its ability to block I(KATP) was reduced when applied externally. CONCLUSIONS: We conclude that dofetilide and d-sotalol block the ATP-sensitive potassium channel, but dofetilide does so only at concentrations much greater than those required for block of the delayed rectifier potassium channel. d-Sotalol in contrast shows modest blockade of I(KATP) at concentrations in the upper range of those seen during its clinical use.
West
PD
Departments of Cardiology, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
Bursill
JA
Wyse
KR
Martin
DK
Campbell
TJ