The effects of dantrolene sodium on dog Purkinje fibers, cat atrial and ventricular muscles were studied. Action potential duration was significantly increased and contractility was significantly decreased by dantrolene in all three types of tissue. The plateau phase of Purkinje fiber and occasionally atrial action potential was slightly depressed. Dantrolene sodium had no significant effect on resting membrane potential, action potential amplitude or upstroke velocity of phase 6. The negative inotropic effects were most pronounced in Purkinje fibers, followed by atrial muscle while papillary muscles were least sensitive. Contractile force of Purkinje fibers was decreased by relatively the same amount at all frequencies of stimulation. At faster rates, atrial and ventricular muscle contractility was depressed relatively more than at slower rates. Slow response action potentials in cat papillary muscle were diminished slightly, but this effect was not significant. All drug effects took 10 to 15 min to develop, reached a steady state after 30 to 40 min, and were irreversible upon washout. Increasing the extracellular calcium concentration reversed the dantrolene-induced changes. These findings suggest that effects of dantrolene are mediated in part by a decrease in the intracellular free calcium concentration in cardiac tissue.