Reducing the sodium content of medium bathing isolated guinea pig atria produces a positive inotropic response associated with a marked decline in action potential amplitude and a decrease in relaxation velocity. The effects of sodium reduction appear to result from a decline in the rate of sodium-dependent calcium efflux across the sarcolemma. Consistent with this hypothesis, caffeine, which may inhibit calcium uptake by sarcoplasmic reticulum, produces a much more pronounced inhibition of relaxation velocity in the absence than in the presence of sodium. Cardiac glycosides also appear to inhibit sodium-dependent calcium efflux, possibly by increasing intracellular free sodium. In the presence of sodium, ouabain increased developed tension in association with a decline in the velocity of relaxation. High concentrations of ouabain (>10 JIM) increased resting tension in quiescent atria. In the complete absence of sodium, ouabain (100 JIM) had no effect on resting or developed tension. When sodium was restored to previously sodium-free medium, resting tension declined. If atria in sodium-free medium were pretreated with ouabain or deprived of potassium, sodium restoration caused an increase in resting tension. These effects can be related to inhibition of sodium-pump activity by ouabain or potassium depletion. We conclude that both sodium reduction and cardiac glycosides increase myocardial tension development by inhibiting sodium-dependent calcium efflux across the sarcolemma. The contractile effects of ouabain are dependent completely on the presence of sodium.Circ Res 46: 553-564, 1980