The effects of calcium chloride on cardiac responses to verapamil and diltiazem were investigated using isolated and perfused rat hearts with a Langendorff technique. Ionized calcium concentrations were increased approximately from 0.5 mM to 2.2 mM when the hearts were pretreated with 0.2 mg/L of verapamil or 0.28 mg/L of diltiazem, or were untreated with calcium blockers. Calcium significantly counteracted the negative inotropic effect produced by diltiazem and verapamil. In contrast, the negative chronotropic effects of both diltiazem and verapamil were potentiated by increasing concentrations of ionized calcium, and this potentiation was not eliminated by 1.0 mg/L of atropine. An atrioventricular block was induced by both verapamil and diltiazem when ionized calcium concentrations were lower than normal. It is suggested from this study that, although calcium chloride counteracts the negative inotropic effects of verapamil and diltiazem, abruptly increased ionized calcium may cause severe bradycardia clinically.