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Background— Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly. Methods and Results— Under physiological conditions (37°C, pH 7.35, 1.25 mmol/L Ca 2+ ), there was a dose-dependent decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with pantoprazole. The concentration leading to 50% maximal response was 17.3±1.3 μg/mL. Similar observations were made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time polymerase chain reaction demonstrated the expression of gastric H + /K + –adenosine triphosphatase in human and rabbit myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant pantoprazole-dependent changes of pH i . Ca 2+ transients recorded from field-stimulated fluo 3–loaded myocytes (F/F 0 ) were significantly depressed by 10.4±2.1% at 40 μg/mL. Intracellular Ca 2+ fluxes were assessed in fura 2–loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 μg/mL) caused an increase in diastolic [Ca 2+ ] i by 33±12%, but peak systolic [Ca 2+ ] i was unchanged, resulting in a decreased Ca 2+ transient amplitude by 25±8%. The amplitude of the L-type Ca 2+ current ( I Ca,L ) was reduced by 35±5%, and sarcoplasmic reticulum Ca 2+ content was reduced by 18±6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca 2+ uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca 2+ sensitivity (K d ) of sarcoplasmic reticulum Ca 2+ adenosine triphosphatase: control, K d =358±15 nmol/L; 40 μg/mL pantoprazole, K d =395±12 nmol/L ( P 2+ -activated force. Conclusions— Pantoprazole depresses cardiac contractility in vitro by depression of Ca 2+ signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo.