Comparative studies of ATP sensitive potassium channels in heart and pancreatic β cells using Vaughan-Williams class Ia antiarrhythmics

Objective: Actions of cibenzoline and disopyramide, agents with Vaughan-Williams class la antiarrhythmic action, on ATP sensitive K+ (KATP) channels were examined in heart and pancreatic β cells. Methods: Single ventricular myocytes and β cells were prepared enzymatically from adult Wistar rat hearts and pancreatic islets. Using patch clamp techniques, KATP channel activities were recorded in whole cell and single channel modes. In whole cell experiments, myocytes were bathed with Tyrode's medium (34°C); inside out patches were bathed with internal solutions (22-24°C) containing 1 (μM ATP and varying concentrations of cibenzoline or disopyramide. Myocytes were voltage clamped at -40 mV and glibenclamide blockable conductance was produced by cromakalim. Results: Micromolar concentrations of both cibenzoline and disopyramide suppressed cromakalim induced conductance. When applied to the cytosolic surface of the cell membrane in inside out configuration, both drugs reversibly inhibited single KATP channel activities. Neither unitary conductance nor intraburst fast kinetics was affected by the compounds. At a holding potential of -40 mV under symmetrical ∼ 150 mM K+ conditions, half maximum doses (IC50) were 0.9 μM [Hill coefficient (h)=1.3] for cibenzoline induced block of cardiac KATP channels and 1.8 μM (h=1.0) for disopyramide block. At +40 mV, IC50 for cibenzoline block was 1.4 μM (h=0.9). Thus there was little voltage dependence in cibenzoline induced channel block. A similar IC50 value of 2.5 μM (h=1.2 at -60 mV under symmetrical ∼ 150 mM K+) was observed for cibenzoline induced block of KATP channels. Conclusions: Near therapeutic concentrations of cibenzoline and disopyramide inhibit KATP channel activities in both heart and pancreatic β cells. This may be causally related to the fasting hypoglycaemia which is sometimes reported in patients receiving the drugs. These antiarrhythmic agents may also modulate myocardial electrical properties during hypoxia or ischaemia. Cardiovascular Research 1992;26:1087-1094