Inhibition of K+ channels by chlorpromazine in rat ventricular myocytes

Isolated rat ventricular myocytes were investigated with the whole-cell patch-clamp technique. Chlorpromazine inhibited inward-rectifying K+ currents (IC50 = 6.1 microM), time-independent outward currents (IC50 = 16 microM) and transient outward K+ currents. In the latter case, 100 microM of chlorpromazine reduced the amplitude of the peak current recorded at a clamp potential of 50 mV from 2.14 +/- 0.59 nA to 1.38 +/- 0.20 nA (n = 4) and decreased the time course of fast inactivation from 8.29 +/- 1.17 msec to 4.01 +/- 0.90 msec (n = 4). In addition, chlorpromazine blocked the ATP-dependent K+ current, which was activated either by the channel opener rilmakalim (10 microM) or by metabolic inhibition with carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP, 500 nM; IC50 for rilmakalim = 2.5 microM; IC50 for FCCP = 11.5 microM). The drug caused marked depolarization of the resting potential at higher concentrations (50 microM) from -79 +/- 3 mV to -27 +/- 11 mV (n = 4). The reversibility from channel block was slow and only partial for time-independent currents, especially inward-rectifying K+ currents, but it was relatively fast and complete for time-independent currents. Thus chlorpromazine blocks a variety of K+ channels in heart muscle cells. Inasmuch as the potency of inhibition is less than the previously reported use-dependent block of Na+ channels, the cardiovascular adverse effects of chlorpromazine are probably caused mainly by the latter effect.