We used saponin-treated skinned fibers isolated from papillary muscles of the right ventricle of guinea pigs to compare the effects of diltiazem on the spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum (SR) of cardiac muscle with the effects of caffeine. Both diltiazem and caffeine increased the frequency of cyclic contractions in EGTA (ethyleneglycol-bis-(beta-aminoethylether) N,N,N',N'-tetra-acetate)-free solution and induced an incomplete, concentration-dependent relaxation of the muscle. The results suggest that the spectrum of the pharmacological effects of diltiazem on the SR is similar to that for caffeine, that is diltiazem accelerates the spontaneous Ca2+ release from the SR and suppresses Ca2+ reuptake by the SR, and that diltiazem as well as caffeine may act on the SR in vivo in a specific condition.