Dantrolene sodium at concentrations between 8.8 and 35.1 microM produced rather selective changes in the electrophysiological properties of isolated dog Purkinje fibers. The action potential duration at 90% repolarization and effective refractory period of normally polarized fibers were increased in a dose- and frequency-dependent fashion. The plateau phase of the action potential was significantly depressed and this effect coincided with a marked decrease in the strength of contraction. Dantrolene sodium had no significant effect on resting membrane potential, upstroke velocity of phase O, conduction velocity or pacemaker activity of Purkinje fibers. Dantrolene diminished or abolished "slow response" action potentials produced by superfusion with 18 mM K+ Tyrode's solution containing 10(-7) M isoproterenol. Drug effects took 10 to 15 min to become apparent, reached a steady-state after 45 to 60 min and were not reversible even after 2 hr of washout with drug-free Tyrode's solution. In contrast, increasing the [Ca++]0 produced nearly a complete reversal of the dantrolene-induced changes. These results suggest that dantrolene produces its effects by interfering with the slow inward current. Thus, dantrolene may be similar in action to other slow channel blocking agents, such as verapamil, and may be useful as an antiarrhythmic agent.