We investigated the effect of the calcium antagonists verapamil, gallopamil, diltiazem and nifedipine on cardiac sarcoplasmic reticulum function. In a cell-free homogenate from rat hearts, oxalate-supported Ca uptake was stimulated by verapamil, gallopamil and diltiazem at concentrations in the order of 10 nM to 100 nM, while higher concentrations were ineffective. Nifedipine was also ineffective. Peak stimulation of Ca uptake averaged 15-20% of control. Ca uptake is the difference between active Ca transport by Ca-ATPase and passive efflux through sarcoplasmic reticulum channels. In the presence of 300 microM ryanodine, which blocks sarcoplasmic reticulum channels, Ca uptake increased by 50%, but no further stimulation was produced by the addition of any calcium antagonist, at concentrations ranging from 1 nM to 100 microM. In a fraction enriched in sarcoplasmic reticulum, no drug affected the activity of Ca-ATPase at concentrations able to stimulate Ca uptake. We conclude that low concentrations of verapamil, gallopamil and diltiazem reduce Ca efflux through the Ca channels of the sarcoplasmic reticulum. Such an action might contribute to the clinical effect of these drugs.