Propafenone, a class 1c antiarrhythmic agent, is known to be a potent blocker of voltage-dependent sodium channels; however, several clinical actions of the drug point toward possible potassium channel blocking capability. The present experiments were designed to assess the extent and potential mechanisms of potassium channel blocking properties of propafenone. Whole-cell voltage-clamp techniques were used to define the actions of propafenone on the transient outward current (Ito), the delayed rectifier current (Ik) and the inward rectifier current (Ik1) in isolated rabbit atrial myocytes. Propafenone blocked all three currents, with the extent of blockade being independent of test potential During depolarizing voltage steps, block of Ito and Ik developed as an exponential function of time, consistent with time-dependent open channel blockade. The rate constant of block onset was concentration dependent. The inactivation of Ito was a monoexponential function of time under control conditions, with a time constant averaging 19.1 +/- 1.3 msec (mean +/- S.E.) at +10 mV. Propafenone accelerated Ito inactivation, resulting in a biexponential process having time constants of 5.1 +/- 0.9 (P < .001 vs. control) and 23.5 +/- 2.0 msec (P = N.S. vs. control) at 5 microM and 3.4 +/- 0.5 (P < .001 vs. control) and 28.5 +/- 4.3 msec (P = N.S.) at 10 microM concentrations, respectively. The rapid phase inactivation time constants were of the same order as time constants for the onset of block (3.1 +/- 0.6 and 1.8 +/- 0.3 msec at 5 and 10 microM respectively), suggesting that the acceleration of Ito inactivation was due to open channel block by the drug. The IC50 for blockade was substantially less for effects on Ik (0.76 microM; 95% confidence limits 0.44-1.30 microM) than for Ito (5.91 microM; 95% confidence limits 4.19-8.33 microM) or Ik1 (7.10; 5.24-9.61 microM). We conclude that 1) propafenone is an efficacious potassium channel blocker; 2) propafenone blockade of time-dependent potassium currents is open-state dependent; and 3) propafenone block of potassium currents is relatively selective for Ik.